Crystal morphology of azetidine PARP1 inhibitors

Abstract

This specification describes the crystalline forms of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1), or its pharmaceutically acceptable salts or solvates. Compound 1. In some embodiments of the crystalline form, the crystalline form is selected from the group consisting of free base form I of Compound 1, free base form II of Compound 1, maleate form IV of Compound 1, and tartrate form I of Compound 1, or any combination thereof. JPEG2026509598000071.jpg28128

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 491,994, filed on 24 March 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays a crucial role in promoting DNA repair, regulating RNA transcription, mediating cell death, and modulating immune responses. These actions make PARP inhibitors targets a wide range of diseases. PARP inhibitors have demonstrated efficacy in numerous disease models, particularly in models of ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection from the adverse effects of cytotoxic compounds, and enhancement of cytotoxic cancer treatment. PARP is also indicated in retroviral infections, and therefore inhibitors may have use in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological trauma, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle. PARP inhibitors are effective in CNS inflammation such as arthritis, gout, inflammatory bowel disease, MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown usefulness in several models of degenerative diseases, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors can reduce hepatotoxicity after acetaminophen overdose, cardiovascular and nephrotoxicity from doxorubicin and platinum-based antitumor agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiotherapy and chemotherapy by increasing cancer cell death, limiting tumor growth, reducing metastasis, and extending the survival of animals with tumors.

[0003] PARP1 and PARP2 are the most widely studied PARPs for their roles in DNA damage repair. PARP1 is activated by DNA damage cleavage and functions to catalyze the addition of a poly(ADP-ribose) (PAR) chain to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of further DNA repair factors to DNA damage.

[0004] Following the completion of this mobilization role, PARP auto-PARization prompts the release of bound PARP from the DNA, allowing access to other DNA repair proteins and completing the repair. Thus, the binding of PARP to the damage site, its catalytic activity, and its final release from the DNA are all crucial steps in the cancer cell's response to DNA damage caused by chemotherapy and radiation therapy.

[0005] Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells with adverse mutations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair via homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors lack homologous recombination repair (HRR) pathways and rely on PARP enzyme function for survival. While PARP inhibitor therapy primarily targets SRCA-mutated cancers, PARP inhibitors have also been clinically tested in non-SRCA-mutated tumors, i.e., tumors exhibiting homologous recombination deficiency (HRD).

[0006] PARP inhibitors with improved selectivity for PARP1 are thought to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Also, selective and potent inhibition of PARP1 is thought to lead to the trapping of PARP1 in DNA, resulting in DNA double-strand breaks (DSBs) through the collapse of replication forks in the S phase. Additionally, PARP1-DNA trapping is thought to be an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors, particularly PARP inhibitors with selectivity for PARP1, and stable forms of PARP1 inhibitors.

Summary of the Invention

Means for Solving the Problems

[0007] 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1):

Chemical Formula

[0008] Also, herein, the free base 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-2-methylazetidin-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1):

Chemical Formula

[0009] In some embodiments of the crystal form, the solvate is a hydrate.

[0010] Furthermore, in this specification, the anhydrous free base 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline form is also disclosed.

[0011] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the maleate of or its pharmaceutically acceptable solvates are also disclosed.

[0012] In some embodiments of the crystalline form, the solvate is a hydrate.

[0013] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline form of the maleate anhydride is also disclosed.

[0014] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the tartrate salt or its pharmaceutically acceptable solvate are also disclosed.

[0015] In some embodiments of the crystalline form, the solvate is a hydrate.

[0016] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline form of the anhydrous tartrate is also disclosed.

[0017] In some embodiments of the crystalline form, the crystalline form is selected from the group consisting of free base form I of compound 1, free base form II of compound 1, maleate form IV of compound 1, and tartrate form I of compound 1, or any combination thereof.

[0018] In some embodiments of the crystalline form, the crystalline form is selected from the group consisting of free base form I of compound 1, free base form II of compound 1, or any combination thereof.

[0019] In some embodiments of the crystalline form, the crystalline form is selected from the group consisting of maleate form IV of compound 1, tartrate form I of compound 1, or any combination thereof.

[0020] In some embodiments of the crystalline form, crystalline compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 20.50 ± 0.1° 2θ, (c) Endothermic DSC thermogram with a peak temperature at approximately 228°C (start), (d) DSC thermogram showing exothermic activity with a peak temperature of approximately 231°C (start), (e) A DSC thermogram with endothermic properties having a peak temperature at approximately 238°C (start), or (f) Free base form I characterized by having at least one of those combinations.

[0021] In some embodiments of the crystalline morphology, the crystalline morphology has substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 1A.

[0022] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks as shown in Table 1.

[0023] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern with a characteristic peak at 20.50 ± 0.1°²θ.

[0024] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes a peak at 14.19 ± 0.1°²θ.

[0025] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes a peak at 15.75 ± 0.1°²θ.

[0026] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes a peak at 16.50 ± 0.1°²θ.

[0027] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 14.19±0.1°2θ, 15.75±0.1°2θ, and 16.50±0.1°2θ.

[0028] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 8.21±0.1°²θ and 12.36±0.1°²θ.

[0029] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 21.22±0.1°²θ and 24.40±0.1°²θ.

[0030] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 12.74±0.1°2θ, 17.52±0.1°2θ, 23.52±0.1°2θ, and 27.32±0.1°2θ.

[0031] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0032] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0033] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0034] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0035] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0036] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least six characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0037] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least seven characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0038] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least eight characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0039] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least nine characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0040] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least 10 characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0041] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has a DSC thermogram that is endothermic with a peak temperature at approximately 228°C (start).

[0042] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has a DSC thermogram that exhibits exothermic properties with a peak temperature at approximately 231°C (start).

[0043] In some embodiments of the crystalline form, crystalline free base compound 1, form I, has a DSC thermogram that is endothermic with a peak temperature at approximately 238°C (start).

[0044] In some embodiments of the crystalline form, crystalline free base compound 1, form I is physically and chemically stable.

[0045] In some embodiments of the crystalline form, crystalline free base compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.1° 2θ, (c) An endothermic DSC thermogram with a peak temperature at approximately 235°C (start), or (d) Embodiment II is characterized by having at least one of the combinations thereof.

[0046] In some embodiments of the crystalline form, crystalline free base compound 1, form II, has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2A.

[0047] In some embodiments of the crystalline form, crystalline free base compound 1, form II, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks as shown in Table 2.

[0048] In some embodiments of the crystalline form, crystalline free base compound 1, form II, has an X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.1°²θ.

[0049] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 8.39±0.1°2θ, 12.62±0.1°2θ, and 16.81±0.1°2θ.

[0050] In some embodiments of the crystalline form, the X-ray powder diffraction pattern further includes peaks at 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0051] In some embodiments of the crystalline form, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0052] In some embodiments of the crystalline form, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0053] In some embodiments of the crystalline form, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0054] In some embodiments of the crystalline form, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0055] In some embodiments of the crystalline form, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0056] In some embodiments of the crystalline form, crystalline free base compound 1, form II, has a DSC thermogram that is endothermic with a peak temperature at approximately 235°C (start).

[0057] In some embodiments of the crystalline form, crystalline compound 1 is free base form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.8, 21.4, and 26.2°²θ as determined by a Cu-Kα diffractometer.

[0058] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the sulfate or pharmaceutically acceptable solvates thereof are also disclosed.

[0059] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the esylates or pharmaceutically acceptable solvates thereof are also disclosed.

[0060] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the tosylate of or a pharmaceutically acceptable solvate thereof are also disclosed.

[0061] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the hemiedisylate or its pharmaceutically acceptable solvates are also disclosed.

[0062] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline forms of the phosphate or pharmaceutically acceptable solvates thereof are also disclosed.

[0063] Furthermore, in this specification, 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [ka] The crystalline form of the L-malate salt or a pharmaceutically acceptable solvate thereof is also disclosed.

[0064] Furthermore, this specification refers to the free base form I of compound 1, the free base form II of compound 1, the free base form III of compound 1, the maleate form IV of compound 1, the tartrate form I of compound 1, the sulfate form III of compound 1, the esylate form I of compound 1, the tosylate form II of compound 1, the hemiedisylate form I of compound 1, the hemiedisylate form II of compound 1, the phosphate form I of compound 1, the phosphate form II of compound 1, the L-tartrate mesophase of compound 1, the L-tartrate form II of compound 1, the L-tartrate form III of compound 1, the L-tartrate form IV of compound 1, the L-tartrate methanol solvate of compound 1, and Crystallized forms of Compound 1 are also provided, selected from the group consisting of the L-tartrate ethanol solvate of Compound 1, L-malate form II of Compound 1, L-malate form III of Compound 1, HCl salt form I of Compound 1, HCl salt form II of Compound 1, sulfate form I of Compound 1, sulfate form II of Compound 1, maleate form I of Compound 1, maleate form II of Compound 1, maleate form III of Compound 1, citrate form I of Compound 1, L-malate form I of Compound 1, mesylate form I of Compound 1, mesylate form II of Compound 1, and tosylate form I of Compound 1, or any combination thereof.

[0065] Furthermore, this specification also discloses crystalline forms disclosed herein and pharmaceutical compositions comprising pharmaceutically acceptable excipients.

[0066] Furthermore, this specification also discloses a method for treating cancer in a person requiring cancer treatment, which includes administering the crystalline form disclosed herein.

[0067] In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer.

[0068] Furthermore, this specification also discloses a method for treating cancer involving BRCA1 and / or BRCA2 mutations in subjects requiring treatment, the method comprising administering the crystalline form disclosed herein.

[0069] In some embodiments, cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0070] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the extent applicable and relevant, and to the same degree, as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawing]

[0071] [Figure 1A] This shows the X-ray powder diffraction (XRPD) pattern of crystalline compound 1, form I.

[0072] [Figure 1B] The XRPD pattern of crystalline compound 1, free base form I, is shown.

[0073] [Figure 1C] The differential scanning calorimetry (DSC) thermogram of crystalline compound 1 and free base form I is shown.

[0074] [Figure 1D] The thermogravimetric analysis (TGA) results for crystalline compound 1 and free base form I are shown.

[0075] [Figure 1E]The DSC and TGA of crystalline compound 1 and free base form I are shown.

[0076] [Figure 2A] The X-ray powder diffraction (XRPD) patterns of crystalline compound 1, form II are shown.

[0077] [Figure 2B] The DSC and TGA of crystalline compound 1 and free base form II are shown.

[0078] [Figure 3] The XRPD pattern of crystalline compound 1, free base form III, is shown.

[0079] [Figure 4] This shows a DSC thermograph of crystalline compound 1 and free base form III.

[0080] [Figure 5] This shows the TGA pattern of crystalline compound 1 and free base form III.

[0081] [Figure 6] The XRPD pattern of crystalline compound 1, sulfate form III, is shown.

[0082] [Figure 7] The DSC thermogram of crystalline compound 1, sulfate form III, is shown.

[0083] [Figure 8] The TGA of crystalline compound 1, sulfate form III, is shown.

[0084] [Figure 9] The DVS curve for crystalline compound 1, sulfate form III, is shown.

[0085] [Figure 10] The XRPD pattern of crystalline compound 1, ethylate form I, is shown.

[0086] [Figure 11] The DSC thermogram of crystalline compound 1, ethylate form I, is shown.

[0087] [Figure 12] Crystalline compound 1, ethylate form I, is shown in TGA.

[0088] [Figure 13] The XRPD pattern of crystalline compound 1, tosylate form II, is shown.

[0089] [Figure 14] The XRPD pattern of crystalline compound 1, hemiedisylate form I, is shown.

[0090] [Figure 15] The XRPD pattern of crystalline compound 1, hemiedisylate form II, is shown.

[0091] [Figure 16] The DSC thermogram of crystalline compound 1, hemiedisylate form II, is shown.

[0092] [Figure 17] Crystalline compound 1, hemiedisylate form II, is shown in TGA.

[0093] [Figure 18] The DVS curve for crystalline compound 1, hemiedisylate form II, is shown.

[0094] [Figure 19] The XRPD pattern of crystalline compound 1, phosphate form I, is shown.

[0095] [Figure 20] The DSC thermogram of crystalline compound 1, phosphate form I, is shown.

[0096] [Figure 21]The XRPD patterns of crystalline compound 1 and phosphate form II are shown.

[0097] [Figure 22] The DSC thermogram of crystalline compound 1, phosphate form II, is shown.

[0098] [Figure 23] The XRPD pattern of crystalline compound 1, L-tartrate mesophase, is shown.

[0099] [Figure 24] The XRPD pattern of crystalline compound 1, L-tartrate form II, is shown.

[0100] [Figure 25] The DSC thermogram of crystalline compound 1, L-tartrate form II, is shown.

[0101] [Figure 26] Crystalline compound 1, L-tartrate form II, is shown in TGA.

[0102] [Figure 27] The DVS curve for crystalline compound 1, L-tartrate form II, is shown.

[0103] [Figure 28] The XRPD pattern of crystalline compound 1, L-tartrate form III, is shown.

[0104] [Figure 29] The DSC thermogram of crystalline compound 1, L-tartrate form III, is shown.

[0105] [Figure 30] The TGA for crystalline compound 1, L-tartrate form III, is shown.

[0106] [Figure 31] The XRPD pattern of crystalline compound 1, L-tartrate form IV, is shown.

[0107] [Figure 32] The DSC thermogram of crystalline compound 1, L-tartrate form IV, is shown.

[0108] [Figure 33] Crystalline compound 1, L-tartrate form IV, shows TGA.

[0109] [Figure 34] The XRPD pattern of crystalline compound 1, L-tartrate methanol solvate, is shown.

[0110] [Figure 35] The XRPD pattern of crystalline compound 1, L-tartrate ethanol solvate, is shown.

[0111] [Figure 36] The XRPD pattern of crystalline compound 1, L-malate form II, is shown.

[0112] [Figure 37] The DSC thermogram of crystalline compound 1, L-malate form II, is shown.

[0113] [Figure 38] Crystalline compound 1, L-malate form II, is shown in TGA.

[0114] [Figure 39] The DVS curve for crystalline compound 1, L-malate form II, is shown.

[0115] [Figure 40] The XRPD pattern of crystalline compound 1, L-malate form III, is shown.

[0116] [Figure 41] The DSC thermogram of crystalline compound 1, L-malate form III, is shown.

[0117] [Figure 42] Crystalline compound 1, L-malate form III, shows TGA.

[0118] [Figure 43A] The XRPD pattern of crystalline compound 1, L-tartrate form I, is shown.

[0119] [Figure 43B] The XRPD pattern of crystalline compound 1, L-tartrate form I, is shown.

[0120] [Figure 44] The DSC thermogram of crystalline compound 1, L-tartrate form I, is shown.

[0121] [Figure 45] Crystalline compound 1, L-tartrate form I, is shown in TGA.

[0122] [Figure 46] The DVS curve for crystalline compound 1, L-tartrate form I, is shown.

[0123] [Figure 47] The DSC and TGA of crystalline compound 1, L-tartrate form I, are shown.

[0124] [Figure 48] This shows the XRPD pattern of crystalline compound 1, maleate form IV.

[0125] [Figure 49] Crystalline compound 1, maleate form IV, is shown in DSC and TGA.

[0126] [Figure 50A] The XRPD pattern of crystalline compound 1, HCl salt form I, is shown.

[0127] [Figure 50B] The DSC and TGA of crystalline compound 1 and HCl salt form I are shown.

[0128] [Figure 51A] The XRPD patterns of crystalline compound 1 and HCl salt form II are shown.

[0129] [Figure 51B] The DSC and TGA of crystalline compound 1 and HCl salt form II are shown.

[0130] [Figure 52A] The XRPD pattern of crystalline compound 1, sulfate form I, is shown.

[0131] [Figure 52B] The DSC and TGA of crystalline compound 1 and sulfate form I are shown.

[0132] [Figure 53A] The XRPD patterns of crystalline compound 1 and sulfate form II are shown.

[0133] [Figure 53B] The DSC thermogram of crystalline compound 1, sulfate form II, is shown.

[0134] [Figure 53C] The TGA of crystalline compound 1 and sulfate form II is shown.

[0135] [Figure 54A] The XRPD pattern of crystalline compound 1, maleate form I, is shown.

[0136] [Figure 54B] Crystalline compound 1, maleate form I, is shown in DSC and TGA.

[0137] [Figure 55A] The XRPD pattern of crystalline compound 1, maleate form II, is shown.

[0138] [Figure 55B]The DSC and TGA of crystalline compound 1 and maleate form II are shown.

[0139] [Figure 56A] This shows the XRPD pattern of crystalline compound 1, maleate form III.

[0140] [Figure 56B] Crystalline compound 1, maleate form III, is shown in DSC and TGA.

[0141] [Figure 56C] This shows the XRPD pattern of crystalline compound 1, maleate form III.

[0142] [Figure 57A] The XRPD pattern of crystalline compound 1, citrate form I, is shown.

[0143] [Figure 57B] The DSC and TGA of crystalline compound 1, citrate form I, are shown.

[0144] [Figure 58A] The XRPD pattern of crystalline compound 1, L-malate form I, is shown.

[0145] [Figure 58B] The DSC and TGA of crystalline compound 1, L-malate form I, are shown.

[0146] [Figure 59A] The XRPD pattern of crystalline compound 1, mesylate form I, is shown.

[0147] [Figure 59B] The DSC and TGA of crystalline compound 1, mesylate form I, are shown.

[0148] [Figure 60A] The XRPD patterns of crystalline compound 1 and mesylate form II are shown.

[0149] [Figure 60B] The DSC and TGA of crystalline compound 1 and mesylate form II are shown.

[0150] [Figure 61A] The XRPD pattern of crystalline compound 1, tosylate form I, is shown.

[0151] [Figure 61B] The DSC and TGA of crystalline compound 1, tosylate form I, are shown. [Modes for carrying out the invention]

[0152] definition The following description includes specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that the invention may be carried out without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless otherwise required by context, the word “comprise” and its variations, e.g., “comprises” and “comprising,” throughout this specification and the claims should be interpreted in an open and comprehensive sense, i.e., “includes, but not limited.” Furthermore, the headings provided herein are for convenience only and do not constitute any interpretation of the scope or meaning of the claimed invention.

[0153] Throughout this specification, any reference to “several embodiments” or “embodiments” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Therefore, the appearance of the phrase “in one embodiment” or “in one embodiment” in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” refer to multiple subjects unless otherwise clearly indicated. And note that the term “or” is generally used to mean “and / or” unless otherwise clearly indicated.

[0154] The term "solvate" refers to a complex formed by a combination of solvent molecules and solute molecules or ions. The solvent may be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term "solvate" includes "hydrate" (i.e., a complex formed by a combination of water molecules and solute molecules or ions), hemihydrate, channel hydrate, and the like. Some examples of solvents include, but are not limited to, acetonitrile, methanol, N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equivalent to non-solvated forms and are included within the scope of this disclosure.

[0155] The term "desolvated" refers to a solvate as described herein, in which solvent molecules have been partially or completely removed. Desolvation techniques for producing a desolvated form include, but are not limited to, exposure of the form (solvate) to a vacuum, exposure of the solvate to a high temperature, exposure of the solvate to a stream of gas such as air or nitrogen, or any combination thereof. Thus, a desolvated or "non-solvated" form may be "anhydrous," i.e., completely free of solvent molecules, or partially solvated, with solvent molecules present in stoichiometric or non-stoichiometric amounts.

[0156] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such materials do not produce a distinctive X-ray diffraction pattern and exhibit solid properties, but are more formally described as liquids. Upon heating, a change occurs from solid to liquid properties, typically characterized by a secondary state change (glass transition).

[0157] As used herein, “physically stable” means that, when exposed to specified conditions (e.g., room temperature and / or ambient humidity) for a specified period (e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 12 months, or longer), a particular form of a compound does not change into one or more different physical forms (e.g., different solid forms measured by XRPD, DSC, TGA, etc.). In some embodiments, when exposed to specified conditions, less than 25% of a particular form of the compound changes into one or more different physical forms. In some embodiments, when exposed to specified conditions, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, or less than about 0.5% of a particular form of the compound changes into one or more different physical forms. In some embodiments, when exposed to specified conditions, a detectable amount of a particular form of the compound does not change into one or more different physical forms.

[0158] As used herein, "chemically stable" means that when exposed to specified conditions (e.g., room temperature and / or ambient humidity) for a specified period (e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 6 months, 12 months, or longer), the chemical structure of a particular compound does not change into another compound (e.g., does not decompose). In some embodiments, when exposed to specified conditions, less than 25% of a particular form of the compound changes into one or more different compounds. In some embodiments, when exposed to specified conditions, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 1%, or less than about 0.5% of a particular form of the compound changes into one or more different compounds. In some embodiments, when exposed to specified conditions, a detectable amount of a particular form of the compound does not change into one or more different compounds.

[0159] "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 99.9% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 99.5% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 99% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 98% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 97% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 96% of the material is the referenced polymorph. "Substantially pure (polymorphic form)" means, in some embodiments, that in the referenced material, at least 95% of the material is the referenced polymorph.

[0160] The term "pharmaceutically acceptable" indicates that the material being described does not possess properties that would cause a reasonably prudent physician to avoid administering the material to a patient, taking into account the disease or condition being treated and the respective route of administration. For example, such materials are generally required to be essentially sterile for injectable substances. The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is biologically or otherwise undesirable. Similarly, the term "pharmaceutically acceptable solvate" of a given compound refers to a solvate or salt of the given compound that retains the biological efficacy and properties of the given compound or salt thereof and is biologically or otherwise undesirable.

[0161] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0162] "Therapy" of an individual (e.g., a mammal such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, therapy includes the administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., preventing the condition from worsening) or alleviation of the condition.

[0163] "Synergistic effect" or "exhibiting a synergistic effect" refers to a combined effect that is greater than the sum of the effects of each component individually at the same dose.

[0164] As used herein, “PARP-related disease or disorder,” or alternatively “PARP-mediated disease or disorder,” means any disease or other adverse condition in which PARP or its variants are known or suspected to play a role.

[0165] As used herein, “PARP1-related disease or disorder,” or alternatively “PARP1-mediated disease or disorder,” means any disease or other adverse condition in which PARP1 or its variants are known or suspected to play a role.

[0166] As used herein, the terms “substantially the same” or “substantially shown” refer to powder X-ray diffraction patterns, DSC thermograms, TGA patterns, or DVS curves that are identical or non-identical to those described herein, but which, as considered by those skilled in the art, are within the range of experimental error.

[0167] As used herein, the term “substantially similar” means a powder X-ray diffraction pattern, DSC thermogram, or TGA pattern that is not identical to those described herein and, as considered by those skilled in the art, shares most of the major peaks within the margin of experimental error.

[0168] compound 1 This specification discloses 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1), or a pharmaceutically acceptable salt or solvate thereof. Compound 1 refers to a compound having the following formula: [ka] Compound 1 refers to the compound having the following name: 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide.

[0169] This specification discloses 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1), or a pharmaceutically acceptable solvate thereof. This specification discloses 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1).

[0170] In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, compound 1 is in the form of a salt as described in the examples. In some embodiments, compound 1 is in the form of a maleate. In some embodiments, compound 1 is in the form of a tartrate. In some embodiments, compound 1 is in the form of an L-tartrate. In some embodiments, compound 1 is in the form of a sulfate. In some embodiments, compound 1 is in the form of an esylate. In some embodiments, compound 1 is in the form of a tosylate. In some embodiments, compound 1 is in the form of a hemiedisylate. In some embodiments, compound 1 is in the form of a phosphate. In some embodiments, compound 1 is in the form of an L-malate. In some embodiments, compound 1 is in the form of an HCl salt. In some embodiments, compound 1 is in the form of a mesylate. In some embodiments, compound 1 is in the form of a citrate.

[0171] In some embodiments, compound 1 is a free base.

[0172] In some embodiments, compound 1 is a solvate. In some embodiments, compound 1 is a hydrate. In some embodiments, compound 1 is non-solvated. In some embodiments, compound 1 is an anhydrous.

[0173] While not intended to be bound by any particular theory, certain solid forms are characterized by physical properties suitable for pharmaceutical and therapeutic dosage forms, such as stability, solubility, and dissolution rate. Furthermore, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, tackiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make a particular solid form suitable for the manufacture of a solid dosage form. Such properties can be determined using certain analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0174] Crystal morphology The identification and selection of the solid form of a pharmaceutical compound is complex, considering that changes in solid form can affect a variety of physical and chemical properties, which, among other important pharmaceutical characteristics, can provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, and handling (e.g., shipping). Useful pharmaceutical solids include crystalline and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by the lack of long-range structural order, while crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends on the specific application; amorphous solids may be selected based, for example, on an enhanced solubility profile, while crystalline solids may be desirable for properties such as physical or chemical stability.

[0175] Whether crystalline or amorphous, the solid forms of pharmaceutical compounds include monocomponent solids and multicomponent solids. Monocomponent solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. The diversity among monocomponent crystalline materials can potentially arise from polymorphism, with multiple three-dimensional configurations existing for a given pharmaceutical compound.

[0176] In particular, it is impossible to predict a priori whether a crystalline form of a compound exists, much less how to successfully prepare them (e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem.Commun.:3635-3645 (with regard to crystal engineering, if the instructions are not very precise and / or if other external factors affect the process, the results may be unpredictable), Jones et al., 2006, "Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31:875-879 (currently, even for the simplest molecules, it is generally impossible to computationally predict the number of observable polymorphs), Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews 56:301-319 ("Price"), and Bernstein, 2004, "Crystal Structure Prediction and See "Polymorphism," ACA Transactions 39:14-23 (before we can state with any degree of confidence that we have the ability to predict crystal structures, much more must be learned and done, and polymorphism even more so).

[0177] The diversity of possible solid forms brings potential diversity to the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are crucial in the development of effective, stable, and marketable pharmaceutical products.

[0178] Crystalline form of compound 1 Polymorphs produced according to the methods of this disclosure can be characterized by any methodology of the art. For example, polymorphs produced according to the methods of this disclosure can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and / or spectroscopy (e.g., Raman, solid-state nuclear magnetic resonance (ssNMR), and infrared (IR)). In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD).

[0179] XRPD: The polymorphs described herein can be characterized by XRPD. The relative intensity of the XRPD peaks may vary depending on particle size, sample preparation technique, sample mounting procedure, and the specific instrument used. Furthermore, instrument variations and other factors may affect the 2θ value. Therefore, the assignment of the XRPD peaks may vary, for example, by plus or minus 0.2 degrees, or by plus or minus 0.1 degrees.

[0180] DSC: The polymorphs described herein can also be identified by their characteristic DSC thermograms. For DSCs, it is known that the observed temperature depends on the rate of temperature change, as well as the sample preparation technique and the specific instrument used. Therefore, the values ​​reported herein with respect to DSC thermograms may vary, for example, by plus or minus 4°C.

[0181] TGA: The polymorphs of this disclosure may exhibit different thermal behavior from those of amorphous materials or other polymorphs. Thermal behavior may be measured by thermogravimetric analysis (TGA), which can be used in the laboratory to distinguish some polymorphs from others. In one embodiment, the polymorph may be characterized by thermogravimetric analysis.

[0182] The polymorphs of compound 1 are useful for the production of pharmaceutical preparations and can be obtained by a crystallization process to produce crystalline and semi-crystalline forms, or by a solidification process to obtain an amorphous form. In some embodiments, crystallization is carried out by generating the desired compound (e.g., compound 1) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by optionally dissolving the starting compound in a solvent while heating, followed by crystallization / solidification of the product by cooling (including active cooling) and / or by adding a poor solvent for a period of time. In some embodiments, crystallization involves adding the species form of the desired polymorph. After crystallization or solidification, drying may be carried out under controlled conditions until the desired water content is reached in the final polymorph.

[0183] In some embodiments, amorphous forms of compound 1 are provided herein.

[0184] Two crystalline forms (forms I and II) were discovered, both of which are anhydrous. Form I was obtained in most polymorph screening experiments, while form II was obtained only by heat treatment. Characteristic data are summarized in the table below. [Table 40]

[0185] Free base form I of compound 1 (compound 1, free base form I, or compound 1 form I) Form I is a slightly hygroscopic anhydrous substance. Form I is obtained over 1 day via a slurry of the sample in acetone / water (19 / 1, v / v) at 50°C, and is used for PLM, XRPD, DSC, TGA and 1 The samples were characterized by 1H-NMR. The morphological I samples showed high crystallinity (Figure 1A). The TGA showed no weight loss before melting, and one exothermic peak at 231°C and two endothermic peaks at 228°C and 238°C (start) were observed in DSC, corresponding to melt-recrystallization. 11H-NMR indicated the presence of 0.1% acetone. DVS results showed that the morphology I sample had 0.5% / 0.6% water uptake at 80%RH / 90%RH and was slightly hygroscopic. The crystal form remained unchanged after the DVS test.

[0186] Form I had less than 1% water uptake at 80% RH, was slightly hygroscopic, and was physically and chemically stable for 7 days under conditions of 60°C (capped) and 40°C / 75% RH (open). Free base Form I showed high solubility (>5 mg / mL) in SGF and low solubility in other media.

[0187] In some embodiments, the crystalline free base compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 20.50 ± 0.1° 2θ, (c) Endothermic DSC thermogram with a peak temperature at approximately 228°C (start), (d) DSC thermogram showing exothermic activity with a peak temperature of approximately 231°C (start), (e) A DSC thermogram with endothermic properties having a peak temperature at approximately 238°C (start), or (f) A form I (free base form I) characterized by having at least one of the combinations thereof.

[0188] In some embodiments, the crystalline free base compound 1, Form I (Compound 1, free base Form I) is characterized by having at least one of the properties selected from (a) to (e). In some embodiments, the crystalline free base compound 1, Form I is characterized by having at least two of the properties selected from (a) to (e). In some embodiments, the crystalline free base compound 1, Form I is characterized by having at least three of the properties selected from (a) to (e). In some embodiments, the crystalline free base compound 1, Form I is characterized by having at least four of the properties selected from (a) to (e). In some embodiments, the crystalline free base compound 1, Form I is characterized by having at least five of the properties selected from (a) to (e). In some embodiments, the crystalline free base compound 1, Form I is characterized by having properties (a) to (e).

[0189] In some embodiments, the crystalline free base compound 1, Form I has an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1A.

[0190] In some embodiments, the crystalline free base compound 1, Form I has an X-ray powder diffraction (XRPD) pattern having characteristic peaks found in Table 1.

[0191] In some embodiments, the crystalline free base compound 1, Form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50 ± 0.1° 2θ.

[0192] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 14.19 ± 0.1° 2θ, 15.75 ± 0.1° 2θ, and 16.50 ± 0.1° 2θ.

[0193] In some embodiments, the X-ray powder diffraction pattern further includes a peak at 14.19 ± 0.1° 2θ.

[0194] In some embodiments, the X-ray powder diffraction pattern further includes a peak at 15.75 ± 0.1°²θ.

[0195] In some embodiments, the X-ray powder diffraction pattern further includes a peak at 16.50 ± 0.1°²θ.

[0196] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 8.21±0.1°2θ and 12.36±0.1°2θ.

[0197] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 21.22±0.1°2θ and 24.40±0.1°2θ.

[0198] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 12.74±0.1°2θ, 17.52±0.1°2θ, 23.52±0.1°2θ, and 27.32±0.1°2θ.

[0199] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0200] In some embodiments, free base crystalline compound 1, form I has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0201] In some embodiments, the free base crystalline compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0202] In some embodiments, the free base crystalline compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0203] In some embodiments, the free base crystalline compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0204] In some embodiments, the free base crystalline compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least six characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0205] In some embodiments, free base crystalline compound 1, form I has an X-ray powder diffraction (XRPD) pattern having at least seven characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0206] In some embodiments, free base crystalline compound 1, form I has an X-ray powder diffraction (XRPD) pattern having at least eight characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0207] In some embodiments, the free base crystalline compound 1, form I, has an X-ray powder diffraction (XRPD) pattern having at least nine characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0208] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having at least 10 characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 20.50±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0209] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least two characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0210] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least three characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ, and 27.32±0.1°2θ.

[0211] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least four characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0212] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least five characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0213] In some embodiments, the crystalline free base compound 1, Form I, has a characteristic peak at 20.50 ± 0.1° 2θ and an X-ray powder diffraction (XRPD) pattern having at least six characteristic peaks selected from 8.21 ± 0.1° 2θ, 12.36 ± 0.1° 2θ, 12.74 ± 0.1° 2θ, 14.19 ± 0.1° 2θ, 15.75 ± 0.1° 2θ, 16.50 ± 0.1° 2θ, 17.52 ± 0.1° 2θ, 21.22 ± 0.1° 2θ, 23.52 ± 0.1° 2θ, 24.40 ± 0.1° 2θ, and 27.32 ± 0.1° 2θ.

[0214] In some embodiments, the crystalline free base compound 1, Form I, has a characteristic peak at 20.50 ± 0.1° 2θ and an X-ray powder diffraction (XRPD) pattern having at least seven characteristic peaks selected from 8.21 ± 0.1° 2θ, 12.36 ± 0.1° 2θ, 12.74 ± 0.1° 2θ, 14.19 ± 0.1° 2θ, 15.75 ± 0.1° 2θ, 16.50 ± 0.1° 2θ, 17.52 ± 0.1° 2θ, 21.22 ± 0.1° 2θ, 23.52 ± 0.1° 2θ, 24.40 ± 0.1° 2θ, and 27.32 ± 0.1° 2θ.

[0215] In some embodiments, the crystalline free base compound 1, Form I, has a characteristic peak at 20.50 ± 0.1° 2θ and an X-ray powder diffraction (XRPD) pattern having at least eight characteristic peaks selected from 8.21 ± 0.1° 2θ, 12.36 ± 0.1° 2θ, 12.74 ± 0.1° 2θ, 14.19 ± 0.1° 2θ, 15.75 ± 0.1° 2θ, 16.50 ± 0.1° 2θ, 17.52 ± 0.1° 2θ, 21.22 ± 0.1° 2θ, 23.52 ± 0.1° 2θ, 24.40 ± 0.1° 2θ, and 27.32 ± 0.1° 2θ.

[0216] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least nine characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0217] In some embodiments, crystalline free base compound 1, form I has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 20.50±0.1°2θ and at least 10 characteristic peaks selected from 8.21±0.1°2θ, 12.36±0.1°2θ, 12.74±0.1°2θ, 14.19±0.1°2θ, 15.75±0.1°2θ, 16.50±0.1°2θ, 17.52±0.1°2θ, 21.22±0.1°2θ, 23.52±0.1°2θ, 24.40±0.1°2θ and 27.32±0.1°2θ.

[0218] In some embodiments, crystalline free base compound 1, form I, has a DSC thermogram that is endothermic with a peak temperature at approximately 228°C (start).

[0219] In some embodiments, crystalline free base compound 1, form I, has a DSC thermogram that exhibits exothermic properties with a peak temperature at approximately 231°C (start).

[0220] In some embodiments, crystalline free base compound 1, form I, has a DSC thermogram that is endothermic with a peak temperature at approximately 238°C (start).

[0221] In some embodiments, crystalline free base compound 1, form I is further characterized by a DSC thermogram substantially the same as that shown in Figure 1E. In some embodiments, crystalline free base compound 1, form I is further characterized by thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 1E.

[0222] In some embodiments, the crystalline free base compound 1, form I, is anhydrous.

[0223] In some embodiments, crystalline free base compound 1, form I is stable. In some embodiments, crystalline free base compound 1, form I is stable from 0°C to 80°C. In some embodiments, crystalline free base compound 1, form I is stable from 25°C to 80°C. In some embodiments, crystalline free base compound 1, form I is physically and chemically stable. [Table 1]

[0224] In some embodiments, crystalline compound 1 is free base form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.4, 12.6, and 20.7°²θ as determined by a Cu-Kα diffractometer.

[0225] In some embodiments of the crystalline form, compound 1 and free base form I are (a) One or more additional peaks (±0.2°) at 17.7, 23.7, or 27.5°²θ, (b) One or more additional peaks (±0.2°) at 21.4, 24.6, or 28.7°²θ, (c) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1B, (c) DSC thermogram including endothermic onset at approximately 223°C, exothermic onset at approximately 227°C, and endothermic onset at approximately 237°C. (d) A DSC thermogram substantially identical to the one shown in Figure 1C, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.1% at approximately 25-157°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 1D, or (g) A combination of these further features

[0226] In some embodiments of the crystalline form, compound 1, free base form I, further features an X-ray power diffractogram including one or more additional peaks (±0.2°) at 17.7, 23.7, or 27.5°²θ, as determined by a diffractometer using Cu-Kα rays. In some embodiments of the crystalline form, compound 1, free base form I, further features an X-ray power diffractogram including one or more additional peaks (±0.2°) at 21.4, 24.6, or 28.7°²θ, as determined by a diffractometer using Cu-Kα rays. In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 17.7, 21.4, 23.7, 24.6, 27.5, or 28.7°2θ, as determined by a diffractometer using Cu-Kα rays. In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by an X-ray powder diffraction pattern substantially the same as that shown in Figure 1B.

[0227] In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by a DSC thermogram including an endothermic initiation at approximately 223°C, an exothermic initiation at approximately 227°C, and an endothermic initiation at approximately 237°C. In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by a DSC thermogram including an endothermic initiation at approximately 223°C, an exothermic event at approximately 229°C (corresponding to crystallization of form II), and an endothermic initiation at approximately 237°C (of form II).

[0228] In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by a DSC thermogram substantially identical to that shown in Figure 1C.

[0229] In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 0.1% at approximately 25–157°C. In some embodiments of the crystalline form, compound 1, free base form I, is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 1D.

[0230] Free base form II of compound 1 (compound 1, free base form II) Morphology II was obtained solely through heat treatment. Characterized Morphology II was obtained by heating Morphology I to 225°C. XRPD results showed that the sample had a high degree of crystallinity (Figure 2A). TGA showed no weight loss before 200°C. DSC showed a single endothermic peak at 235°C (start) due to melting.

[0231] In some embodiments, the crystalline free base compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.1° 2θ, (c) An endothermic DSC thermogram with a peak temperature at approximately 235°C (start), or (d) A form II (free base form II) characterized by having at least one of the combinations thereof.

[0232] In some embodiments, the crystalline free base compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.2° 2θ, (c) An endothermic DSC thermogram with a peak temperature at approximately 235°C (start), or (d) A form II (free base form II) characterized by having at least one of the combinations thereof.

[0233] In some embodiments, the free base crystalline compound 1, form II (compound 1, free base form II) is characterized by having at least one of the properties selected from (a) to (c). In some embodiments, the crystalline free base compound 1, form II is characterized by having at least two of the properties selected from (a) to (c). In some embodiments, the crystalline free base compound 1, form II is characterized by having properties (a) to (c).

[0234] In some embodiments, crystalline free base compound 1, form II has substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 2A.

[0235] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern with characteristic peaks as shown in Table 2.

[0236] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.1°²θ. In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.2°²θ.

[0237] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 8.39±0.1°2θ, 12.62±0.1°2θ, and 16.81±0.1°2θ. In some embodiments, the X-ray powder diffraction pattern further includes peaks at 8.39±0.2°2θ, 12.62±0.2°2θ, and 16.81±0.2°2θ.

[0238] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ. In some embodiments, the X-ray powder diffraction pattern further includes peaks at 17.39±0.2°2θ, 20.11±0.2°2θ, 24.31±0.2°2θ, and 25.4±0.2°2θ.

[0239] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0240] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0241] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0242] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0243] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 13.39±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0244] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 13.39±0.1°2θ and at least two characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0245] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 13.39±0.1°2θ and at least three characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0246] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 13.39±0.1°2θ and at least four characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0247] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 13.39±0.1°2θ and at least five characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0248] In some embodiments, crystalline free base compound 1, form II has an X-ray powder diffraction (XRPD) pattern having a characteristic peak at 13.39±0.1°2θ and at least six characteristic peaks selected from 8.39±0.1°2θ, 12.62±0.1°2θ, 16.81±0.1°2θ, 17.39±0.1°2θ, 20.11±0.1°2θ, 24.31±0.1°2θ, and 25.4±0.1°2θ.

[0249] In some embodiments, crystalline free base compound 1, form II has a DSC thermogram that is endothermic with a peak temperature at approximately 235°C (start).

[0250] In some embodiments, crystalline free base compound 1, form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 2B. In some embodiments, crystalline free base compound 1, form II is further characterized by thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 2B.

[0251] In some embodiments, crystalline free base compound 1, form II, is anhydrous. [Table 2]

[0252] Free base form III of compound 1 (compound 1, free base form III, or compound 1, form III) In some embodiments of the crystalline form, crystalline compound 1 is free base form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.8, 21.4, and 26.2°²θ as determined by a Cu-Kα diffractometer.

[0253] In some embodiments of the crystalline form, compound 1 free base form III is (a) One or more additional peaks (±0.2°) at 7.6, 17.5, or 22.8°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 3, (c) DSC thermogram including endothermic onset at approximately 193°C, exothermic onset at approximately 204°C, and endothermic onset at approximately 231°C. (d) A DSC thermogram substantially the same as the one shown in Figure 4, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.2% at approximately 25-100°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 5, or (g) A combination of these further features

[0254] In some embodiments of the crystalline form, compound 1 free base form III is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 7.6, 17.5, or 22.8°²θ as determined by a diffractometer using Cu-Kα rays. In some embodiments of the crystalline form, compound 1 free base form III is further characterized by an X-ray powder diffraction pattern substantially the same as that shown in Figure 3.

[0255] In some embodiments of the crystalline form, compound 1 free base form III is further characterized by a DSC thermogram including an endothermic initiation at approximately 193°C, an exothermic initiation at approximately 204°C, and an endothermic initiation at approximately 231°C. In some embodiments of the crystalline form, compound 1 free base form III is further characterized by a DSC thermogram substantially the same as that shown in Figure 4.

[0256] In some embodiments of the crystalline form, free base form III of compound 1 is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 1.2% at approximately 25–100°C. In some embodiments of the crystalline form, free base form III of compound 1 is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 5.

[0257] Compound 1, Maleate Salt Form IV (Compound 1, Maleate Salt Form IV or Maleate Form IV) Maleate form IV, PLM, XRPD, DSC, TGA and 1 The sample was characterized by 1H-NMR. Maleate form IV was highly crystalline. The sample showed no apparent weight loss before 150°C in TGA, and a single endothermic peak at 183°C (start) was observed in DSC due to melting. 1.0 equivalent of maleic acid 1 It was detected by 1H-NMR.

[0258] Maleate form IV was slightly hygroscopic with less than 1% water absorption at 80% RH and was physically and chemically stable for 7 days under conditions of 60°C (capped) and 40°C / 75% RH (open). Compared to free base form I, maleate form IV showed improved solubility in water, FaSSIF, and FeSSIF.

[0259] In some embodiments, crystalline compound 1 has the following properties: (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.1°2θ, 19.60±0.1°2θ, and 22.55±0.1°2θ. (b) A DSC thermogram with endothermic properties having a peak temperature at approximately 183°C (start), or (c) A maleate form IV (maleate form IV of compound 1) characterized by having at least one of the combinations thereof.

[0260] In some embodiments, crystalline compound 1 has the following properties: (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.2°2θ, 19.60±0.2°2θ, and 22.55±0.2°2θ. (b) A DSC thermogram with endothermic properties having a peak temperature at approximately 183°C (start), or (c) Maleate form IV (maleate form IV of compound 1) characterized by having at least one of those combinations.

[0261] In some embodiments, crystalline compound 1, maleate form IV is characterized by having at least one of the properties selected from (a) to (b).

[0262] In some embodiments, crystalline compound 1, maleate form IV, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks as shown in Table 3.

[0263] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.1°²θ, 19.60±0.1°²θ, and 22.55±0.1°²θ. In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.2°²θ, 19.60±0.2°²θ, and 22.55±0.2°²θ.

[0264] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 7.84±0.1°2θ, 10.12±0.1°2θ, and 15.66±0.1°2θ. In some embodiments, the X-ray powder diffraction pattern further includes peaks at 7.84±0.2°2θ, 10.12±0.2°2θ, and 15.66±0.2°2θ.

[0265] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 8.83±0.1°2θ, 18.32±0.1°2θ, 22.06±0.1°2θ, and 27.54±0.1°2θ. In some embodiments, the X-ray powder diffraction pattern further includes peaks at 8.83±0.2°2θ, 18.32±0.2°2θ, 22.06±0.2°2θ, and 27.54±0.2°2θ.

[0266] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0267] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0268] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0269] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0270] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0271] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least six characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0272] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least seven characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0273] In some embodiments, crystalline compound 1, maleate form IV has an X-ray powder diffraction (XRPD) pattern having at least eight characteristic peaks selected from 3.93±0.1°2θ, 7.84±0.1°2θ, 8.83±0.1°2θ, 10.12±0.1°2θ, 15.66±0.1°2θ, 18.32±0.1°2θ, 19.60±0.1°2θ, 22.06±0.1°2θ, 22.55±0.1°2θ, and 27.54±0.1°2θ.

[0274] In some embodiments, crystalline compound 1, maleate form IV has substantially the same X-ray powder diffraction (XRPD) pattern as that shown in Figure 48.

[0275] In some embodiments, crystalline compound 1, maleate form IV has a DSC thermogram that is endothermic with a peak temperature at approximately 183°C (start). In some embodiments, crystalline compound 1, maleate form IV is further characterized by a DSC thermogram substantially the same as that shown in Figure 49. In some embodiments, crystalline compound 1, maleate form IV is further characterized by thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 49. [Table 3]

[0276] Tartrate form I of compound 1 (Compound 1, L-tartrate form I) Tartrate form I was obtained in acetone / water (19 / 1, v / v). The sample had a 5.2% weight loss at 80–160°C in TGA, and a single endothermic peak at 116°C (start) was detected in DSC due to dehydration. Approximately 0.2% acetone was present. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:1. Tartrate form I is a hydrate.

[0277] Tartrate form I was slightly hygroscopic with less than 1% water absorption at 80% RH and was physically and chemically stable for 7 days under both conditions of 60°C (capped) and 40°C / 75% RH (open). Compared to free base form I, tartrate form I showed improved solubility in water, FaSSIF, and FeSSIF. Tartrate form I showed a slower conversion rate to free base in FaSSIF and FeSSIF than maleate form IV, providing better and improved water solubility.

[0278] Tartrates showed several advantages in terms of improved solubility compared to maleates.

[0279] In some embodiments, crystalline compound 1 has the following properties: (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.16±0.1°2θ, 14.96±0.1°2θ, and 21.17±0.1°2θ. (b) A DSC thermogram with endothermic properties having a peak temperature at approximately 116°C (start), or (c) A tartrate form I (tartrate form I of compound 1) characterized by having at least one of the combinations thereof.

[0280] In some embodiments, crystalline compound 1, tartrate form I, is characterized by having at least one of the properties selected from (a) to (b).

[0281] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks as shown in Table 4.

[0282] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.16±0.1°²θ, 14.96±0.1°²θ, and 21.17±0.1°²θ.

[0283] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 10.63±0.1°2θ, 15.67±0.1°2θ, and 20.41±0.1°2θ.

[0284] In some embodiments, the X-ray powder diffraction pattern further includes peaks at 7.36±0.1°2θ, 17.49±0.1°2θ, and 22.96±0.1°2θ.

[0285] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0286] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least two characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0287] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least three characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0288] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least four characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0289] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least five characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0290] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least six characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0291] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least seven characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0292] In some embodiments, crystalline compound 1, tartrate form I, has an X-ray powder diffraction (XRPD) pattern having at least eight characteristic peaks selected from 6.16±0.1°2θ, 7.36±0.1°2θ, 10.63±0.1°2θ, 14.96±0.1°2θ, 15.67±0.1°2θ, 17.49±0.1°2θ, 20.41±0.1°2θ, 21.17±0.1°2θ, and 22.96±0.1°2θ.

[0293] In some embodiments, crystalline compound 1, tartrate form I, has substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 43B.

[0294] In some embodiments, crystalline compound 1, tartrate form I has a DSC thermogram that is endothermic with a peak temperature at approximately 116°C (start). In some embodiments, tartrate form I is further characterized by a DSC thermogram substantially the same as that shown in Figure 47. In some embodiments, crystalline compound 1, tartrate form I is further characterized by thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 47. [Table 4-1] [Table 4-2]

[0295] In some embodiments of the crystalline form, crystalline compound 1 is L-tartrate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.5, 14.9, and 15.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0296] In some embodiments of the crystalline form, compound 1L-tartrate form I is (a) One or more additional peaks (±0.2°) at 21.3, 22.5, or 23.0°²θ, (b) One or more additional peaks (±0.2°) at 6.3, 24.1, or 28.2°²θ, (c) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 43A, (d) DSC thermogram including the start of endothermic heating at approximately 113°C. (e) A DSC thermogram substantially identical to the one shown in Figure 44, (f) Thermogravimetric analysis (TGA) shows a weight loss of approximately 6.1% at approximately 25-130°C. (g) TGA including a thermogram substantially shown in Figure 45, (h) Dynamic vapor adsorption (DVS) curve showing approximately 1.1% water uptake at 25°C and 0-90% relative humidity (RH). (i) The DVS curve substantially shown in Figure 46, or (j) Further characterized by combinations of those.

[0297] In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 21.3, 22.5, or 23.0°². In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 6.3, 24.1, or 28.2°²θ. In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 6.3, 21.3, 22.5, 23.0, 24.1, or 28.2°²θ. In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by an X-ray power diffraction pattern substantially the same as that shown in Figure 43A.

[0298] In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by a DSC thermogram including an endothermic initiation at approximately 113°C. In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by a DSC thermogram including an endothermic peak at approximately 128°C. In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by a DSC thermogram substantially identical to that shown in Figure 44.

[0299] In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 6.1% at about 25–130°C. In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 45.

[0300] In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by a dynamic vapor adsorption (DVS) curve showing approximately 1.1% water uptake at 25°C and 0–90% relative humidity (RH). In some embodiments of the crystalline form, compound 1L-tartrate form I is further characterized by a dynamic vapor adsorption (DVS) curve substantially shown in Figure 46. In some embodiments of the crystalline form, compound 1L-tartrate form I is hygroscopic.

[0301] Sulfate form III of Compound 1 (Compound 1, sulfate form III) In some embodiments of the crystalline form, crystalline compound 1 is sulfate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 23.4, 24.0, and 28.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0302] In some embodiments of the crystalline form, the sulfate form III of compound 1 is (a) One or more additional peaks (±0.2°) at 19.1, 19.7, or 24.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 6, (c) DSC thermograms including the start of endothermic heating at approximately 34°C and the start of endothermic heating at approximately 163°C. (d) A DSC thermogram substantially the same as that shown in Figure 7, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.6% at approximately 25-150°C. (f) TGA including the thermogram substantially shown in Figure 8, (g) Dynamic vapor adsorption (DVS) curve showing approximately 6% water uptake at 25°C and 0-90% relative humidity (RH). (h) The DVS curve substantially shown in Figure 9, or (i) further characterized by combinations of those.

[0303] In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 19.1, 19.7, or 24.9°²θ. In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by an X-ray power diffraction pattern substantially the same as that shown in Figure 6.

[0304] In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by a DSC thermogram including an endothermic initiation at approximately 34°C and an endothermic initiation at approximately 163°C. In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by a DSC thermogram including an endothermic peak at approximately 82°C and an endothermic peak at approximately 170°C. In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by a DSC thermogram substantially the same as that shown in Figure 7.

[0305] In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 6.6% at approximately 25–150°C. In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 8.

[0306] In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by a dynamic vapor adsorption (DVS) curve showing approximately 6% water uptake at 25°C and 0–90% RH. In some embodiments of the crystalline form, sulfate form III of compound 1 is further characterized by a dynamic vapor adsorption (DVS) curve substantially shown in Figure 9. In some embodiments of the crystalline form, sulfate form III of compound 1 is hygroscopic.

[0307] Compound 1, esylate form I (Compound 1, esylate form I) In some embodiments of the crystalline form, crystalline compound 1 is esylate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.5, 25.5, and 26.9°²θ as determined by a diffractometer using Cu-Kα rays.

[0308] In some embodiments of the crystalline form, compound 1, ethylate form III, (a) One or more additional peaks (±0.2°) at 13.2, 15.8, or 21.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 10, (c) DSC thermograms including the start of endothermic heating at approximately 58°C and the start of endothermic heating at approximately 140°C. (d) A DSC thermogram substantially identical to the one shown in Figure 11, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 12.5% ​​at approximately 25-100°C. (f) A TGA including a thermogram substantially shown in Figure 12, or (g) A combination of these further features

[0309] In some embodiments of the crystalline form, compound 1, esylate form III is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 13.2, 15.8, or 21.6°²θ. In some embodiments of the crystalline form, compound 1, esylate form III is further characterized by an X-ray power diffraction pattern substantially the same as that shown in Figure 10.

[0310] In some embodiments of the crystalline form, compound 1, ethylate form III is further characterized by a DSC thermogram including an endothermic initiation at approximately 58°C and an endothermic initiation at approximately 140°C. In some embodiments of the crystalline form, compound 1, ethylate form III is further characterized by a DSC thermogram including an endothermic peak at approximately 82°C and an endothermic peak at approximately 150°C. In some embodiments of the crystalline form, compound 1, ethylate form III is further characterized by a DSC thermogram substantially the same as that shown in Figure 11.

[0311] In some embodiments of the crystalline form, compound 1, ethylate form III is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 12.5% ​​at about 25–100°C. In some embodiments of the crystalline form, compound 1, ethylate form III is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 12.

[0312] Compound 1, tosylate form II (Compound 1, tosylate form II) In some embodiments of the crystalline form, crystalline compound 1 is tosylate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.3, 14.9, and 19.7°²θ as determined by a diffractometer using Cu-Kα rays.

[0313] In some embodiments of the crystalline form, compound 1 and tosylate form II are (a) One or more additional peaks (±0.2°) at 16.8, 22.1, or 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 13, or (c) Combinations of these further feature

[0314] In some embodiments of the crystalline form, compound 1, tosylate form II is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 16.8, 22.1, or 29.9°²θ. In some embodiments of the crystalline form, compound 1, tosylate form II is further characterized by an X-ray power diffraction pattern substantially the same as that shown in Figure 13.

[0315] Hemiedisylate form I of compound 1 (compound 1, hemiedisylate form I) In some embodiments of the crystalline form, crystalline compound 1 is hemiedisylate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.9, 26.5, and 27.7°²θ as determined by a diffractometer using Cu-Kα rays.

[0316] In some embodiments of the crystalline form, compound 1, hemiedisylate form I, (a) One or more additional peaks (±0.2°) at 16.3, 18.0, or 26.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 14, or (c) Combinations of these further feature

[0317] In some embodiments of the crystalline form, compound 1, hemiedisylate form I, is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 16.3, 18.0, or 26.9°²θ. In some embodiments of the crystalline form, compound 1, hemiedisylate form I, is further characterized by an X-ray power diffraction pattern substantially the same as that shown in Figure 14.

[0318] Compound 1, hemiedisylate form II (Compound 1, hemiedisylate form II) In some embodiments of the crystalline form, crystalline compound 1 is hemiedisylate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.4, 21.2, and 27.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0319] In some embodiments of the crystalline form, compound 1 hemiedisylate form II is (a) One or more additional peaks (±0.2°) at 11.4, 17.9, or 25.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 15, (c) DSC thermograms including the start of endothermic heating at approximately 96°C and the start of endothermic heating at approximately 194°C. (d) A DSC thermogram substantially identical to the one shown in Figure 16, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 1.7% at approximately 25-87°C and approximately 2.8% at approximately 87-120°C. (f) TGA including the thermogram substantially shown in Figure 17, (g) Dynamic vapor adsorption (DVS) curve showing approximately 3.6% water uptake at 25℃ and 0-90%RH. (h) The DVS curve substantially shown in Figure 18, or (i) further characterized by combinations of those.

[0320] In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 11.4, 17.9, or 25.6°²θ. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 15.

[0321] In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 96°C and an endothermic initiation at approximately 194°C. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by a DSC thermogram including an endothermic peak at approximately 128°C and an endothermic peak at approximately 204°C. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 16.

[0322] In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 1.7% from about 25–87°C and about 2.8% from about 87–120°C. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 17.

[0323] In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by a dynamic vapor adsorption (DVS) curve showing approximately 3.6% water uptake at 25°C and 0–90% RH. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is further characterized by a dynamic vapor adsorption (DVS) curve substantially shown in Figure 18. In some embodiments of the crystalline form, compound 1, hemiedisylate form II is hygroscopic.

[0324] Compound 1, phosphate form I (Compound 1, phosphate form I) In some embodiments of the crystalline form, crystalline compound 1 is phosphate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.8, 25.7, and 26.9°²θ as determined by a diffractometer using Cu-Kα rays.

[0325] In some embodiments of the crystalline form, compound 1, phosphate form I, (a) One or more additional peaks (±0.2°) at 15.1, 17.3, or 21.5°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 19, (c) DSC thermograms including the start of endothermic heating at approximately 28°C and at approximately 133°C. (d) A DSC thermogram substantially identical to that shown in Figure 20, or (e) further characterized by combinations thereof.

[0326] In some embodiments of the crystalline form, compound 1, phosphate form I, is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 15.1, 17.3, or 21.5°²θ. In some embodiments of the crystalline form, compound 1, phosphate form I, is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 19.

[0327] In some embodiments of the crystalline form, compound 1, phosphate form I, is further characterized by a DSC thermogram including an endothermic onset at approximately 28°C and an endothermic onset at approximately 133°C. In some embodiments of the crystalline form, compound 1, phosphate form I, is further characterized by a DSC thermogram including an endothermic peak at approximately 67°C and an endothermic peak at approximately 147°C. In some embodiments of the crystalline form, compound 1, phosphate form I, is further characterized by a DSC thermogram substantially the same as that shown in Figure 20.

[0328] Compound 1, phosphate form II (Compound 1, phosphate form II) In some embodiments of the crystalline form, crystalline compound 1 is phosphate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 4.7, 16.0, and 17.2°²θ, as determined by a diffractometer using Cu-Kα rays.

[0329] In some embodiments of the crystalline form, compound 1 and phosphate form II are (a) One or more additional peaks (±0.2°) at 5.7, 6.8, or 9.4°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 21, (c) DSC thermograms including the start of endothermic heating at approximately 21°C and the start of endothermic heating at approximately 142°C. (d) A DSC thermogram substantially identical to that shown in Figure 22, or (e) further characterized by combinations thereof.

[0330] In some embodiments of the crystalline form, compound 1, phosphate form II, is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 5.7, 6.8, or 9.4°²θ. In some embodiments of the crystalline form, compound 1, phosphate form II, is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 21.

[0331] In some embodiments of the crystalline form, compound 1, phosphate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 21°C and an endothermic initiation at approximately 142°C. In some embodiments of the crystalline form, compound 1, phosphate form II is further characterized by a DSC thermogram including an endothermic peak at approximately 58°C and an endothermic peak at approximately 150°C. In some embodiments of the crystalline form, compound 1, phosphate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 22.

[0332] L-tartrate mesophase of compound 1 (Compound 1, L-tartrate mesophase) In some embodiments of the crystalline form, crystalline compound 1 is an L-tartrate mesophase characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.5, 24.1, and 25.4°²θ as determined by a diffractometer using Cu-Kα rays.

[0333] In some embodiments of the crystalline form, the L-tartrate mesophase of compound 1 is (a) One or more additional peaks (±0.2°) at 4.4, 8.8, or 13.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 23, or (c) Combinations of these further feature

[0334] In some embodiments of the crystalline form, the L-tartrate mesophase of compound 1 is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 4.4, 8.8, or 13.9°²θ. In some embodiments of the crystalline form, the L-tartrate mesophase of compound 1 is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 23.

[0335] Compound 1, L-tartrate form II (Compound 1, L-tartrate form II or Tartrate Form II) In some embodiments of the crystalline form, crystalline compound 1 is L-tartrate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.4, 15.7, and 18.4°²θ as determined by a diffractometer using Cu-Kα rays.

[0336] In some embodiments of the crystalline form, compound 1L-tartrate form II is (a) One or more additional peaks (±0.2°) at 9.1, 20.4, or 32.1°2θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 24, (c) DSC thermograms including the start of endothermic heating at approximately 49°C, approximately 91°C, and approximately 119°C. (d) A DSC thermogram substantially the same as the one shown in Figure 25, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 8% at approximately 25-70°C and approximately 1.6% at approximately 70-100°C. (f) TGA including the thermogram substantially shown in Figure 26, (g) Dynamic vapor adsorption (DVS) curve showing approximately 10.2% water uptake at 25℃ and 0-90%RH. (h) The DVS curve substantially shown in Figure 27, or (i) further characterized by combinations of those.

[0337] In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 9.1, 20.4, or 32.1°2θ. In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 24.

[0338] In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 49°C, an endothermic initiation at approximately 91°C, and an endothermic initiation at approximately 119°C. In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by a DSC thermogram including an endothermic peak at approximately 68°C, an endothermic peak at approximately 101°C, and an endothermic peak at approximately 127°C. In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 25.

[0339] In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 8% at about 25–70°C and about 1.6% at about 70–100°C. In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 26.

[0340] In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by a dynamic vapor adsorption (DVS) curve showing approximately 10.2% water uptake at 25°C and 0-90% RH. In some embodiments of the crystalline form, compound 1L-tartrate form II is further characterized by a dynamic vapor adsorption (DVS) curve substantially shown in Figure 27. In some embodiments of the crystalline form, compound 1L-tartrate form II is hygroscopic.

[0341] Compound 1, L-Tartrate Salt Form III (or L-Tartrate Form III) In some embodiments of the crystalline form, crystalline compound 1 is L-tartrate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 4.7, 9.4, and 14.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0342] In some embodiments of the crystalline form, compound 1L-tartrate form III is (a) One or more additional peaks (±0.2°) at 16.8, 17.4, or 18.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 28, (c) DSC thermogram including the start of endothermic heating at approximately 174°C. (d) A DSC thermogram substantially identical to the one shown in Figure 29, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2% at approximately 25-70°C. (f) A TGA including a thermogram substantially shown in Figure 30, or (g) A combination of these further features

[0343] In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 16.8, 17.4, or 18.9°²θ. In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in Figure 28.

[0344] In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by a DSC thermogram including an endothermic initiation at approximately 174°C. In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by a DSC thermogram including an endothermic peak at approximately 180°C. In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by a DSC thermogram substantially the same as that shown in Figure 29.

[0345] In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2% at about 25–70°C. In some embodiments of the crystalline form, compound 1L-tartrate form III is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 30.

[0346] Compound 1, L-tartrate form IV (Compound 1, L-tartrate form IV or Tartrate Form IV) In some embodiments of the crystalline form, crystalline compound 1 is L-tartrate form IV, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 15.8, 16.6, and 22.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0347] In some embodiments of the crystalline form, compound 1L-tartrate form IV is (a) One or more additional peaks (±0.2°) at 6.5, 12.9, or 20.4°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 31, (c) DSC thermograms including the start of endothermic heating at approximately 79°C and the start of endothermic heating at approximately 127°C. (d) A DSC thermogram substantially the same as that shown in Figure 32, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5% at approximately 25-125°C. (f) A TGA including a thermogram substantially shown in Figure 33, or (g) A combination of these further features

[0348] In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by an X-ray powder diffractogram including one or more additional peaks (±0.2°) at 6.5, 12.9, or 20.4°²θ. In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 31.

[0349] In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by a DSC thermogram including an endothermic initiation at approximately 79°C and an endothermic initiation at approximately 127°C. In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by a DSC thermogram including an endothermic peak at approximately 112°C and an endothermic peak at approximately 135°C. In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by a DSC thermogram substantially the same as that shown in Figure 32.

[0350] In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 5% at about 25–125°C. In some embodiments of the crystalline form, compound 1L-tartrate form IV is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 33.

[0351] Compound 1, L-tartrate methanol solvate (Compound 1, L-tartrate methanol solvate) In some embodiments of the crystalline form, crystalline compound 1 is an L-tartrate methanol solvate characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.7, 16.7, and 17.4°²θ as determined by a diffractometer using Cu-Kα rays.

[0352] In some embodiments of the crystalline form, the compound 1L-tartrate methanol solvate is (a) One or more additional peaks (±0.2°) at 9.4, 18.9, or 21.0°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 34, or (c) Combinations of these further feature

[0353] In some embodiments of the crystalline form, the compound 1L-tartrate methanol solvate is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 9.4, 18.9, or 21.0°²θ. In some embodiments of the crystalline form, the compound 1L-tartrate methanol solvate is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 34.

[0354] L-tartrate ethanol solvate of Compound 1 (Compound 1, L-tartrate ethanol solvate) In some embodiments of the crystalline form, crystalline compound 1 is an L-tartrate ethanol solvate characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.7, 17.3, and 19.4°²θ as determined by a diffractometer using Cu-Kα rays.

[0355] In some embodiments of the crystalline form, the compound 1L-tartrate ethanol solvate is (a) One or more additional peaks (±0.2°) at 4.4, 21.7, or 24.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 35, or (c) Combinations of these further feature

[0356] In some embodiments of the crystalline form, the compound 1L-tartrate ethanol solvate is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 4.4, 21.7, or 24.6°²θ. In some embodiments of the crystalline form, the compound 1L-tartrate ethanol solvate is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 35.

[0357] L-malate form II of Compound 1 (Compound 1, L-malate form II) In some embodiments of the crystalline form, crystalline compound 1 is L-malate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.3, 21.5, and 24.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0358] In some embodiments of the crystalline form, compound 1L-malate form II is (a) One or more additional peaks (±0.2°) at 14.7, 23.8, and 27.7°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 36, (c) DSC thermogram including the start of endothermic heating at approximately 165°C. (d) A DSC thermogram substantially identical to the one shown in Figure 37, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.8% at approximately 25-100°C. (f) TGA including the thermogram substantially shown in Figure 38, (g) Dynamic vapor adsorption (DVS) curve showing approximately 4.6% water uptake at 25℃ and 0-90%RH. (h) The DVS curve substantially shown in Figure 39, or (i) further characterized by combinations of those.

[0359] In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 14.7, 23.8, and 27.7°2θ. In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 36.

[0360] In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 165°C. In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by a DSC thermogram including an endothermic peak at approximately 169°C. In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 37.

[0361] In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 1.8% at approximately 25–100°C. In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 38.

[0362] In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by a dynamic vapor adsorption (DVS) curve showing approximately 4.6% water uptake at 25°C and 0-90% RH. In some embodiments of the crystalline form, compound 1L-malate form II is further characterized by a dynamic vapor adsorption (DVS) curve substantially shown in Figure 39. In some embodiments of the crystalline form, compound 1L-malate form II is hygroscopic.

[0363] L-malate form III of Compound 1 (Compound 1, L-malate form III) In some embodiments of the crystalline form, crystalline compound 1 is L-malate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.1, 17.9, and 26.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0364] In some embodiments of the crystalline form, compound 1L-malate form III is (a) One or more additional peaks (±0.2°) at 8.8, 24.2, or 28.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 40, (c) DSC thermograms including the start of endothermic heating at approximately 120°C and the start of endothermic heating at approximately 153°C. (d) A DSC thermogram substantially identical to the one shown in Figure 41, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.7% at approximately 25-50°C. (f) A TGA including a thermogram substantially shown in Figure 42, or (g) A combination of these further features

[0365] In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by an X-ray power diffractogram including one or more additional peaks (±0.2°) at 8.8, 24.2, or 28.9°²θ. In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 40.

[0366] In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by a DSC thermogram including an endothermic initiation at approximately 120°C and an endothermic initiation at approximately 153°C. In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by a DSC thermogram including an endothermic peak at approximately 128°C and an endothermic peak at approximately 161°C. In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by a DSC thermogram substantially the same as that shown in Figure 41.

[0367] In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 0.7% from about 25–50°C. In some embodiments of the crystalline form, compound 1L-malate form III is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 42.

[0368] Compound 1, HCl salt form I (Compound 1, HCl salt form I) In some embodiments of the crystalline form, crystalline compound 1 is the HCl salt form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.2, 12.2, and 14.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0369] In some embodiments of the crystalline form, compound 1, HCl salt form I, (a) One or more additional peaks (±0.2°) at 15.3, 25.2, 27.1, 27.7, 28.0, and 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 50A, (c) DSC thermogram including the start of endothermic heating at approximately 216°C. (d) A DSC thermogram substantially identical to the one shown in Figure 50B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.2% at approximately 25-200°C. (f) A TGA including a thermogram substantially shown in Figure 50B, or (g) A combination of these further features

[0370] In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by one or more additional peaks (±0.2°) at 15.3, 25.2, 27.1, 27.7, 28.0, and 29.9°²θ. In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 50A.

[0371] In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by a DSC thermogram that includes an endothermic initiation at approximately 216°C. In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by a DSC thermogram that is substantially the same as that shown in Figure 50B.

[0372] In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.2% at about 25–200°C. In some embodiments of the crystalline form, compound 1, HCl salt form I is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 50B.

[0373] Compound 1, HCl salt form II (Compound 1, HCl salt form II) In some embodiments of the crystalline form, crystalline compound 1 is the HCl salt form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 5.0, 9.9, and 17.6°²θ as determined by a diffractometer using Cu-Kα rays.

[0374] In some embodiments of the crystalline form, compound 1, HCl salt form II, (a) One or more additional peaks (±0.2°) at 9.0, 12.7, 18.8, 24.9, 25.4, 26.5, and 27.0°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 51A, (c) DSC thermograms including the start of endothermic heating at approximately 115°C and the start of endothermic heating at approximately 147°C. (d) A DSC thermogram substantially identical to the one shown in Figure 51B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.8% at approximately 25-165°C. (f) A TGA including a thermogram substantially shown in Figure 51B, or (g) A combination of these further features

[0375] In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by one or more additional peaks (±0.2°) at 9.0, 12.7, 18.8, 24.9, 25.4, 26.5, and 27.0°²θ. In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 51A.

[0376] In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by a DSC thermogram including endothermic initiation at approximately 115°C and endothermic initiation at approximately 147°C. In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 51B.

[0377] In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 6.8% at approximately 25–165°C. In some embodiments of the crystalline form, compound 1, HCl salt form II is further characterized by thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 51B.

[0378] Sulfate form I of compound 1 (compound 1, sulfate form I or sulfate form I) In some embodiments of the crystalline form, crystalline compound 1 is sulfate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.3, 17.4, and 18.9°²θ as determined by a diffractometer using Cu-Kα rays.

[0379] In some embodiments of the crystalline form, compound 1, sulfate form I, (a) One or more additional peaks (±0.2°) at 4.8, 10.1, 16.7, 19.2, 25.2, and 25.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 52A, (c) DSC thermograms including the start of endothermic heating at approximately 52°C, the start of endothermic heating at approximately 99°C, and the start of endothermic heating at approximately 152°C. (d) A DSC thermogram substantially the same as that shown in Figure 52B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5.3% at approximately 25-170°C. (f) A TGA including a thermogram substantially shown in Figure 52B, or (g) A combination of these further features

[0380] In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by one or more additional peaks (±0.2°) at 4.8, 10.1, 16.7, 19.2, 25.2, and 25.9°²θ. In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 52A.

[0381] In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by a DSC thermogram including endothermic initiation at approximately 52°C, endothermic initiation at approximately 99°C, and endothermic initiation at approximately 152°C. In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by a DSC thermogram substantially the same as that shown in Figure 52B.

[0382] In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 5.3% at approximately 25–170°C. In some embodiments of the crystalline form, compound 1, sulfate form I, is further characterized by TGA including a thermogram substantially shown in Figure 52B.

[0383] Sulfate form II of Compound 1 (Compound 1, sulfate form II) In some embodiments of the crystalline form, crystalline compound 1 is sulfate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 6.2, 18.5, and 24.7°²θ as determined by a diffractometer using Cu-Kα rays.

[0384] In some embodiments of the crystalline form, compound 1 and sulfate form II are, (a) One or more additional peaks (±0.2°) at 10.4, 12.0, 16.0, 21.8, and 31.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 53A, (c) DSC thermogram including the start of endothermic heating at approximately 223°C. (d) A DSC thermogram substantially identical to the one shown in Figure 53B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.5% at approximately 25-150°C. (f) A TGA including a thermogram substantially shown in Figure 53C, or (g) A combination of these further features

[0385] In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by one or more additional peaks (±0.2°) at 10.4, 12.0, 16.0, 21.8, and 31.1°²θ. In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 53A.

[0386] In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 223°C. In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by a DSC thermogram including an endothermic initiation at approximately 223°C, followed by an exothermic initiation, which may be associated with decomposition. In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 53B.

[0387] In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 1.5% at about 25–150°C. In some embodiments of the crystalline form, compound 1, sulfate form II is further characterized by TGA including a thermogram substantially shown in Figure 53C.

[0388] Compound 1, Maleate Salt Form I (Compound 1, Maleate Salt Form I or Maleate Form I) In some embodiments of the crystalline form, crystalline compound 1 is maleate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 3.9, 19.6, and 20.9°²θ as determined by a diffractometer using Cu-Kα rays.

[0389] In some embodiments of the crystalline form, compound 1, maleate form I, (a) One or more additional peaks (±0.2°) at 15.6, 17.4, 20.7, 24.6, 28.3, and 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 54A, (c) DSC thermogram including the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially identical to the one shown in Figure 54B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 1.0% at approximately 25-70°C and approximately 3.7% at approximately 150-200°C. (f) A TGA including a thermogram substantially shown in Figure 54B, or (g) A combination of these further features

[0390] In some embodiments of the crystalline form, compound 1, maleate form I is further characterized by one or more additional peaks (±0.2°) at 15.6, 17.4, 20.7, 24.6, 28.3, and 29.9°²θ. In some embodiments of the crystalline form, compound 1, maleate form I is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 54A.

[0391] In some embodiments of the crystalline form, compound 1, maleate form I, is further characterized by a DSC thermogram that includes an endothermic initiation at approximately 177°C. In some embodiments of the crystalline form, compound 1, maleate form I, is further characterized by a DSC thermogram substantially the same as that shown in Figure 54B.

[0392] In some embodiments of the crystalline form, compound 1, maleate form I is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 1.0% at about 25–70°C and about 3.7% at about 150–200°C. In some embodiments of the crystalline form, compound 1, maleate form I is further characterized by TGA including a thermogram substantially shown in Figure 54B.

[0393] Compound 1, Maleate Salt Form II (Compound 1, Maleate Salt Form II or Maleate Form II) In some embodiments of the crystalline form, crystalline compound 1 is maleate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 3.6, 18.1, and 22.9°²θ, as determined by a diffractometer using Cu-Kα rays.

[0394] In some embodiments of the crystalline form, compound 1 and maleate form II are (a) One or more additional peaks (±0.2°) at 7.2, 9.7, 10.8, 16.0, and 18.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 55A, (c) DSC thermograms including the start of endothermic heating at approximately 131°C and the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially the same as that shown in Figure 55B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 3.3% at approximately 120-160°C and approximately 5.4% at approximately 160-210°C. (f) A TGA including a thermogram substantially shown in Figure 55B, or (g) A combination of these further features

[0395] In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by one or more additional peaks (±0.2°) at 7.2, 9.7, 10.8, 16.0, and 18.9°²θ. In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 55A.

[0396] In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by a DSC thermogram including endothermic initiation at approximately 131°C and endothermic initiation at approximately 177°C. In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 55B.

[0397] In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 3.3% at about 120–160°C and about 5.4% at about 160–210°C. In some embodiments of the crystalline form, compound 1, maleate form II is further characterized by TGA including a thermogram substantially shown in Figure 55B.

[0398] Compound 1, Maleate Salt Form III (or Maleate Form III) In some embodiments of the crystalline form, crystalline compound 1 is maleate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.9, 11.9, and 17.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0399] In some embodiments of the crystalline form, compound 1, maleate form III, (a) One or more additional peaks (±0.2°) at 9.8, 12.6, 15.0, 16.1, 18.8, and 19.4°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 56A, (c) DSC thermograms including endothermic onset at approximately 102°C, endothermic onset at approximately 113°C, exothermic onset at approximately 115°C, and endothermic onset at approximately 148°C. (d) A DSC thermogram substantially identical to the one shown in Figure 56B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 2.7% at approximately 25-125°C and approximately 2.2% at approximately 125-160°C. (f) A TGA including a thermogram substantially shown in Figure 56B, or (g) A combination of these further features

[0400] In some embodiments of the crystalline form, crystalline compound 1 is maleate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.0, 17.9, and 25.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0401] In some embodiments of the crystalline form, compound 1, maleate form III, (a) One or more additional peaks (±0.2°) at 12.1, 15.2, 19.0, 19.6, 24.7, and 28.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 56C, or (c) Combinations of these further feature

[0402] In some embodiments of the crystalline form, compound 1, maleate form III is further characterized by one or more additional peaks (±0.2°) 12.1, 15.2, 19.0, 19.6, 24.7, and 28.1°²θ. In some embodiments of the crystalline form, compound 1, maleate form III is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 56C.

[0403] Compound 1, Citrate Salt Form I (or Citrate Form I) In some embodiments of the crystalline form, crystalline compound 1 is citrate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.9, 15.5, and 16.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0404] In some embodiments of the crystalline form, compound 1, citrate form I, (a) One or more additional peaks (±0.2°) at 12.8, 17.1, 19.2, 19.8, 23.6, and 24.5°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 57A, (c) DSC thermograms including the start of endothermic heating at approximately 27°C and the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially the same as that shown in Figure 57B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 2.3% at approximately 25-100°C and approximately 12% at approximately 150-210°C. (f) A TGA including a thermogram substantially shown in Figure 57B, or (g) A combination of these further features

[0405] In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by one or more additional peaks (±0.2°) at 12.8, 17.1, 19.2, 19.8, 23.6, and 24.5°²θ. In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 57A.

[0406] In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by a DSC thermogram including endothermic initiation at approximately 27°C and endothermic initiation at approximately 177°C. In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by a DSC thermogram substantially the same as that shown in Figure 57B.

[0407] In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.3% at about 25–100°C and about 12% at about 150–210°C. In some embodiments of the crystalline form, compound 1, citrate form I, is further characterized by TGA including a thermogram substantially shown in Figure 57B.

[0408] Compound 1, L-malate form I (Compound 1, L-malate form I or Malate form I) In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.9, 11.9, and 17.8°²θ as determined by a diffractometer using Cu-Kα rays.

[0409] In some embodiments of the crystalline form, compound 1, L-malate form I, (a) One or more additional peaks (±0.2°) at 9.8, 12.6, 15.0, 18.8, 19.4, and 25.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 58A, (c) DSC thermograms including the start of endothermic heating at approximately 29°C, the start of endothermic heating at approximately 161°C, and the start of endothermic heating at approximately 180°C. (d) A DSC thermogram substantially the same as that shown in Figure 58B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 2.9% at approximately 25-110°C and approximately 1.5% at approximately 150-210°C. (f) A TGA including a thermogram substantially shown in Figure 58B, or (g) A combination of these further features

[0410] In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by one or more additional peaks (±0.2°) at 9.8, 12.6, 15.0, 18.8, 19.4, and 25.1°2θ. In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 58A.

[0411] In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by a DSC thermogram including endothermic initiation at approximately 29°C, endothermic initiation at approximately 161°C, and endothermic initiation at approximately 180°C. In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by a DSC thermogram substantially identical to that shown in Figure 58B.

[0412] In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.9% at about 25–110°C and about 1.5% at about 150–210°C. In some embodiments of the crystalline form, crystalline compound 1 is L-malate form I, characterized by TGA including a thermogram substantially shown in Figure 58B.

[0413] Compound 1, mesylate salt form I (Compound 1, mesylate salt form I or mesylate form I) In some embodiments of the crystalline form, crystalline compound 1 is the mesylate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 6.5, 15.2, and 25.3°²θ as determined by a diffractometer using Cu-Kα rays.

[0414] In some embodiments of the crystalline form, compound 1, mesylate form I, (a) One or more additional peaks (±0.2°) at 10.0, 16.6, 17.5, 18.5, 19.7, and 26.2°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 59A, (c) DSC thermograms including the start of endothermic heating at approximately 37°C and the start of endothermic heating at approximately 148°C. (d) A DSC thermogram substantially the same as that shown in Figure 59B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.1% at approximately 25-100°C. (f) A TGA including a thermogram substantially shown in Figure 59B, or (g) A combination of these further features

[0415] In some embodiments of the crystalline form, compound 1, mesylate form I is further characterized by one or more additional peaks (±0.2°) at 10.0, 16.6, 17.5, 18.5, 19.7, and 26.2°²θ. In some embodiments of the crystalline form, compound 1, mesylate form I is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 59A.

[0416] In some embodiments of the crystalline form, compound 1, mesylate form I is further characterized by a DSC thermogram including endothermic initiation at approximately 37°C and endothermic initiation at approximately 148°C. In some embodiments of the crystalline form, compound 1, mesylate form I is further characterized by a DSC thermogram substantially the same as that shown in Figure 59B.

[0417] In some embodiments of the crystalline form, compound 1, mesylate form I, is further characterized by thermogravimetric analysis (TGA) showing a weight loss of approximately 6.1% at approximately 25–100°C. In some embodiments of the crystalline form, compound 1, mesylate form I, is further characterized by TGA including a thermogram substantially shown in Figure 59B.

[0418] Compound 1, Mesylate Salt Form II (or Mesylate Form II) In some embodiments of the crystalline form, crystalline compound 1 is the mesylate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 10.7, 13.0, and 17.1°²θ as determined by a diffractometer using Cu-Kα rays.

[0419] In some embodiments of the crystalline form, compound 1 and mesylate form II are (a) One or more additional peaks (±0.2°) at 6.5, 8.5, 15.4, 19.7, 21.9, and 25.3°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 60A, (c) DSC thermograms including the start of endothermic heating at approximately 37°C and the start of endothermic heating at approximately 149°C. (d) A DSC thermogram substantially the same as that shown in Figure 60B, (e) Thermogravimetric analysis (TGA) showed a weight loss of approximately 4.7% at approximately 25-120°C and approximately 0.7% at approximately 120-170°C. (f) A TGA including a thermogram substantially shown in Figure 60B, or (g) A combination of these further features

[0420] In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by one or more additional peaks (±0.2°) at 6.5, 8.5, 15.4, 19.7, 21.9, and 25.3°²θ. In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 60A.

[0421] In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by a DSC thermogram including endothermic initiation at approximately 37°C and endothermic initiation at approximately 149°C. In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by a DSC thermogram substantially the same as that shown in Figure 60B.

[0422] In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 4.7% at about 25–120°C and about 0.7% at about 120–170°C. In some embodiments of the crystalline form, compound 1, mesylate form II is further characterized by TGA including a thermogram substantially shown in Figure 60B.

[0423] Compound 1, Tosylate Salt Form I (or Tosylate Form I) In some embodiments of the crystalline form, crystalline compound 1 is tosylate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 24.0, 24.6, and 25.6°²θ as determined by a diffractometer using Cu-Kα rays.

[0424] In some embodiments of the crystalline form, compound 1, tosylate form I, (a) One or more additional peaks (±0.2°) at 5.2, 8.0, 17.7, 11.8, 23.7, and 27.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 61A, (c) DSC thermograms including the start of endothermic heating at approximately 82°C and the start of endothermic heating at approximately 142°C. (d) A DSC thermogram substantially the same as that shown in Figure 61B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.6% at approximately 25-170°C. (f) A TGA including a thermogram substantially shown in Figure 61B, or (g) A combination of these further features

[0425] In some embodiments of the crystalline form, form I of compound 1 tosylate is further characterized by one or more additional peaks (±0.2°) at 5.2, 8.0, 17.7, 11.8, 23.7, and 27.9°²θ. In some embodiments of the crystalline form, form I of compound 1 tosylate is further characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 61A.

[0426] In some embodiments of the crystalline form, compound 1, tosyl form I is further characterized by a DSC thermogram including endothermic initiation at approximately 82°C and endothermic initiation at approximately 142°C. In some embodiments of the crystalline form, compound 1, tosylate form I is further characterized by a DSC thermogram substantially the same as that shown in Figure 61B.

[0427] In some embodiments of the crystalline form, compound 1, tosylate form I, is further characterized by thermogravimetric analysis (TGA) showing a weight loss of about 2.6% at about 25–170°C. In some embodiments of the crystalline form, compound 1, tosylate form I, is further characterized by TGA including a thermogram substantially shown in Figure 61B.

[0428] Preparation of Free Base Crystalline Compound 1 In some embodiments, the crystalline form of compound 1 is prepared as outlined in the examples. Note that the solvent, temperature, and other reaction conditions presented herein may vary.

[0429] In some embodiments, this specification provides a method for preparing a solid form of compound 1, comprising: 1) suspending compound 1 in a solvent at a first temperature (e.g., ambient temperature); 2) circulating the compound 1 mixture between ambient temperature and a second temperature (e.g., about 40°C); 3) collecting the solid if a precipitate is present, or evaporating the solvent and collecting the solid if no precipitate is present; and 4) optionally drying the mixture. In some embodiments, this specification provides a method for preparing a solid form of compound 1, comprising: 1) obtaining a saturated solution of compound 1 in a solvent; 2) adding a poor solvent to the saturated solution; 3) cooling to about 2-8°C and about -20°C; 4) collecting the solid if a precipitate is present, or evaporating the solvent and collecting the solid if no precipitate is present; and 5) optionally drying the mixture. In some embodiments, the volume ratio of solvent to poor solvent is about 1:9. In some embodiments, the volume ratio of solvent to poor solvent is about 1:4. In some embodiments, the volume ratio of solvent to poor solvent is approximately 1:2. In some embodiments, the volume ratio of solvent to poor solvent is approximately 1:1. In some embodiments, the method for producing the solid form of compound 1 is a poor solvent recrystallization experiment.

[0430] In some embodiments, compound 1, form I was prepared via a slurry. In some embodiments, form I was prepared by suspending compound 1 in a solvent, stirring at a temperature of 25°C to 80°C for a period of 1 to 7 days, and collecting the solid by filtration.

[0431] In some embodiments, the solvent is methanol, ethanol, isopropanol, acetone, ethyl acetate, toluene, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile, water, dichloromethane, n-butanol, heptane, isopropyl acetate, methyl ethyl ketone, or any combination thereof.

[0432] In some embodiments, the solvent is acetone, water, or any combination thereof.

[0433] In some embodiments, the solvent is acetone / water (20 / 1 v / v). In some embodiments, the solvent is acetone / water (19 / 1 v / v). In some embodiments, the solvent is acetone / water (18 / 1 v / v). In some embodiments, the solvent is acetone / water (17 / 1 v / v). In some embodiments, the solvent is acetone / water (16 / 1 v / v). In some embodiments, the solvent is acetone / water (15 / 1 v / v). In some embodiments, the solvent is acetone / water (14 / 1 v / v). In some embodiments, the solvent is acetone / water (13 / 1 v / v). In some embodiments, the solvent is acetone / water (12 / 1 v / v). In some embodiments, the solvent is acetone / water (11 / 1 v / v). In some embodiments, the solvent is acetone / water (10 / 1 v / v). In some embodiments, the solvent is acetone / water (9 / 1 v / v). In some embodiments, the solvent is acetone / water (8 / 1 v / v). In some embodiments, the solvent is acetone / water (7 / 1 v / v). In some embodiments, the solvent is acetone / water (6 / 1 v / v). In some embodiments, the solvent is acetone / water (5 / 1 v / v). In some embodiments, the solvent is acetone / water (4 / 1 v / v). In some embodiments, the solvent is acetone / water (3 / 1 v / v). In some embodiments, the solvent is acetone / water (2 / 1 v / v). In some embodiments, the solvent is acetone / water (1 / 1 v / v).

[0434] In some embodiments, the temperature is 25°C to 70°C. In some embodiments, the temperature is 25°C to 60°C. In some embodiments, the temperature is 25°C to 50°C. In some embodiments, the temperature is 25°C to 40°C. In some embodiments, the temperature is 25°C to 30°C. In some embodiments, the temperature is 30°C to 80°C. In some embodiments, the temperature is 40°C to 80°C. In some embodiments, the temperature is 50°C to 80°C. In some embodiments, the temperature is 60°C to 80°C. In some embodiments, the temperature is 70°C to 80°C. In some embodiments, the temperature is approximately 25°C. In some embodiments, the temperature is approximately 30°C. In some embodiments, the temperature is approximately 40°C. In some embodiments, the temperature is approximately 50°C. In some embodiments, the temperature is approximately 60°C. In some embodiments, the temperature is approximately 70°C. In some embodiments, the temperature is approximately 80°C.

[0435] In some embodiments, the duration is 1 to 6 days. In some embodiments, the duration is 1 to 5 days. In some embodiments, the duration is 1 to 4 days. In some embodiments, the duration is 1 to 3 days. In some embodiments, the duration is 1 to 2 days. In some embodiments, the duration is 2 to 6 days. In some embodiments, the duration is 3 to 6 days. In some embodiments, the duration is 4 to 6 days. In some embodiments, the duration is 5 to 6 days. In some embodiments, the duration is 1 day. In some embodiments, the duration is 2 days. In some embodiments, the duration is 3 days. In some embodiments, the duration is 4 days. In some embodiments, the duration is 5 days. In some embodiments, the duration is 6 days.

[0436] In some embodiments, form I was obtained via slurry in acetone / water (19 / 1, v / v) at 50°C for 1 day.

[0437] In some embodiments, compound 1, form I was prepared via cold crystallization. In some embodiments, form I was prepared by suspending compound 1 in a solvent with stirring at 50°C for 30 minutes, followed by filtration, and then rapidly cooling to 5°C at 0.1°C / min or by direct quenching by storage in a refrigerator (approximately 4°C), and collecting the solid by filtration.

[0438] In some embodiments, the solvent is methanol / water (9 / 1, v / v, 500V), acetonitrile / water (9 / 1, v / v, 200V), acetone / water (9 / 1, v / v, 200V), acetone / ethanol (1 / 1, v / v, 500V), ethanol (500V), or acetone.

[0439] In some embodiments, compound 1, form I was prepared by evaporation crystallization. In some embodiments, form I was prepared by slurring compound 1 in a solvent at 50°C for 30 minutes to obtain a clear solution, which was then filtered, the container was covered with a pinhole film, and left under ambient conditions to evaporate slowly until the solid precipitated.

[0440] In some embodiments, the solvent is methanol / water (9 / 1, 500V), acetonitrile / water (9 / 1, 200V), acetone / water (9 / 1, 200V), acetone / ethanol (1 / 1, 500V), or dichloromethane / methanol (1 / 1, 50V).

[0441] In some embodiments, compound 1, form I, was prepared via poor solvent precipitation.

[0442] In some embodiments, the solvents are DCM / MeOH (4 / 1, 15V) and DMSO (50V).

[0443] In some embodiments, the poor solvent is ethanol, isopropanol, n-butanol, acetone, methyl ethyl ketone, ethyl acetate, water, toluene, acetonitrile, n-heptane, methyl tert-butyl ether, or 2-methyltetrahydrofuran.

[0444] In some embodiments, the volume ratio (V g / V anti ) of the solvent to the poor solvent is from 1 / 10 to 1 / 1. In some embodiments, the volume ratio (V g / V anti ) of the solvent to the poor solvent is 1 / 10, 1 / 9, 1 / 8, 1 / 7, 1 / 6, 1 / 5, 1 / 4, 1 / 3, 1 / 2, or 1 / 1.

[0445] In another embodiment, crystalline compound 1 is substantially pure. In some embodiments, substantially pure crystalline compound 1 is substantially free of other solid forms, such as amorphous solids. In some embodiments, the purity of substantially pure crystalline compound 1 is about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In some embodiments, the purity of substantially pure crystalline compound 1 is about 95%, about 96%, about 97%, about 98%, about 98.5%, about 99%, about 99.5%, or about 99.8%.

[0446] Therapeutic methods Disclosed herein are methods of treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. Also disclosed herein are methods of treating diseases in which inhibition of PARP1 is beneficial, the methods comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.

[0447] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0448] In some embodiments, cancers comprising BRCA1 and / or BRCA2 mutations include bladder cancer, brain and CNS cancers, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0449] In some embodiments, the cancer is characterized by a deficiency in homologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms, reforming the continuous DNA helix. The components of the FIR-dependent DNA DSB repair pathway are ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), and MRE1 1. Examples include, but are not limited to, A(NM_005590) and NBS1(NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, a cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells with reduced or lost ability to repair DNA DSBs via the pathway compared to normal cells; that is, the activity of the FIR-dependent DNA DSB repair pathway may be reduced or lost in one or more cancer cells.

[0450] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is lost in one or more cancer cells of an individual with cancer lacking FIR-dependent DNA DSB repair.

[0451] In some embodiments, cancer cells have a BRCA1 and / or BRCA2 deficiency phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells having this phenotype may also be deficient in BRCA1 and / or BRCA2, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, by mutation or polymorphism in the coding nucleic acid, or by amplification, mutation or polymorphism in a gene encoding a regulator, e.g., the EMSY gene encoding a BRCA2 regulator. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene encoding a BRCA2 binding factor is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at high risk for certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal, and lung cancers.

[0452] To minimize the risk of off-target effects, it is desirable that drug molecules have selectivity for specific targets.

[0453] Avoiding inhibition of PARP family isoforms other than PARP1 may be important in minimizing the toxicity that may result from inhibition of non-PARP1 isoforms. Pharmacological inhibition of PARP isoforms other than PARP1 may drive toxicity that reduces the therapeutic index of drugs with lower selectivity for PARP isoforms compared to PARP1. PARP3, like PARP1, is involved in DNA damage, but it has also been shown to play an important role in spindle integrity and telomerase integrity (Boehler, C., Gauthier, LR., Mortusewicz O. et al. Poly(ADP-ribose)polymerase3(PARP3), a newcomer in cellular response to DNA damage and mitotic progression. PNAS, January 26, 2011, 108(7)2783-2788). PARP5A, also known as tankyrase 1, plays a crucial role in Wnt signaling and telomere length (Kulak, O., Chen, H., Holohan B. et al. Disruption of Wnt / β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol. 2015 Jul;35(14),2425-2435). PARP6 is an essential microtubule regulatory gene in mice, and germline mutations in PARP6 that suppress catalytic activity have adverse effects on neuronal function in humans (Vermehren-Schmaedick, A., Huang JY, Levinson, M. et al. Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay. Cells, 2021 Jun;10(6),1289).PARP7 catalytic inhibition causes hyperstimulation of type I interferon, which produces an autoimmune phenotype (Gozgit, JM, Vasbinder, MM, Abo, RP et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Volume 39, Issue 9, 13 September 2021, Pages 1214-1226). The precise function of PARP8 has not been established, but its knockout has been shown to induce defects in mitosis and nuclear morphology, as well as a decrease in cell viability (Vyas, S., Chesarone-Cataldo, M., Todorova, T., et al. A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat.Commun. 2013, 4(1), 2240). PARP10 has been described as a MYC-interacting protein with tumor suppressor activity (Yu, M., Schreeek, S., Cerni, C. et al. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose)polymerase activity, inhibits transformation. Oncogene, 2005 volume 24, pages 1982-1993).

[0454] dosage In certain embodiments, a composition containing compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered for therapeutic purposes. In a particular therapeutic use, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress at least one of the symptoms of the disease or condition. The effective dose for this use depends on the severity and course of the disease or condition, the patient's medical history, their health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective dose is determined arbitrarily by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0455] In certain embodiments where the patient's condition does not improve, the compound may be administered over a long period, i.e., over the entire life of the patient, at the discretion of the physician, to alleviate, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0456] Once the patient's condition improves, a maintenance dose is administered as needed. Subsequently, in specific embodiments, the dosage, frequency, or both are reduced to a level that maintains the improved disease, disorder, or condition, depending on the function of the symptoms. However, in certain embodiments, the patient requires long-term, intermittent, or daily treatment at any relapse of symptoms.

[0457] The amount of a given drug corresponding to such a quantity varies depending on factors such as the specific compound, the disease state and its severity, and the identity of the person or host requiring treatment (e.g., weight, sex). Nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the person or host being treated.

[0458] However, generally, the dose used for treating adults is typically in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dose used for treating adults is approximately 1 mg to approximately 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

[0459] In one embodiment, the appropriate daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dose or amount of the active substance in the dosage form is lower or higher than the range shown herein, based on the number of variables relating to the individual treatment regimen. In various embodiments, the daily dose and unit dose are modified depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the physician's judgment.

[0460] The toxicity and therapeutic efficacy of such treatment regimens are LD 10 and ED 90 This is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to the determination of the following: The dose ratio between toxicity and therapeutic effect is the therapeutic index, LD50. 50 and ED 50 It is expressed as a ratio between [value] and [value]. In certain embodiments, data obtained from cell culture assays and animal experiments are used when formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dose of the compounds described herein is an ED with minimal toxicity. 50 It is within the range of blood concentrations including [the specified substance]. In certain embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form used and the route of administration utilized.

[0461] In any of the embodiments described herein, in further embodiments, an effective amount of the compound or a pharmaceutically acceptable salt thereof described herein is administered (a) systemically to a mammal and / or (b) orally to a mammal and / or (c) intravenously to a mammal and / or (d) by injection to a mammal and / or (e) topically to a mammal and / or (f) non-systemically or topically to a mammal.

[0462] Route of administration Preferred routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, ear, nose, and topical administration. In addition, as merely an example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as subarachnoid, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0463] In certain embodiments, the compounds described herein are administered topically, rather than systemically, by direct injection of the compound into an organ, for example, often in the form of a depot preparation or sustained-release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, by liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0464] Compositions / Pharmaceutical compositions / Formulations In some embodiments, compositions are provided that include a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), as described herein.

[0465] In one embodiment, a composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 50% to 99% (for example, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of compound 1 present in the composition is in the form of a specified salt, solid form, crystalline form, or crystalline salt form.

[0466] In one embodiment, a composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 95% of compound 1 present in the composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0467] In one embodiment, a composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 90% of compound 1 present in the composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0468] In one embodiment, a composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 85% of compound 1 present in the composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0469] In one embodiment, a pharmaceutical composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 95% of compound 1 present in the pharmaceutical composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0470] In one embodiment, a pharmaceutical composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 90% of compound 1 present in the pharmaceutical composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0471] In one embodiment, a pharmaceutical composition is provided comprising a salt or solid form of 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1), or a solvate thereof, wherein at least 85% of compound 1 present in the pharmaceutical composition is in the form of the specified salt, solid form, crystalline form, or crystalline salt form.

[0472] In some embodiments, compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject requiring it, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition, according to standard pharmacopoeias. In one embodiment, compound 1, or a pharmaceutically acceptable salt or solvate thereof, may be administered to animals. Compound 1, or a pharmaceutically acceptable salt or solvate thereof, may be administered orally or parenterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical administration routes.

[0473] In another embodiment, this specification provides a pharmaceutical composition comprising compound 1, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the chosen route of administration. Outlines of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are incorporated herein by reference.

[0474] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0475] The pharmaceutical compositions described herein are administered to the subject by an appropriate route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapid-release formulations, tablets, capsules, pills, powders, sugar-coated tablets, effervescent formulations, lyophilized formulations, delayed-release formulations, long-release formulations, pulsed-release formulations, multiparticulate formulations, and mixed immediate and controlled-release formulations.

[0476] combination This specification discloses a method for treating cancer using compound 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with additional therapeutic agents.

[0477] In some embodiments, additional therapeutic agents are anticancer drugs.

[0478] In some embodiments, the additional therapeutic agent is administered simultaneously with compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional therapeutic agent and compound 1, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional therapeutic agent is administered more frequently than compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional therapeutic agent is administered before the administration of compound 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the additional therapeutic agent is administered after the administration of compound 1, or a pharmaceutically acceptable salt or solvate thereof. [Examples]

[0479] Example 1 [ka] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equivalent) in MeOH (50 mL), NaOMe (15.76 g, 87.49 mmol, 1.10 equivalent, 30 wt%) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was observed by TLC (PE:EA = 1:1, R). f The mixture was monitored by (=0.4). The resulting mixture was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with dimethyl ammonium (3 × 100 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0480] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridine-2-yl)-N,N-dimethylethene-1-amine: A mixture of DMF-DMA (100 mL) and 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equivalent) in DMF (100 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The reaction was monitored by TLC. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0481] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinealdehyde To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridine-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL), NaIO4 (28.00 g, 131.07 mmol, 2.20 equivalents) was gradually added at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by TLC. The reactants were quenched by adding saturated sodium hyposulfite (aqueous solution) (100 mL) at room temperature. The resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0482] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equivalents) in EtOH (100 mL), SnCl2 (26.25 g, 134.09 mmol, 5.00 equivalents) was gradually added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90°C under a nitrogen atmosphere. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with ELISA (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the crude product. The crude product was purified by trituration with hexane (50 mL) to obtain ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, in 3 steps). LC-MS:(ES+H,m / z):[M+H] + =311.0 / 313.0. 1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.78(s,1H),8.58(s,1H),4.42(q,2H),4.12(s,3H),1.39(t3H).

[0483] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate:

[0484] To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthirizine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equivalent) in DMF (10 mL), CuCl (0.57 g, 5.78 mmol, 1.50 equivalent) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 120 °C. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with toluene (20 mL). The resulting mixture was washed with 3 × 30 mL of water (10% NH3 × H2O). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 7-chloro-6-methoxy-1,5-naphthirizine-3-carboxylate (800 mg, 77.78%). LC-MS:(ES+H,m / z):[M+H] + =267.0. 1 H NMR(300MHz,DMSO-d6)δ9.27(d,1H),8.63(d,1H),8.57(s,1H),4.41(q,2H),4.12(s,3H),1.37(t,3H).

[0485] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthirizine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equivalent) in CH3CN (8 mL), TMSI (1.80 g, 9.00 mmol, 3.00 equivalent) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. The reaction was monitored by LC-MS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with Âr (50 mL). The aqueous layer was washed with 3 × 50 mL of water (10% Et3N). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 7-chloro-6-oxo-5H-1,5-naphthirizine-3-carboxylate (740 mg, 97.64%). LC-MS:(ES+H,m / z):[M+H] + =252.9. 1H NMR(300MHz,DMSO-d6)δ12.61(s,1H),8.94(d,1H),8.37(d,1H),8.20(s,1H),4.39(q,2H),1.36(t,3H).

[0486] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyrizin-2-one: To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthirizine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equivalent) in THF (6 mL), LiAlH4 (2.5 mL, 5.85 mmol, 2.00 equivalent) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for a further 2 hours. The reaction was monitored by LC-MS. The mixture was acidified to pH 5 with 1 M HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthirizine-2-one (250 mg, 40.53%). LC-MS:(ES+H,m / z):[M+H] + =211.00. 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.45(d,1H),8.28(s,1H),7.69(d,1H),5.53(t,1H),4.64(d,2H).

[0487] Step 8: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyrizin-2-one: To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthirizin-2-one (250 mg, 1.18 mmol, 1.00 equivalent) in CH2Cl2 (5 mL), SOCl2 (423 mg, 3.56 mmol, 3.00 equivalent) and DMF (8 mg, 0.11 mmol, 0.10 equivalent) were added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. This yielded 3-chloro-7-(chloromethyl)-1H-1,5-naphthirizin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification. LC-MS:(ES+H,m / z):[M+H] + =228.95.

[0488] Step 9: Preparation of 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyrizin-3-yl)methyl]-2-methylazetidine-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide: A mixture of N-cyclopropyl-5-{[(2R,3S)-2-methylazetidine-3-yl]oxy}pyridine-2-carboxamide hydrochloride (178 mg, 0.72 mmol, 1.10 equivalents), 3-chloro-7-(chloromethyl)-1H-1,5-naphthyrizin-2-one (150 mg, 0.65 mmol, 1.00 equivalent), KI (21 mg, 0.13 mmol, 0.20 equivalents), and DIEA (423 mg, 3.27 mmol, 5.00 equivalents) in ACN (3 mL) was stirred at 50°C for 8 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was cooled to room temperature and poured into 50 mL of water. The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 5-{[(2R,3S)-1-[(7-chloro-6-oxo-5H-1,5-naphthyrizin-3-yl)methyl)-2-methylazetidine-3-yl]oxy}-N-cyclopropylpyridine-2-carboxamide (82.1 mg, 27.93%). LC-MS:(ES+H,m / z):[M+H] + =440.15. 1 H NMR(300MHz,DMSO-d6)δ12.45(s,1H),8.52(d,1H),8.46(d,1H),8.27(s,1H),8.21(d,1H),7.95(d,1H),7.66(d,1H),7.44(d d,1H),4.62(q,1H),3.95(d,1H),3.82(t,1H),3.67(d,1H),3.40(q,1H),2.93-2.74(m,2H),1.21(d,3H),0.76-0.57(m,4H).

[0489] reagent acid As shown in Table 5, a total of 11 acids were used for salt screening. Two other acids, ethanesulfonic acid and 1,2-ethanedisulfonic acid, were also used. [Table 5]

[0490] solvent Table 6 shows the solvents used for solubility evaluation and salt screening. [Table 6]

[0491] Example 2: Characterization of the starting material Compound 1 is used in XRPD, DSC, TGA, PLM and 1 The material was characterized by 1H-NMR. The characteristic data is summarized in Table 7. Under a microscope, the sample showed irregular particles with weak birefringence. XRPD confirmed that this material was morphology I with low crystallinity. Approximately 0.1% DMSO was present. 1 It was detected by 1H-NMR. TGA showed weight losses of 0.9% and 0.8% at RT ~80°C and 210~265°C, respectively. DSC showed an exothermic peak at 187°C and an endothermic peak at 234°C (start), likely due to recrystallization and melting. In addition, the starting material was converted to free base form II after heating to 220°C. [Table 7]

[0492] Example 3: Polymorph Screening The polymorph screening experiments are summarized in Table 8. Morphology I was obtained from most of the polymorph screening experiments. [Table 8]

[0493] Preliminary solubility test The solubility of Compound 1 (starting material) was evaluated by visual observation using RT in 18 single solvents and 6 solvent mixtures. Approximately 5 mg of the solid was weighed into an 8 mL glass vial, and then the solvent was added stepwise until the solid was completely dissolved or the total volume of the solvent reached 5 mL. The results are summarized in Table 9. Sample morphology I showed low solubility (<5 mg / mL) in most solvent systems and good solubility (>50 mg / mL) in DCM / MeOH (4 / 1, v / v). The solubility was estimated, but this is for reference only. [Table 9] The value is reported as "<" if no dissolution is observed, and as ">" if dissolution occurs after the addition of the first aliquot.

[0494] Slurry conversion Appropriate amounts of compound 1 (starting material) were added to different solvents to prepare suspensions, which were stirred continuously at RT and 50°C for 3 and 7 days, and at 80°C for 3 days. Solid samples were collected by filtration and analyzed by XRPD. Form I was obtained after slurrying in the selected solvent. The results are summarized in Tables 10-12. [Table 10] [Table 11] [Table 12]

[0495] Cooling crystallization Cooling crystallization was performed in six selected solvents. Approximately 10 mg of compound 1 (starting material) was weighed into a glass vial, and then the selected solvent was added to prepare a suspension while stirring at 50°C for 30 minutes. The filtrate was then rapidly cooled by slowly cooling to 5°C at 0.1°C / min using Crystal 16, or by direct storage in a refrigerator (approximately 4°C). All obtained solids were characterized by XRPD. The results are summarized in Table 13. Morphology I was obtained in all cooling experiments. [Table 13]

[0496] Evaporation crystallization Approximately 10 mg of compound 1 (starting material) was slurryed in five solvents at 50°C for 30 minutes to obtain a clear solution. After filtration, the clear solution was covered with a pinhole film and left under ambient conditions to slowly evaporate until the solid precipitated. The results are summarized in Table 14. Only morphology I was obtained. [Table 14]

[0497] Poor solvent precipitation Approximately 20 mg of compound 1 (starting material) was weighed into a glass vial, and then the selected solvent was added to prepare a nearly saturated solution. After filtration, a poor solvent was gradually added to the filtrate until a solid precipitated, or a 10V poor solvent was added via RT. If precipitation occurred, the solid was isolated by filtration and characterized as appropriate. The results are summarized in Table 15. Morphology I was obtained in most solvent systems. [Table 15] V g / V anti This is the volume ratio of solvent to poor solvent.

[0498] Periodic heating-cooling Periodic heating-cooling experiments were performed using a Crystal 16 Parallel Crystallizer. Approximately 20 mg of compound 1 (starting material) was added to 1 mL of solvent, and the heating-cooling program was executed. 1. First, equilibrate at 20°C and heat to 75 or 100°C at a rate of 0.2°C / min (the higher temperature is set according to the boiling point of the solvent). 2. The samples were held at 75 or 100°C for 1 hour. 3. Cool to 20°C at a rate of 0.2°C / min and hold for 1 hour. 4. The above procedure was repeated once.

[0499] A turbidimeter from Crystal 16 recorded whether the solid completely dissolved during heating. The results are shown in Table 16. Form I was obtained in most solvent systems. [Table 16]

[0500] Salt decomposition To explore potential hydrates, we attempted to use salt decomposition. Salt decomposition was carried out using selected base / acid pairs in water. Approximately 20 mg of the starting material was dissolved in 3 mL of 0.02 M aqueous HCl solution. Then, 3 mL of 0.02 M aqueous NaOH solution was added for neutralization, and the mixture was stirred at RT for approximately 5 hours. The precipitated solid was isolated for XRPD testing. Form I was obtained via salt decomposition in pure water.

[0501] Example 4: Stability Relationship Study Form II was prepared by heating the starting material in a DSC pan to 220°C. Approximately 15 mg of Form II was then stirred in 0.5 mL of a selected solvent at the desired temperature for 2 and 5 days. Solid samples were collected by filtration and characterized by XRPD. The results are summarized in Table 17. Form II was converted to Form I under all conditions, suggesting that Form I is more stable at RT ~80°C. [Table 17]

[0502] Example 5: pH solubility profile of Form I Different pH buffers (pH 1.0, 3.0, 5.0, 6.8, and 9.0) were prepared according to the method in Table 18. Appropriate amounts of Form I were added to 1.4 mL of each different buffer (pH = 1.0, 3.0, 5.0, 6.8, and 9.0) to prepare suspensions. The suspensions were shaken at 1000 rpm for 4 hours and 24 hours at 25°C. At each time point, the suspensions were centrifuged, the supernatant was examined by UPLC / pH, and the wet cake was analyzed by XRPD. Duplicate samples were prepared.

[0503] All results are summarized in Table 19. The solubility of form I was pH-dependent, being low in buffers at pH 6.8 and 9. The maximum solubility in 0.1N HCl was >40 mg / mL. Form I converted to citrate form I in pH 3 buffer over 24 hours and remained unchanged under other conditions. [Table 18] [Table 19]

[0504] Example 6: Mechanical stability of form I Appropriate amounts of Form I were manually ground using a mortar and pestle for approximately 1 minute and 5 minutes, respectively. The ground samples were analyzed by XRPD. The crystalline morphology of Form I remained unchanged after grinding with little decrease in crystallinity, demonstrating acceptable mechanical stability.

[0505] Example 7: Periodic heat treatment Periodic heat treatment was performed by DSC. Approximately 1-5 mg of Form I was placed in an aluminum pan with pinholes and heated under the following parameters. 1. First, equilibrate at 25°C, then heat to 300°C at a rate of 10°C / min. 2. Cool to 0°C at a rate of 10°C / min. 3. Reheat to 300°C or 178°C at a rate of 10°C / min.

[0506] A glass transition was observed at 99°C during the reheating process.

[0507] Example 8: Salt Screening pK a Based on the estimated solubility results, salts were prepared using 11 acids in three solvent systems: EtOH, THF, and acetone / water (19 / 1, v / v).

[0508] Approximately 25 mg of free base form I was suspended in a selected solvent by RT. Then, for reactive crystallization, 1.1 equivalents of acid were added to the suspension by RT (the liquid acid was diluted in the corresponding solvent and added to the suspension), followed by the addition of 2.2 equivalents of HCl. Several concentrated systems were diluted by adding an additional 0.5 mL of solvent over 4 hours (see summary table). * (This is emphasized.) If a clear solution or oil was obtained, precipitation was induced using various crystallization methods. The solid was collected by filtration or centrifugation and dried under vacuum at 40°C for approximately 4 hours. The salt screening results are summarized in Table 20. The details of the experiment and the results of the characterization are shown in the following section. [Table 20] * The concentrated suspension was diluted by adding an additional 0.5 mL of solvent over 4 hours.

[0509] HCl salt Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents or 2.2 equivalents of HCl were added to the suspension. Detailed information and results are summarized in Table 21. Two crystalline HCl salts, form I and form II, were obtained.

[0510] The HCl salt form I was obtained in EtOH containing 1.1 equivalents of HCl. The sample had a weight loss of 2.2% before 200°C in TGA. One endothermic peak at 216°C (start) was observed due to melting before decomposition by DSC. Approximately 1.0% EtOH was present. 1It was detected by 1H-NMR. Peak splitting was observed in samples reacted with strong acids (HCl, H2SO4, PTSA, and MsOH). 1 Observed in the 1H-NMR spectrum, it suggested salt formation. The HCl salt form I may be a hydrate or a hygroscopic anhydride.

[0511] The HCl salt form II was obtained in acetone / water (19 / 1, v / v) containing 1.1 equivalents of HCl. The sample had a weight loss of 6.8% before 165°C in TGA. Two endothermic peaks at 115°C and 147°C (start) were detected by DSC due to dehydration. Approximately 0.1% acetone was present. 1 It was detected by 1H-NMR. Therefore, the HCl salt form II is a hydrate. [Table 21]

[0512] Sulfate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of H2SO4 solution were added to the suspension. Detailed information and results are summarized in Table 22. Sulfate form I with moderate crystallinity was obtained.

[0513] Sulfate form I was obtained in acetone / water (19 / 1, v / v). The sample had a 5.3% weight loss before 170°C in TGA. Three endothermic peaks were detected by DSC at 52°C, 99°C, and 152°C (start), which may be due to dehydration and melting. Approximately 0.1% acetone was present. 1 It was detected by 1H-NMR. Therefore, sulfate form I is a hydrate. [Table 22]

[0514] maleate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of maleic acid were added to the suspension. Detailed information and results are summarized in Table 23. Two crystalline maleates, form I and form II, were obtained.

[0515] Maleate form I was obtained in acetone / water (19 / 1, v / v). The sample had a weight loss of 1.0% before 70°C and a weight loss of 3.7% at 150–200°C in TGA. One endothermic peak at 177°C (start) was detected in DSC due to melting. Obvious acetone residue was present. 1 It was not detected by 1H-NMR, and the salt ratio was determined to be 1:1. Maleate form I may be an anhydrous form with little hygroscopicity.

[0516] Maleate form II was obtained in THF. The sample had a weight loss of 3.3% at 120–160°C and a weight loss of 5.4% at 160–210°C in TGA. Two endothermic peaks at 131°C and 177°C (start) were detected in DSC due to desolvation and melting. Approximately 4.5% of THF was obtained. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:1. The maleate form II is the THF solvate. [Table 23]

[0517] Phosphate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of H3PO4 were added to the suspension. Detailed information and results are summarized in Table 24. Crystalline phosphate was not obtained in any of the selected solvents. [Table 24]

[0518] Tartrate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of L-tartaric acid were added to the suspension. Detailed information and results are summarized in Table 25. Tartrate form I was obtained.

[0519] Tartrate form I was obtained in acetone / water (19 / 1, v / v). The sample had a 5.2% weight loss at 80–160°C in TGA, and a single endothermic peak at 116°C (start) was detected in DSC due to dehydration. Approximately 0.2% acetone was present. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:1. Tartrate form I is a hydrate. [Table 25]

[0520] Compound 1, tartrate form I, was also obtained as follows: Approximately 100 mg of Compound 1, free base form I, was stirred at approximately 22°C with approximately 37.5 mg (1.1 equivalents) of L-tartaric acid in approximately 1 mL of acetone. After approximately 20 hours, a paste was formed. The paste was diluted with approximately 1 mL of acetone. The paste was heated twice at approximately 22–70°C, and remained as a paste. XRPD analysis showed that it was similar to the L-tartrate mesophase (described herein). Approximately 0.2 mL of water was added to the paste. The mixture was heated briefly to approximately 70°C and then allowed to cool naturally to approximately 22°C to form a fluid slurry. The solid was isolated by filtration and dried under vacuum at 50°C. XRPD analysis showed that it was L-tartrate form I. Proton NMR showed approximately 1 equivalent of L-tartaric acid and 0.3 wt% acetone.

[0521] A representative XRPD pattern of compound 1, tartrate form I (which may also be referred to as "compound 1, L-tartrate form I") is shown in Figure 43A, which is characterized by one or more peaks selected from 7.5, 14.9, and 15.8 ± 0.2°²q, and further by one or more peaks selected from (2) 6.3, 21.3, 22.5, 23.0, 24.1, 28.2, ± 0.2°²q.

[0522] The DSC thermogram (Figure 44) shows the initiation of melting at approximately 113°C. The TGA thermogram shows a weight loss of 6.1% between 25 and 130°C (Figure 45), which is close to 5.8% dihydrate (theoretical value) when the 0.3% acetone content is subtracted according to the proton NMR data. DVS analysis is shown in Figure 46, indicating that this morphology is slightly hygroscopic with approximately 1.1% water uptake at 25°C and 0-90% RH.

[0523] Fumarate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of fumaric acid were added to the suspension. Detailed information and results are summarized in Table 26. Crystalline fumarate was not obtained. [Table 26]

[0524] citrate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of citrate were added to the suspension. Detailed information and results are summarized in Table 27. Citrate form I with moderate crystallinity was obtained.

[0525] Citrate form I was obtained in acetone / water (19 / 1, v / v). The sample showed weight losses of 2.3% and 11.6% at RT ~100°C and 150~210°C in TGA. Two endothermic peaks were detected in DSC at 27°C and 177°C (start), which may be due to dehydration and melting. Approximately 1.0% acetone was present. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:0.9. Citrate form I may be a hydrate. [Table 27]

[0526] Malate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of L-malic acid were added to the suspension. Detailed information and results are summarized in Table 28. Malate form I was obtained in all selected solvents.

[0527] Malate form I was obtained in acetone / water (19 / 1, v / v). The sample exhibited weight losses of 2.9% and 1.5% at RT ~110°C and 150~210°C, respectively, in TGA. Three endothermic peaks were detected in DSC at 29°C, 161°C, and 180°C (start), which may be due to dehydration, melting, and decomposition. Approximately 0.1% acetone was present. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:0.5. Malate form I may be a hydrate. [Table 28]

[0528] succinate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of succinic acid were added to the suspension. Detailed information and results are summarized in Table 29. Crystalline succinate was not obtained. [Table 29]

[0529] Tosylate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of p-toluenesulfonic acid were added to the suspension. Detailed information and results are summarized in Table 30. Tosylate form I was obtained in acetone / water (19 / 1, v / v).

[0530] Tosylate form I was obtained in acetone / water (19 / 1, v / v). The sample had a weight loss of 2.6% before 170°C in TGA. Two endothermic peaks were detected in DSC at 82°C and 142°C (start), which may be due to dehydration. Approximately 0.1% acetone 1It was detected by 1H-NMR, and the salt ratio was determined to be 1:1. Tosylate form I is a hydrate. [Table 30]

[0531] Mesylate Approximately 25 mg of free base form I was suspended in a selected solvent by RT, and then 1.1 equivalents of methanesulfonic acid were added to the suspension. Detailed information and results are summarized in Table 31. Two crystalline mesylates, form I and form II, were obtained.

[0532] Mesylate form I was obtained in acetone / water (v / v, 19 / 1). The sample had a 6.1% weight loss before 100°C in TGA. Two endothermic peaks at 37°C and 148°C (start) were detected in DSC due to dehydration and melting. Obvious acetone residue was present. 1 It was not detected by 1H-NMR, and the salt ratio was determined to be 1:1.2. Mesylate form I is a hydrate.

[0533] Mesylate form II was obtained in THF. The sample showed a 4.7% weight loss before 120°C and a 0.7% weight loss between 120°C and 170°C in TGA. Two endothermic peaks were detected in DSC at 37°C and 149°C (start), which may be due to dehydration and melting. Approximately 1% of THF was absorbed. 1 It was detected by 1H-NMR, and the salt ratio was determined to be 1:1. The mesylate form II is a hydrate. [Table 31]

[0534] Example 9: Re-preparation of target morphology and complete characterization Free base form I, maleate form I, and tartrate form I were re-prepared in 300 mg scales for complete characterization and DVS testing to eliminate hygroscopic salts. Detailed experimental procedures are described in Table 32.

[0535] Free base form I was obtained in approximately 90% yield, and PLM, XRPD, DSC, TGA and 1 The material was characterized by 1H-NMR. Free base form I showed improved crystallinity compared to the starting material and consisted of irregular crystals with aggregation. TGA did not show any significant weight loss before melting, and an exothermic peak at 231°C, as well as two endothermic peaks at 228°C and 238°C (start), were observed in DSC, corresponding to melt-recrystallization. 1 1H-NMR showed the detection of 0.1% acetone.

[0536] Maleate form III and maleate form IV are two novel polymorphs observed during the scale-up process, with maleate form IV being an anhydrous form with less weight loss than maleate form I. Maleate form III was characterized by XRPD (Figure 56A), DSC (Figure 56B), and TGA (Figure 56B). Maleate form III was highly crystalline. TGA showed that the sample had weight losses of 2.7% and 2.2% at 80–160°C and 125–160°C, respectively. Multiple thermal events were observed in DSC. The characterization results indicated that maleate form III may be a solvate or hydrate.

[0537] Compound 1, maleate form III was also obtained by stirring Compound 1, maleate form I in water for 3 days at approximately 21°C. The slurry was isolated by centrifugation, and the wet cake was analyzed by XRPD as shown in Figure 56C, which is characterized by peaks at (1) 9.0, 17.9, and 25.3 ± 0.2°²θ, and one or more peaks selected from 12.1, 15.2, 19.0, 19.6, 24.7, and 28.1 ± 0.2°²θ.

[0538] Maleate form IV, PLM, XRPD, DSC, TGA and 1The sample was characterized by 1H-NMR. Maleate form IV was highly crystalline and consisted of irregular crystals with aggregation. The sample showed no apparent weight loss before 150°C in TGA, and a single endothermic peak at 183°C (start) was observed in DSC due to melting. There was no apparent EtOH residue, and 1.0 equivalent of maleic acid was present. 1 It was detected by 1H-NMR.

[0539] Tartrate form I was obtained in 93% yield, along with PLM, XRPD, DSC, TGA and 1 Characterization was performed by 1H-NMR. Tartrate form I was highly crystalline and consisted of irregular crystals with aggregation. TGA showed a weight loss of 5.2% at 80–160°C, and a single endothermic peak at 115°C (start) was observed in DSC due to dehydration. Approximately 0.2% acetone residue and 1.0 equivalent of L-tartaric acid were added. 1 Detection was performed by 1H-NMR. The KFT results showed that 6.52% water was detected, close to the calculated 5.8% water content of the dihydrate, and the difference was likely due to surface water. Therefore, it is assumed that tartrate form I is the dihydrate. [Table 32]

[0540] Targeted morphology DVS trial To eliminate hygroscopic salts, DVS (Deep Vase Level) tests were performed on three target forms: free base form I, maleate form IV, and tartrate form I. The DVS results showed that free base form I, maleate form IV, and tartrate form I all had water uptake of 0.5% / 0.6%, 0.6% / 0.9%, and 0.8% / 1.4% at 80%RH / 90%RH, respectively, indicating slight hygroscopicity. All three target forms remained unchanged after the DVS test. Therefore, free base form I, maleate form IV, and tartrate form I were further used to evaluate solubility and stability.

[0541] Example 10: Stability and solubility tests of free base form I, maleate form IV, and tartrate form I. Solid State Stability Solid-state stability tests were performed on free base form I, maleate form IV, and tartrate form I at 60°C (capped) and 40°C / 75%RH (open) for 7 days. Duplicate samples were prepared under each condition. Stability samples were dissolved in a diluent to prepare a solution of approximately 1 mg / mL for HPLC purity analysis. The solid samples were analyzed by XRPD to confirm the crystal morphology. The results are summarized in Table 33. The crystal morphology of the two salts and the free base remained unchanged, and no decrease in purity was observed. All three selected forms were physically and chemically stable for at least 7 days at 60°C (capped) and 40°C / 75%RH (open). [Table 33]

[0542] Solubility in biomedical media The solubility of free base form I, maleate form IV, and tartrate form I was measured at 37°C in biocompatible media (SGF, FaSSIF, and FeSSIF) and water at 1000 rpm for up to 24 hours. Approximately 9 mg of free base equivalent of free base form I, maleate form IV, and tartrate form I was weighed into a sample vial, and then 1.8 mL of the three biocompatible media and water were added to prepare suspensions. Approximately 0.6 mL of each suspension was filtered at 0.5, 2, and 24 hours, and the filtrate was analyzed by HPLC and pH meter, and the filtration cake was analyzed by XRPD. Samples were prepared in pairs (n=2) for each condition. Mean values ​​(n=2) are shown. All results are summarized in Table 34.

[0543] Free base form I exhibited high solubility (>5 mg / mL) in SGF and low solubility in other media, showing pH-dependent solubility. Compared to free base form I, maleate form IV and tartrate form I showed improved solubility in water, FaSSIF, and FeSSIF. In FaSSIF and FeSSIF, maleate form IV and tartrate form I dissociated to free base form I, and a slower morphogenesis was observed for tartrate form I, which maintained supersaturated solubility for a longer period. In water, tartrate form I transformed into a new pattern after 24 hours, resulting in decreased solubility. Overall, tartrate form I showed several advantages in improved solubility compared to maleate form IV. The crystalline form of free base form I remained unchanged after the solubility test.

[0544] A new pattern of sample obtained by suspending tartrate form I in water was isolated, and DSC, TGA and 1 Further characterization was performed by 1H-NMR. Thermal analysis revealed that the sample had two weight losses in TGA, 7.4% and 1.1% at 50–110°C and 110–140°C, respectively. Three endothermic peaks were detected by DSC at 66°C, 107°C, and 127°C (start), which may be due to dehydration. Obvious solvent residues were found. 1 It was not detected by 1H-NMR, and the salt ratio was determined to be 1:1. Therefore, this new pattern is a hydrate of the tartrate, which is more stable in water, and is designated as tartrate form II. [Table 34]

[0545] Analysis method PLM Optical microscopy analysis was performed using an ECLIPSE LV100POL (Nikon, JPN) microscope. Each sample was placed on a glass slide with one drop of immersion oil and covered with a glass slip. The samples were observed using polarized 4-20' objective lenses.

[0546] XRPD XRPD diffractograms were collected using an X-ray diffractometer. Samples were prepared on a zero-background silicon wafer by gently pressing them onto a flat surface. The XRPD diffraction parameters are shown in Table 35. [Table 35]

[0547] TGA TGA analysis was performed using the TA Instrument. Approximately 1–3 mg of sample was placed on an aluminum pan pre-weighed and heated according to the parameters in Table 36. Data was analyzed using TRIOS. [Table 36]

[0548] DSC DSC analysis was performed using a TA Instrument. Approximately 1–3 mg of the sample was placed in an aluminum pan with a pinhole and heated according to the parameters in Table 37. The data was analyzed using TRIOS. [Table 37]

[0549] 1 H-NMR 1 1H-NMR spectra were collected using a Bruker 400 MHz instrument. Unless otherwise specified, samples were prepared in DMSO-d6 solvent and measured using the parameters in Table 38. Data were analyzed using MestReNova. [Table 38]

[0550] HPLC HPLC analysis was performed using Agilent HPLC 1260 series instruments. The HPLC method for solubility testing is shown in Table 39. [Table 39]

[0551] Additional methods / equipment The following apparatus and methods were also used herein for Examples 11-26 and other examples.

[0552] XRPD patterns were collected using a PANalytical Empyrean diffractometer employing an incident Cu Kα beam generated using a long, high-precision focal source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometric shape. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed location of the Si111 peak coincided with the NIST-certified location. The sample was prepared as a thin, centered circular layer on a silicon-free background substrate. An antiscatter slit (SS) was used to minimize background generated by air. Solar slits were used for the incident and diffracted beams to minimize spreading from axial divergence. Diffraction patterns were collected using a scan-line detector located 240 mm from the sample, a PIXcel1D-Medipix3 PASS (programmable antiscatter slit), and Data Collector software v.7.2b.

[0553] Differential scanning calorimetry (DSC) was performed using a Model Q2000 (TA Instruments, New Castle, DE). Approximately 1–5 mg of material was placed in a Tzero standard aluminum pan with a manually perforated pinhole in the lid. By default, the sample pan and reference pan were heated to 20–300°C under a nitrogen purge of 50 mL / min. DSC was performed at a heating rate of 10°C / min. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0554] Using thermogravimetric analysis (TGA), the weight loss of the sample was evaluated as a function of temperature using either Model Q5000 or Q500 (TA Instruments, New Castle, DE). Approximately 1–5 mg of material was placed on a sample pan, and the sample was heated from ambient temperature to over 300°C at a rate of 10°C / min. The sample pan was purged with nitrogen at a rate of 40 mL / min. Data analysis was completed using Universal Analysis 2000 Version 4.5A (TA Instruments, New Castle, DE).

[0555] The hygroscopic properties were studied using dynamic vapor adsorption (DVS) with a Model Q5000 SA (TA Instruments, New Castle, DE). Samples (1-10 mg) were placed in aluminum pans and positioned on the sample side of a twin-pan balance. Water adsorption and desorption were studied as a function of relative humidity (RH) at 25°C, increasing from 0% RH to 90% RH in 10% RH increments, and then returning to 0%. Each relative humidity increment had an equilibrium time of 120 minutes unless the weight change % was less than 0.002% in 20 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE).

[0556] Proton nuclear magnetic resonance ( 1 ¹H NMR spectra were acquired using a Bruker Avance III-HD 400 with SampleXpress. Default proton parameters were: spectral width: 16.19 to -3.84 ppm (80-12.8 Hz), relaxation delay: 1 second, pulse: 90 degrees, acquisition time: 4.0894 seconds, number of scans or repetitions: 16, temperature: 25°C. Offline analysis was performed using MNova software.

[0557] Example 11: Compound 1, Form III preparation Compound 1 free base form III was obtained by neutralizing a saturated aqueous solution of Compound 1, HCl salt form I (or sulfate form III, prepared as described herein) with sodium bicarbonate to a pH of about 6–7. The precipitate was filtered, washed with water, and then dried in a vacuum oven at about 50°C for about 4 hours.

[0558] Feature evaluation A typical XRPD pattern for compound 1 free base form III is shown in Figure 3, which is characterized by one or more broad peaks selected from 7.6, 10.8, 16.8, 17.5, 21.4, and 22.8, ±0.2°²θ.

[0559] The DSC thermogram of compound 1 free base form III (Figure 4) shows a small endothermic transition starting at approximately 193°C, followed by an exothermic event starting at approximately 204°C due to conversion to free base form II, and then an endothermic event starting at approximately 231°C corresponding to the melting of free base form II. The TGA thermogram shows a weight loss of approximately 1.2% between 25 and 100°C (Figure 5).

[0560] Example 12: Compound 1, sulfate form III preparation A mixture of Compound 1 Form I, 1 equivalent of sulfuric acid, 3.8 mL of acetone, and 0.2 mL of water was stirred in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod at approximately 22°C for approximately 1 day. XRPD analysis of the isolated solid, dried under vacuum at approximately 50°C, showed a novel pattern designated as Compound 1, Sulfate Form III.

[0561] Feature evaluation A typical XRPD pattern for compound 1, sulfate form III, is shown in Figure 6, which is characterized by one or more peaks selected from 19.1, 19.7, 23.4, 24.0, 24.9, 25.7, 26.8, 28.8, and 29.6, ±0.2°²θ.

[0562] The DSC thermograms of compound 1, sulfate form III (Figure 7), show two endothermic events starting at approximately 34°C and 163°C, respectively. The TGA thermogram shows a weight loss of approximately 6.6% between 25 and 150°C (Figure 8). DVS analysis is shown in Figure 9, indicating that this form is hygroscopic with approximately 6% water uptake at 25°C and 0–90% RH.

[0563] Example 13: Compound 1, Esilate Form I preparation A mixture consisting of approximately 250 mg of Compound 1, Form I, 1 equivalent of ethanesulfonic acid, 2.25 mL of acetone, and 0.25 mL of water was stirred at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately 16 hours, the solid was isolated by centrifugation and dried at approximately 50°C. XRPD analysis of the dried solid showed a novel pattern designated as Compound 1, Esilate Form I.

[0564] Feature evaluation A typical XRPD pattern of compound 1, esylate form I, is shown in Figure 10, which is characterized by one or more peaks selected from 6.6, 11.0, 13.2, 15.8, 16.6, 17.5, 21.6, 25.5, and 26.9, ±0.2°²θ.

[0565] The DSC thermograms of compound 1, ethylate form I (Figure 11), show two endothermic events starting at approximately 58°C and 140°C, respectively. The TGA thermogram shows a weight loss of approximately 12.5% ​​between 25 and 100°C (Figure 12).

[0566] Example 14: Compound 1, tosylate form II preparation Approximately 50 mg of Compound 1 free base form I was stirred with 1 equivalent of p-toluenesulfonic acid monohydrate in a mixture of 1.9 mL of acetone and 0.1 mL of water in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. The mixture was heated briefly to approximately 70°C and allowed to cool naturally to approximately 22°C to crystallize. After stirring overnight, the sample was filtered and dried under vacuum at approximately 50°C. XRPD analysis of the solid showed a novel pattern designated as Compound 1 tosylate form II.

[0567] Feature evaluation A representative XRPD pattern of Compound 1, tosylate form II, is shown in Figure 13, which is characterized by one or more peaks selected from 5.0, 9.8, 12.3, 14.9, 16.8, 19.7, 22.1, 24.3, and 29.9, ±0.2°²θ. Example 15: Compound 1, hemiedisylate forms I and II

[0568] preparation A mixture consisting of approximately 250 mg of Compound 1 Form I, 0.5 equivalents of 1,2-ethanedisulfonic acid, 2.25 mL of acetone, and 0.25 mL of water was stirred at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately 16 hours, the solid was isolated by centrifugation and then dried under vacuum at approximately 50°C. XRPD analysis of the wet and dry solids showed different patterns. Proton NMR of the dry solid showed approximately 0.6 equivalents of 1,2-ethanedisulfonic acid. The wet and dry solids were designated as Compound 1, Hemiedisylate Form I, and Form II, respectively.

[0569] Feature evaluation A representative XRPD pattern for compound 1, hemiedisylate form I, is shown in Figure 14, which is characterized by one or more peaks selected from 6.0, 9.3, 12.9, 15.0, 16.3, 18.0, 26.5, 26.9, and 27.7, ±0.2°²θ.

[0570] A representative XRPD pattern for compound 1, hemiedisylate form II, is shown in Figure 15, which is characterized by one or more peaks selected from 8.2, 11.4, 13.4, 16.4, 17.9, 21.2, 25.6, 27.0, and 27.8, ±0.2°²θ.

[0571] The DSC thermogram of compound 1, hemiedisylate form II (Figure 16) shows two endothermic events starting at approximately 96°C and 194°C, respectively. The TGA thermogram of compound 1, hemiedisylate form II shows its weight loss in two steps, with a loss of approximately 1.7% at 25–87°C and a weight loss of approximately 2.8% at 87–120°C (Figure 17). The DVS analysis of compound 1, hemiedisylate form II is shown in Figure 18, indicating that this form is hygroscopic with approximately 3.6% water uptake at 25°C and 0–90% RH.

[0572] Example 16: Compound 1, phosphate form I preparation A solution consisting of approximately 1 g of Compound 1 Form I, 1 equivalent of phosphoric acid (85% aqueous solution), 20 mL of MeCN, and 2 mL of water was stirred at approximately 22°C in a 40 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for 1 hour, a thick, gel-like mixture was formed. The mixture was heated to approximately 50°C, and an additional 1.5 equivalents of phosphoric acid (85% aqueous solution) and 10 mL of MeCN were added. After stirring overnight at approximately 50°C, the sample was filtered, washed with 5 mL of MeCN, and dried in a vacuum oven at approximately 50°C. XRPD analysis of the dried material showed a distinctive pattern, and the material was identified as Compound 1, Phosphate Form I.

[0573] Feature evaluation A representative XRPD pattern for compound 1, phosphate form I, is shown in Figure 19, which is characterized by one or more peaks selected from 4.2, 8.7, 12.8, 15.1, 17.3, 19.8, 21.5, 25.7, and 26.9, ±0.2°²θ.

[0574] The DSC thermograms of compound 1, phosphate form I (Figure 20), show two endothermic events that begin at approximately 28°C and 133°C, respectively.

[0575] Example 17: Compound 1, Phosphate Form II preparation Compound 1, phosphate form II was obtained by stirring Compound 1, phosphate form I in water or a water / EtOH 1:1 mixture at approximately 22°C. After stirring for approximately 1 day, the slurry was filtered, and the solid was dried in a vacuum oven at approximately 50°C. The solid was characterized by XRPD and designated as Compound 1, phosphate form II.

[0576] Feature evaluation A representative XRPD pattern for compound 1, phosphate form II, is shown in Figure 21, which is characterized by one or more peaks selected from 4.7, 5.7, 6.8, 9.4, 11.4, 13.6, 16.0, 17.2, and 20.3, ±0.2°²θ.

[0577] The DSC thermograms of compound 1 and phosphate form II (Figure 22) show two endothermic events that begin at approximately 21°C and 142°C, respectively.

[0578] Example 18: Compound 1, L-tartrate mesophase preparation Compound 1, L-tartrate form I (hydrate) was mixed in organic solvents such as acetonitrile, acetone, acetone, IPA, MEK, MIBK, DCM, THF, MeTHF, ¼, IPAc, MTBE, and toluene. The organic solvents and water were dried in a vacuum oven at approximately 120°C, and then fresh solvent was added and the mixture was stirred at approximately 22°C for 10 days to obtain the compound 1, L-tartrate mesophase.

[0579] Feature evaluation A typical XRPD pattern of compound 1, L-tartrate mesophase, is shown in Figure 23, which is characterized by one or more broad peaks selected from 4.4, 8.8, 13.9, 17.5, 24.1, and 25.4, ±0.2°²θ.

[0580] Example 19: Compound 1, L-tartrate F salt form II preparation Compound 1, L-tartrate form II was obtained by stirring Compound 1, L-tartrate form I in water at approximately 22°C. After stirring for two days, the slurry was filtered, and the solid was dried in a vacuum oven at 50°C. The solid was characterized by XRPD and designated as Compound 1, L-tartrate form II. Proton NMR showed approximately 0.94 equivalents of L-tartaric acid.

[0581] Feature evaluation A representative XRPD pattern for compound 1, L-tartrate form II, is shown in Figure 24, which is characterized by one or more peaks selected from 9.4, 12.2, 15.7, 18.4, 20.4, 21.2, 24.7, 27.7, and 32.1, ±0.2°²θ.

[0582] The DSC thermogram of compound 1, L-tartrate form II (Figure 25) shows three major endothermic events starting at approximately 49, 91, and 119°C, respectively. The TGA thermogram shows weight loss in two steps, approximately 8% at 25–70°C and approximately 1.6% at 70–100°C, respectively (Figure 26). DVS analysis is shown in Figure 27, indicating that this form is hygroscopic with approximately 10.2% water uptake at 25°C and 0–90% RH.

[0583] Example 20: Compound 1, L-tartrate form III preparation Compound 1, L-tartrate Form III was obtained by drying Compound 1, L-tartrate methanol solvate or ethanol solvate, each prepared as described herein, under vacuum at approximately 50°C.

[0584] Feature evaluation A representative XRPD pattern for compound 1, L-tartrate form III, is shown in Figure 28, which is characterized by one or more peaks selected from 4.7, 9.4, 14.3, 16.8, 17.4, 18.9, 21.1, 24.0, and 33.8, ±0.2°²θ.

[0585] The DSC thermogram of compound 1, L-tartrate form III (Figure 29), shows the initiation of melting at approximately 174°C. The TGA thermogram shows a weight loss of approximately 2% between 25 and 70°C (Figure 30).

[0586] Example 21: Compound 1, L-tartrate form IV Preparation: 6 g of compound form 1 I (approximately 99% by weight purity) was dissolved at approximately 32°C in a mixture of approximately 96 g of DCM and approximately 20 g of MeOH. The solution was filtered by polishing, and the container was then rinsed forward with a mixture of approximately 20 g of DCM and approximately 3.6 g of MeOH. To the filtrate, a solution containing approximately 2.28 g of L-tartaric acid, dissolved in approximately 6 mL of water at approximately 22°C, was added. After stirring for approximately 1 day, a solid slurry was formed. The slurry was distilled under vacuum at approximately 40°C to approximately 3 V (approximately 20 mL), and then cooled to approximately 22°C. Approximately 87 g of acetone was added, and the mixture was held at approximately 22°C for approximately 1 hour, and then cooled to approximately 0°C. After holding for approximately 4 hours, the slurry was filtered and rinsed twice with approximately 24 g of pre-cooled acetone. The moist cake was dried at 50°C for approximately 4 days under nitrogen sweep and full house vacuum to obtain approximately 7.36 g of L-tartrate form IV (containing a small amount of L-tartrate form I). NMR showed that the tartaric acid content was approximately 1.02 equivalents. Upon exposure to air at approximately 38% RH and 22°C, a small sample of compound 1, L-tartrate form IV was completely converted to compound 1, L-tartrate form III in less than 20 minutes.

[0587] Feature evaluation A representative XRPD pattern of compound 1, L-tartrate form IV (containing a small amount of L-tartrate form I, indicated by small peaks at 7.4, 10.6, and 15.0°±0.2°2θ) is shown in Figure 31, which is characterized by one or more peaks selected from 6.5, 7.9, 11.1, 12.9, 15.8, 16.6, 20.4, 22.3, and 28.4°±0.2°2θ. The XRPD was obtained using a Kapton disk covering the sample to prevent exposure to moisture in the air.

[0588] The DSC thermogram (Figure 32) shows two major endothermic events starting at approximately 79°C and 127°C, respectively. The TGA thermogram shows a weight loss of approximately 5% between 25 and 125°C (Figure 33).

[0589] Example 22: Compound 1, L-tartrate methanol solvate preparation A mixture consisting of approximately 200 mg of compound 1 form I, 1 equivalent of L-tartaric acid, and 4 mL of methanol was stirred at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately 4 days, the mixture remained in free base form I. After stirring for a further 3 days, an additional 1 equivalent of L-tartaric acid was added. After stirring overnight, XRPD analysis showed that the solid had been converted to the methanol solvate of compound 1, L-tartrate.

[0590] Feature evaluation A typical XRPD pattern of compound 1, L-tartrate methanol solvate, is shown in Figure 34, which is characterized by one or more peaks selected from 4.6, 8.7, 9.4, 14.2, 16.7, 17.4, 18.9, 21.0, and 24.1, ±0.2°²θ.

[0591] Example 23: Compound 1, L-tartrate ethanol solvate preparation A mixture consisting of approximately 200 mg of compound 1 form I, 1 equivalent of L-tartaric acid, and 4 mL of ethanol was stirred at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately one week, some free base form I remained. After adding 0.2 equivalents of L-tartaric acid and stirring for a further approximately two weeks, XRPD analysis of the wet solid showed that it had been converted to the ethanol solvate of compound 1, L-tartrate.

[0592] Feature evaluation A typical XRPD pattern of compound 1, L-tartrate ethanol solvate, is shown in Figure 35, which is characterized by one or more peaks selected from 4.4, 8.7, 13.8, 17.3, 18.0, 19.4, 21.7, 24.6, and 26.0, ±0.2°²θ.

[0593] Example 24: Compound 1, L-malate form II preparation A mixture consisting of approximately 100 mg of Compound 1 form I, 1 equivalent of L-malic acid, 1.9 mL of acetone, and 0.1 mL of water was briefly heated to approximately 70°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod, and then cooled to approximately 22°C. After stirring for approximately 1 day, the solid remained as Compound 1 free base form I. Further water (0.1 mL) was added. After stirring for a further approximately 3 days, the sample remained as free base form I. After stirring for approximately 4 weeks, the sample was dried in a vacuum oven at approximately 50°C, and then approximately 2 mL of acetone was added. After stirring overnight at approximately 22°C, it became a mixture of Compound 1 free base form I and Compound 1 L-malate form II.

[0594] A sample of compound 1 in L-malate form II was obtained as follows: A mixture consisting of approximately 250 mg of compound 1 in form I, 1.1 equivalents of L-malic acid, 2.5 mL of acetone, and a small amount of compound 1 L-malate form II seed (a mixture with free base form I) from the above experiment was stirred at approximately 50°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately 1 day, it became a mixture of compound 1 free base form I and L-malate form II. The sample was diluted with 2.5 mL of acetone and stirred overnight, but no change was observed by XRPD. 0.25 mL of water was added to the sample and stirred at approximately 50°C for approximately 3 days, after which the solid returned to compound 1 free base form I. The sample was cooled to approximately 22°C and seed crystals were added again. After stirring for approximately 1 week, it became a mixture of free base form I and L-malate form II. After adding 1.1 equivalents of L-malate to the sample and stirring for approximately 2 days, the sample was isolated by centrifugation. XRPD analysis of the wet solid showed the disappearance of the free base form I peak. Proton NMR showed approximately 1.2 equivalents of L-malate in the dry solid.

[0595] Feature evaluation A representative XRPD pattern of compound 1L-malate form II is shown in Figure 36, which is characterized by one or more peaks selected from 14.7, 15.6, 16.3, 19.7, 21.5, 23.8, 24.8, 26.6, and 27.7, ±0.2°²θ.

[0596] The DSC thermogram of compound 1L-malate form II (Figure 37) shows the initiation of melting at approximately 165°C. The TGA thermogram shows a weight loss of approximately 1.8% between 25 and 100°C (Figure 38). DVS analysis is shown in Figure 39, indicating that this form is hygroscopic, with approximately 4.6% water uptake at 25°C and 0-90% RH.

[0597] Example 25: Compound 1, L-malate form III preparation A mixture consisting of approximately 200 mg of Compound 1 Form I, 2 equivalents of L-malic acid, and 2.5 mL of acetone was stirred at approximately 22°C in a 4 mL vial equipped with a Teflon®-coated magnetic stirring rod. After stirring for approximately 4 days, the sample was isolated by centrifugation and then dried in a vacuum oven at approximately 50°C. XRPD analysis of the solid showed a distinctive pattern, which was designated as Compound 1 L-malate Form III. Proton NMR showed approximately 1.6 equivalents of L-malic acid in the dried solid.

[0598] Feature evaluation A representative XRPD pattern of compound 1L-malate form III is shown in Figure 40, which is characterized by one or more peaks selected from 8.8, 14.3, 17.1, 17.9, 20.1, 24.2, 26.3, 28.9, and 34.3, ±0.2°²θ.

[0599] The DSC thermogram of compound 1L-malate form III (Figure 41) shows two endothermic events starting at approximately 120°C and 153°C, respectively. The TGA thermogram shows a weight loss of approximately 0.7% between 25 and 50°C (Figure 42).

[0600] Example 26: Compound 1, sulfate form II preparation Approximately 100 mg of Compound 1, free base form I, was mixed with 22.3 mg (approximately 1 equivalent) of sulfuric acid. The mixture was stirred in 4 mL of EtOH for approximately 20 hours at approximately 22°C to form a paste. Approximately 0.2 mL of water was added to the paste, which almost dissolved, and then crystallized in 1 hour. The slurry was isolated by filtration, and the solid was dried under vacuum in a vacuum oven at approximately 50°C. The dried solid was designated Compound 1, sulfate form II.

[0601] Feature evaluation A representative XRPD pattern for compound 1, sulfate form II, is shown in Figure 53A, which is characterized by peaks at (1) 6.2, 18.5, and 24.7 ± 0.2°²θ, and one or more peaks selected from 10.4, 12.0, 16.0, 21.8, and 31.1 ± 0.2°²θ. The DSC thermogram (Figure 53B) shows endothermic reaction starting at approximately 223°C, followed by exothermic reaction, possibly related to decomposition. The TGA thermogram (Figure 53C) shows a weight loss of approximately 1.5% between 25 and 150°C.

Claims

1. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 16】 Or the crystalline form of the pharmaceutically acceptable salt or solvate thereof.

2. Free base 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): 【Chemistry 17】 Or the crystalline form of the pharmaceutically acceptable solvate thereof.

3. The crystalline form according to claim 2, wherein the solvate is a hydrate.

4. Anhydrous free base 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (compound 1): [Chemistry 18] The crystalline form.

5. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 19】 The maleate of or a pharmaceutically acceptable solvate thereof in crystalline form.

6. The crystalline form according to claim 5, wherein the solvate is a hydrate.

7. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 20】 The crystalline form of maleate anhydride.

8. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 21】 The tartrate salt of or a pharmaceutically acceptable solvate thereof in crystalline form.

9. The crystalline form according to claim 8, wherein the solvate is a hydrate.

10. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 22】 The crystalline form of anhydrous tartrate.

11. The crystal form according to any one of claims 1 to 9, wherein the crystal form is selected from the group consisting of free base form I of compound 1, free base form II of compound 1, maleate form IV of compound 1, and tartrate form I of compound 1, or any combination thereof.

12. Crystalline compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 20.50 ± 0.1° 2θ, (c) Endothermic DSC thermogram with a peak temperature at approximately 228°C (start), (d) DSC thermogram exhibiting exothermic properties with a peak temperature of approximately 231°C (start), (e) An endothermic DSC thermogram with a peak temperature of approximately 238°C (start), or (f) The crystal form according to claim 1 or 2, characterized by having at least one of the combinations thereof.

13. The crystalline form according to claim 1 or 2, wherein the crystalline compound 1 is a free base form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.4, 12.6, and 20.7°²θ as determined by a Cu-Kα diffractometer.

14. (a) One or more additional peaks (±0.2°) at 17.7, 23.7, or 27.5°²θ, (b) One or more additional peaks (±0.2°) at 21.4, 24.6, or 28.7°²θ, (c) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 1B, (c) DSC thermogram including endothermic start at approximately 223°C, exothermic start at approximately 227°C, and endothermic start at approximately 237°C. (d) A DSC thermogram substantially the same as the one shown in Figure 1C, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.1% at approximately 25 to 157°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 1D, or (g) The crystalline form according to claim 13, further characterized by a combination thereof.

15. The crystalline free base compound 1 has the following properties: (a) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 2A, (b) X-ray powder diffraction (XRPD) pattern with a characteristic peak at 13.39 ± 0.1° 2θ, (c) An endothermic DSC thermogram with a peak temperature at approximately 235°C (start), or (d) The crystal form according to claim 1 or 2, which is form II characterized by having at least one of the combinations thereof.

16. The crystalline form according to claim 1 or 2, wherein the crystalline compound 1 is a free base form III characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.8, 21.4, and 26.2°2θ as determined by a Cu-Kα diffractometer.

17. (a) One or more additional peaks (±0.2°) at 7.6, 17.5, or 22.8°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 3, (c) DSC thermogram including endothermic start at approximately 193°C, exothermic start at approximately 204°C, and endothermic start at approximately 231°C. (d) A DSC thermogram that is substantially the same as the one shown in Figure 4, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.2% at approximately 25 to 100°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 5, or (g) The crystalline form according to claim 16, further characterized by a combination thereof.

18. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 23】 The crystalline form of the sulfate, or a pharmaceutically acceptable solvate thereof.

19. The crystalline form according to claim 18, wherein the crystalline compound 1 is sulfate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 23.4, 24.0, and 28.8°²θ as determined by a Cu-Kα diffractometer.

20. (a) One or more additional peaks (±0.2°) at 19.1, 19.7, or 24.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 6, (c) DSC thermograms including the start of endothermic heating at approximately 34°C and the start of endothermic heating at approximately 163°C. (d) A DSC thermogram substantially the same as that shown in Figure 7, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.6% at approximately 25 to 150°C. (f) Thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 8, (g) Dynamic vapor adsorption (DVS) curve showing approximately 6% water uptake at 25°C and 0-90% relative humidity (RH). (h) The dynamic vapor adsorption (DVS) curve substantially shown in Figure 9, or (i) The crystalline form according to claim 19, further characterized by a combination thereof.

21. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 24】 The crystalline form of the esylate salt, or a pharmaceutically acceptable solvate thereof.

22. The crystalline form according to claim 21, wherein the crystalline compound 1 is an esylate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.5, 25.5, and 26.9°²θ as determined by a Cu-Kα diffractometer.

23. (a) One or more additional peaks (±0.2°) at 13.2, 15.8, or 21.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 10, (c) DSC thermograms including the start of endothermic reaction at approximately 58°C and the start of endothermic reaction at approximately 140°C. (d) A DSC thermogram substantially the same as the one shown in Figure 11, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 12.5% ​​at approximately 25 to 100°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 12, or (g) The crystalline form according to claim 22, further characterized by a combination thereof.

24. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 25】 The crystalline form of the tosylate salt of or a pharmaceutically acceptable solvate thereof.

25. The crystalline form according to claim 24, wherein the crystalline compound 1 is a tosylate form II characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.3, 14.9, and 19.7°²θ as determined by a Cu-Kα diffractometer.

26. (a) One or more additional peaks (±0.2°) at 16.8, 22.1, or 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 13, or (c) The crystalline form according to claim 25, further characterized by a combination thereof.

27. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 26】 The hemiedisylate salt, or a pharmaceutically acceptable solvate thereof, in crystalline form.

28. The crystalline form according to claim 27, wherein the crystalline compound 1 is a hemiedisylate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.9, 26.5, and 27.7°²θ as determined by a Cu-Kα diffractometer.

29. (a) One or more additional peaks (±0.2°) at 16.3, 18.0, or 26.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 14, or (c) The crystalline form according to claim 28, further characterized by a combination thereof.

30. The crystalline form according to claim 27, wherein the crystalline compound 1 is a hemiedisylate form II characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.4, 21.2, and 27.8°2θ as determined by a Cu-Kα diffractometer.

31. (a) One or more additional peaks (±0.2°) at 11.4, 17.9, or 25.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 15, (c) DSC thermograms including the start of endothermic heating at approximately 96°C and the start of endothermic heating at approximately 194°C. (b) A DSC thermogram substantially the same as that shown in Figure 16, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.7% at approximately 25–87°C and approximately 2.8% at approximately 87–120°C. (f) Thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 17, (g) Dynamic vapor adsorption (DVS) curve showing approximately 3.6% water uptake at 25°C and 0-90% RH. (h) Dynamic vapor adsorption (DVS) curve substantially shown in Figure 18, or (i) The crystalline form according to claim 30, further characterized by a combination thereof.

32. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 27】 The phosphate of or a pharmaceutically acceptable solvate thereof in crystalline form.

33. The crystalline form according to claim 32, wherein the crystalline compound 1 is a phosphate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 12.8, 25.7, and 26.9°²θ as determined by a Cu-Kα diffractometer.

34. (a) One or more additional peaks (±0.2°) at 15.1, 17.3, or 21.5°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 19, (c) DSC thermograms including the start of endothermic heating at approximately 28°C and the start of endothermic heating at approximately 133°C. (d) A DSC thermogram substantially the same as that shown in Figure 20, or (e) The crystalline form according to claim 33, further characterized by a combination thereof.

35. The crystalline form according to claim 32, wherein the crystalline compound 1 is a phosphate form II characterized by an X-ray power diffractogram containing peaks (±0.2°) at 4.7, 16.0, and 17.2°²θ as determined by a Cu-Kα diffractometer.

36. (a) One or more additional peaks (±0.2°) at 5.7, 6.8, or 9.4°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 21, (c) DSC thermograms including the start of endothermic heating at approximately 21°C and the start of endothermic heating at approximately 142°C. (d) A DSC thermogram substantially the same as that shown in Figure 22, or (e) The crystalline form according to claim 35, further characterized by a combination thereof.

37. The crystalline form according to claim 8, wherein the crystalline compound 1 is an L-tartrate mesophase characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.5, 24.1, and 25.4°2θ as determined by a Cu-Kα diffractometer.

38. (a) One or more additional peaks (±0.2°) at 4.4, 8.8, or 13.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 23, or (c) The crystalline form according to claim 37, further characterized by a combination thereof.

39. The crystalline form according to claim 8, wherein the crystalline compound 1 is L-tartrate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.5, 14.9, and 15.8°²θ as determined by a Cu-Kα diffractometer.

40. (a) One or more additional peaks (±0.2°) at 21.3, 22.5, or 23.0°²θ, (b) One or more additional peaks (±0.2°) at 6.3, 24.1, or 28.2°²θ, (c) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 43A, (d) DSC thermogram including the start of endothermic heating at approximately 113°C. (e) A DSC thermogram substantially the same as that shown in Figure 44, (f) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.1% at approximately 25 to 130°C. (g) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 45, (h) Dynamic vapor adsorption (DVS) curve showing approximately 1.1% water uptake at 25°C and 0-90% relative humidity (RH). (i) The dynamic vapor adsorption (DVS) curve substantially shown in Figure 46, or (j) The crystalline form according to claim 39, further characterized by a combination thereof.

41. The crystalline form according to claim 8, wherein the crystalline compound 1 is L-tartrate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.4, 15.7, and 18.4°²θ as determined by a Cu-Kα diffractometer.

42. (a) One or more additional peaks (±0.2°) at 9.1, 20.4, or 32.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 24, (c) DSC thermograms including the start of endothermic reaction at approximately 49°C, the start of endothermic reaction at approximately 91°C, and the start of endothermic reaction at approximately 119°C. (d) A DSC thermogram substantially the same as the one shown in Figure 25, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 8% at approximately 25-70°C and approximately 1.6% at approximately 70-100°C. (f) Thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 26, (g) Dynamic vapor adsorption (DVS) curve showing approximately 10.2% water uptake at 25°C and 0-90% RH. (h) The dynamic vapor adsorption (DVS) curve substantially shown in Figure 27, or (i) The crystalline form according to claim 41, further characterized by a combination thereof.

43. The crystalline form according to claim 8, wherein the crystalline compound 1 is an L-tartrate form III characterized by an X-ray power diffractogram containing peaks (±0.2°) at 4.7, 9.4, and 14.3°²θ as determined by a Cu-Kα diffractometer.

44. (a) One or more additional peaks (±0.2°) at 16.8, 17.4, or 18.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 28, (c) DSC thermogram including the start of endothermic heating at approximately 174°C. (d) A DSC thermogram substantially the same as the one shown in Figure 29, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2% at approximately 25-70°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 30, or (g) The crystalline form according to claim 43, further characterized by a combination thereof.

45. The crystalline form according to claim 8, wherein the crystalline compound 1 is L-tartrate form IV, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 15.8, 16.6, and 22.3°²θ as determined by a Cu-Kα diffractometer.

46. (a) One or more additional peaks (±0.2°) at 6.5, 12.9, or 20.4°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 31, (c) DSC thermograms including the start of endothermic heating at approximately 79°C and the start of endothermic heating at approximately 127°C. (d) A DSC thermogram substantially the same as that shown in Figure 32, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5% at approximately 25 to 125°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 33, or (g) The crystalline form according to claim 45, further characterized by a combination thereof.

47. The crystalline form according to claim 8, wherein the crystalline compound 1 is an L-tartrate methanol solvate characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.7, 16.7, and 17.4°²θ as determined by a Cu-Kα diffractometer.

48. (a) One or more additional peaks (±0.2°) at 9.4, 18.9, or 21.0°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 34, or (c) The crystalline form according to claim 47, further characterized by a combination thereof.

49. The crystalline form according to claim 8, wherein the crystalline compound 1 is an L-tartrate ethanol solvate characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.7, 17.3, and 19.4°²θ as determined by a Cu-Kα diffractometer.

50. (a) One or more additional peaks (±0.2°) at 4.4, 21.7, or 24.6°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 35, or (c) The crystalline form according to claim 49, further characterized by a combination thereof.

51. 5-(((2R,3S)-1-((7-chloro-6-oxo-5,6-dihydro-1,5-naphthyridine-3-yl)methyl)-2-methylazetidine-3-yl)oxy)-N-cyclopropylpicolinamide (Compound 1): 【Chemistry 28】 The crystalline form of the L-malate salt, or a pharmaceutically acceptable solvate thereof.

52. The crystalline form according to claim 51, wherein the crystalline compound 1 is L-malate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 16.3, 21.5, and 24.8°²θ as determined by a Cu-Kα diffractometer.

53. (a) One or more additional peaks (±0.2°) at 14.7, 23.8, and 27.7°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 36, (c) DSC thermogram including the start of endothermic heating at approximately 165°C. (d) A DSC thermogram substantially the same as that shown in Figure 37, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.8% at approximately 25 to 100°C. (f) Thermogravimetric analysis (TGA) including the thermogram substantially shown in Figure 38, (g) Dynamic vapor adsorption (DVS) curve showing approximately 4.6% water uptake at 25°C and 0-90% RH. (h) The dynamic vapor adsorption (DVS) curve substantially shown in Figure 39, or (i) The crystalline form according to claim 52, further characterized by a combination thereof.

54. The crystalline form according to claim 51, wherein the crystalline compound 1 is L-malate form III, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 17.1, 17.9, and 26.3°²θ as determined by a Cu-Kα diffractometer.

55. (a) One or more additional peaks (±0.2°) at 8.8, 24.2, or 28.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 40, (c) DSC thermograms including the start of endothermic reaction at approximately 120°C and the start of endothermic reaction at approximately 153°C. (d) A DSC thermogram substantially the same as the one shown in Figure 41, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 0.7% at approximately 25-50°C. (f) Thermogravimetric analysis (TGA) including a thermogram substantially shown in Figure 42, or (g) The crystalline form according to claim 54, further characterized by a combination thereof.

56. Crystalline compound 1 has the following properties: (a) X-ray powder diffraction (XRPD) pattern with characteristic peaks at 3.93±0.1°²θ, 19.60±0.1°²θ, and 22.55±0.1°²θ. (b) An endothermic DSC thermogram with a peak temperature at approximately 183°C (start), or (c) The crystalline form according to claim 5, which is a maleate form IV characterized by having at least one of the combinations thereof.

57. The crystalline form according to claim 1, wherein the crystalline compound 1 is an HCl salt form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.2, 12.2, and 14.3°²θ as determined by a Cu-Kα diffractometer.

58. (a) One or more additional peaks (±0.2°) at 15.3, 25.2, 27.1, 27.7, 28.0, and 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 50A, (c) DSC thermogram including the start of endothermic heating at approximately 216°C. (d) A DSC thermogram substantially the same as the one shown in Figure 50B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.2% at approximately 25-200°C. (f) A TGA including a thermogram substantially shown in Figure 50B, or (g) The crystalline form according to claim 57, further characterized by a combination thereof.

59. The crystalline form according to claim 1, wherein the crystalline compound 1 is an HCl salt form II characterized by an X-ray power diffractogram containing peaks (±0.2°) at 5.0, 9.9, and 17.6°²θ as determined by a Cu-Kα diffractometer.

60. (a) One or more additional peaks at 9.0, 12.7, 18.8, 24.9, 25.4, 26.5, and 27.0°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 51A, (c) DSC thermograms including the start of endothermic heating at approximately 115°C and the start of endothermic heating at approximately 147°C. (d) A DSC thermogram substantially the same as that shown in Figure 51B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.8% at approximately 25 to 165°C. (f) A TGA including a thermogram substantially shown in Figure 51B, or (g) The crystalline form according to claim 59, further characterized by a combination thereof.

61. The crystalline form according to claim 18, wherein the crystalline compound 1 is a sulfate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 7.3, 17.4, and 18.9°²θ as determined by a Cu-Kα diffractometer.

62. (a) One or more additional peaks at 4.8, 10.1, 16.7, 19.2, 25.2, and 25.9°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 52A, (c) DSC thermograms including the start of endothermic reaction at approximately 52°C, the start of endothermic reaction at approximately 99°C, and the start of endothermic reaction at approximately 152°C. (d) A DSC thermogram substantially the same as that shown in Figure 52B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 5.3% at approximately 25 to 170°C. (f) A TGA including a thermogram substantially shown in Figure 52B, or (g) The crystalline form according to claim 61, further characterized by a combination thereof.

63. The crystalline form according to claim 18, wherein the crystalline compound 1 is sulfate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 6.2, 18.5, and 24.7°²θ as determined by a Cu-Kα diffractometer.

64. (a) One or more additional peaks (±0.2°) at 10.4, 12.0, 16.0, 21.8, and 31.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 53A, (c) DSC thermogram including the start of endothermic heating at approximately 223°C. (d) A DSC thermogram substantially the same as that shown in Figure 53B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.5% at approximately 25 to 150°C. (f) A TGA including a thermogram substantially shown in Figure 53C, or (g) The crystalline form according to claim 63, further characterized by a combination thereof.

65. The crystalline form according to claim 1, wherein the crystalline compound 1 is a maleate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 3.9, 19.6, and 20.9°²θ as determined by a Cu-Kα diffractometer.

66. (a) One or more additional peaks (±0.2°) at 15.6, 17.4, 20.7, 24.6, 28.3, and 29.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 54A, (c) DSC thermogram including the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially the same as the one shown in Figure 54B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 1.0% at approximately 25-70°C and approximately 3.7% at approximately 150-200°C. (f) A TGA including a thermogram substantially shown in Figure 54B, or (g) The crystalline form according to claim 65, further characterized by a combination thereof.

67. The crystalline form according to claim 1, wherein the crystalline compound 1 is maleate form II, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 3.6, 18.1, and 22.9°²θ as determined by a Cu-Kα diffractometer.

68. (a) One or more additional peaks (±0.2°) at 7.2, 9.7, 10.8, 16.0, and 18.9°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 55A, (c) DSC thermograms including the start of endothermic heating at approximately 131°C and the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially the same as the one shown in Figure 55B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 3.3% at approximately 120-160°C and approximately 5.4% at approximately 160-210°C. (f) A TGA including a thermogram substantially shown in Figure 55B, or (g) The crystalline form according to claim 67, further characterized by a combination thereof.

69. The crystalline form according to claim 1, wherein the crystalline compound 1 is a maleate form III characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.0, 17.9, and 25.3°²θ as determined by a Cu-Kα diffractometer.

70. (a) One or more additional peaks (±0.2°) at 12.1, 15.2, 19.0, 19.6, 24.7, and 28.1°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 56C, or (c) The crystalline form according to claim 69, further characterized by a combination thereof.

71. The crystalline form according to claim 1, wherein the crystalline compound 1 is a citrate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 9.9, 15.5, and 16.3°²θ as determined by a Cu-Kα diffractometer.

72. (a) One or more additional peaks (±0.2°) at 12.8, 17.1, 19.2, 19.8, 23.6, and 24.5°²θ, (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 57A, (c) DSC thermograms including the start of endothermic heating at approximately 27°C and the start of endothermic heating at approximately 177°C. (d) A DSC thermogram substantially the same as the one shown in Figure 57B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.3% at approximately 25-100°C and approximately 12% at approximately 150-210°C. (f) A TGA including a thermogram substantially shown in Figure 57B, or (g) The crystalline form according to claim 71, further characterized by a combination thereof.

73. The crystalline form according to claim 1, wherein the crystalline compound 1 is L-malate form I, characterized by an X-ray power diffractogram containing peaks (±0.2°) at 8.9, 11.9, and 17.8°²θ as determined by a Cu-Kα diffractometer.

74. (a) One or more additional peaks at 9.8, 12.6, 15.0, 18.8, 19.4, and 25.1°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 58A, (c) DSC thermograms including the start of endothermic reaction at approximately 29°C, the start of endothermic reaction at approximately 161°C, and the start of endothermic reaction at approximately 180°C. (d) A DSC thermogram substantially the same as that shown in Figure 58B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.9% at approximately 25–110°C and approximately 1.5% at approximately 150–210°C. (f) A TGA including a thermogram substantially shown in Figure 58B, or (g) The crystalline form according to claim 73, further characterized by a combination thereof.

75. The crystalline form according to claim 1, wherein the crystalline compound 1 is a mesylate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 6.5, 15.2, and 25.3°²θ as determined by a Cu-Kα diffractometer.

76. (a) One or more additional peaks at 10.0, 16.6, 17.5, 18.5, 19.7, and 26.2°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 59A, (c) DSC thermograms including the start of endothermic heating at approximately 37°C and the start of endothermic heating at approximately 148°C. (d) A DSC thermogram substantially the same as that shown in Figure 59B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 6.1% at approximately 25 to 100°C. (f) A TGA including a thermogram substantially shown in Figure 59B, or (g) The crystalline form according to claim 75, further characterized by a combination thereof.

77. The crystalline form according to claim 1, wherein the crystalline compound 1 is a mesylate form II characterized by an X-ray power diffractogram containing peaks (±0.2°) at 10.7, 13.0, and 17.1°²θ as determined by a Cu-Kα diffractometer.

78. (a) One or more additional peaks at 6.5, 8.5, 15.4, 19.7, 21.9, and 25.3°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 60A, (c) DSC thermograms including the start of endothermic heating at approximately 37°C and the start of endothermic heating at approximately 149°C. (d) A DSC thermogram substantially the same as that shown in Figure 60B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 4.7% at approximately 25-120°C and approximately 0.7% at approximately 120-170°C. (f) A TGA including a thermogram substantially shown in Figure 60B, or (g) The crystalline form according to claim 77, further characterized by a combination thereof.

79. The crystalline form according to claim 1, wherein the crystalline compound 1 is a tosylate form I characterized by an X-ray power diffractogram containing peaks (±0.2°) at 24.0, 24.6, and 25.6°²θ, as determined by a diffractometer using Cu-Kα rays.

80. (a) One or more additional peaks at 5.2, 8.0, 17.7, 11.8, 23.7, and 27.9°²θ (±0.2°), (b) A substantially the same X-ray powder diffraction (XRPD) pattern as shown in Figure 61A, (c) DSC thermograms including the start of endothermic heating at approximately 82°C and the start of endothermic heating at approximately 142°C. (d) A DSC thermogram substantially the same as the one shown in Figure 61B, (e) Thermogravimetric analysis (TGA) showing a weight loss of approximately 2.6% at approximately 25 to 170°C. (f) A TGA including a thermogram substantially shown in Figure 61B, or (g) The crystalline form according to claim 79, further characterized by a combination thereof.

81. The crystalline forms are: free base form I of compound 1, free base form II of compound 1, free base form III of compound 1, maleate form IV of compound 1, tartrate form I of compound 1, sulfate form III of compound 1, esylate form I of compound 1, tosylate form II of compound 1, hemyedisylate form I of compound 1, hemyedisylate form II of compound 1, phosphate form I of compound 1, phosphate form II of compound 1, L-tartrate mesophase of compound 1, L-tartrate form II of compound 1, L-tartrate form III of compound 1, L-tartrate form IV of compound 1, L-tartrate methanol solvate of compound 1, The crystalline form according to claim 1, selected from the group consisting of L-tartrate ethanol solvate of compound 1, L-malate form II of compound 1, L-malate form III of compound 1, HCl salt form I of compound 1, HCl salt form II of compound 1, sulfate form I of compound 1, sulfate form II of compound 1, maleate form I of compound 1, maleate form II of compound 1, maleate form III of compound 1, citrate form I of compound 1, L-malate form I of compound 1, mesylate form I of compound 1, mesylate form II of compound 1, and tosylate form I of compound 1, or any combination thereof.

82. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 81 and a pharmaceutically acceptable excipient.

83. A method for treating cancer in a person requiring cancer treatment, wherein the method includes administering a crystalline form described in any one of claims 1 to 81.

84. The method according to claim 83, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer.

85. A method for treating cancer in a subject requiring treatment for cancer comprising a BRCA1 and / or BRCA2 mutation, wherein the method comprises administering a crystalline form according to any one of claims 1 to 81.

86. The method according to claim 85, wherein the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

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