Crystal forms of a PARP1 inhibitor and preparation thereof

Abstract

The present disclosure provides crystal forms of PARP1 inhibitor 5-(4-((9-fluoro-4-oxo- 4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-l-yl)-N,6-dimethylpicolinamide and preparation method thereof. The crystal forms are applicable for the treatment or prevention of diseases or conditions such as cancer that respond to PARP1 activity inhibition.

Description

[0001] CRYSTAL FORMS OF A PARP1 INHIBITOR AND PREPARATION THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Chinese Provisional Application No.202410573249.5, entitled “Crystal Forms of a PARP1 Inhibitor and Preparation Thereof,” filed May 9, 2024, the entirety of which is hereby incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to crystal forms of PARP1 inhibitor 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N,6- dimethylpicolinamide and preparation thereof. BACKGROUND OF THE INVENTION

[0003] Poly(ADP-ribose) polymerase (PARP1) catalyzes the addition of poly(ADP-ribose)to the target protein molecule using NAD+, which is an important process in DNA repair. This is an essential process for maintaining DNA and chromosome integrity and stability, and for ensuring the survival of mammalian cells. PARP1 catalyzes most of the intracellular ADP-ribose polymerization reactions, although PARP2 and other subtypes also have this function. PARP1 knockout mice do not have the repair function for single-stranded DNA damage (Krishnakumar R and Kraus WL, Mol Cell, 2010, 39(1): 8-24). At the same time, cancer cells with DNA repair defects, such as BRCA1 (breast cancer 1) or BRCA2 (breast cancer 2) deficiency, are particularly sensitive to PARP1 inhibitors.

[0004] The catalytic domain of PARP2 is very similar to that of PARP1. PARP2 is alsofound to have similar functions to PARP1 and is involved in the repair of DNA damage through the base excision repair (BER) mechanism (Schreiber et al., 2002 J Biol Chem 277: 23028-23036). Marketed PARP1 inhibitors, such as olaparib, niraparib, talazoparib and rucaparib, not only have inhibitory activities against PARP1, but also have similar inhibitory activities against PARP2. Based on the results of clinical trials, the therapeutic effects of these marketed PARP1 inhibitors are comparable whereas their toxicity profiles are quite different. For example, talazoparib has toxicity similar to chemotherapy drugs such as hair loss. Talazoparib also shows more potent inhibitory activity against TNKS1 / 2 (tankyrase 1 or tankyrase 2) than other PARP1 inhibitors (PARP1i) in biochemical assays (Ryan et al., 2021 J Biol Chem 296: 100251 / 1-100251 / 13). TNKS1 and TNKS2 share 83% sequence identity overall, and their catalytic domain sequences are 89% identical. They play roles in DNA repair, telomere maintenance, and Wnt / β-catenin signaling. Targeting PARP1s other than PARP1 may be the reason why PARP1 inhibitors cause off-targeted toxicity, such as hair loss and diarrhea. In addition, inhibition of PARP2 activity has been found to lead to hematotoxicity (Farrés et al., 2013 Blood 122: 44-54; Farrés et al., 2015 Cell Death and Differentiation 22: 1144-1157). The toxicity of these PARP1 inhibitors limits their clinical application as well as their combination with other targeted drugs.

[0005] Therefore, the development of highly selective PARP1 inhibitors may reduce bothmechanism-related and non-mechanism-related toxicities. Currently, several PARP1 selective inhibitors are in clinical development.

[0006] WO2023025307 discloses the following compound of Formula I (also referred toherein as “the compound of Formula (I)”), 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5- a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide, as a PARP1 selective inhibitor and its preparation method, the contents of which are incorporated herein by reference.

[0007] Certain crystal have beneficialproperties, for example, solubility, stability, bioavailability, impurity profile, filtration properties, drying properties, and lack of hygroscopicity, and may be easier to handle, micronize and tablet. In addition, there remains a need for alternative or improved methods of synthetic preparation, especially for large-scale, environmentally friendly production. SUMMARY OF THE INVENTION

[0008] The present disclosure provides crystal forms of 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (Formula I), including the crystal forms A and B.

[0009] In a first aspect, the present disclosure provides a crystal form of a compound ofFormula (I), I).

[0010] In som cterized by an X-ray powderdiffraction (XRPD) spectrum that exhibits peaks at least four of the following positions: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, and 21.8 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at:10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

[0011] In a second aspect, the present disclosure provides crystal Form A of a compound ofFormula (I): .

[0012] In some Form A (also referred to as thecrystal form of the second aspect or “the second aspect”) includes diffraction peaks at least four (e.g.4, 5, 6, 7, 8, 9, 10, or 11) of the following positions: 5.4±0.2° 2θ, 9.9±0.2° 2θ, 10.8±0.2° 2θ, 11.4±0.2° 2θ, 13.2±0.2° 2θ, 16.2±0.2° 2θ, 17.7±0.2° 2θ, 20.2±0.2° 2θ, 20.5±0.2° 2θ, 22.6±0.2° 2θ, and 24.3±0.2° 2θ. In some embodiments of crystal Form A, the XRPD spectrum includes diffraction peaks at positions of: 5.4±0.2° 2θ, 10.8±0.2° 2θ, 16.2±0.2° 2θ and 20.2±0.2° 2θ. In some embodiments, the XRPD spectrum further includes at least one of the diffraction peaks at positions of: 13.2±0.2° 2θ, 20.5±0.2° 2θ, 22.6±0.2° 2θ. In some embodiments, the XRPD spectrum further includes at least one of the diffraction peaks at positions of: 9.9±0.2° 2θ, 11.4±0.2° 2θ, 17.7±0.2° 2θ. In some embodiments, the XRPD spectrum includes diffraction peaks at 5.4±0.2° 2θ, 9.9±0.2° 2θ, 10.8±0.2° 2θ, 11.4±0.2° 2θ, 13.2±0.2° 2θ, 16.2±0.2° 2θ, 17.7±0.2° 2θ, 20.2±0.2° 2θ, 20.5±0.2° 2θ, 22.6±0.2° 2θ, and 24.3±0.2° 2θ.

[0013] In some embodiments of crystal Form A, the crystal form has an XRPD spectrumsubstantially the same as that shown in Figure 1.

[0014] In some embodiments of crystal Form A, the crystal form has a thermogravimetricanalysis (TGA) curve substantially the same as that shown in Figure 2.

[0015] In some embodiments of crystal Form A, the crystal form has a differential scanningcalorimetry (DSC) curve substantially the same as that shown in Figure 3.

[0016] In some embodiments of crystal Form A, the crystal form has at least one (e.g. one,two or all) of the following: (a) an XRPD spectrum substantially the same as that shown in Figure 1; (b) a TGA curve substantially the same as that shown in Figure 2; and (c) a DSC curve substantially the same as that shown in Figure 3.

[0017] In some embodiments of crystal Form A, the crystal form has a DSC curve thatexhibits a peak at 322.4°C ± 5°C.

[0018] In a third aspect, the present disclosure provides crystal Form B of compound ofFormula (I), .

[0019] In some to as the crystal form of thethird aspect or “the third aspect”) is characterized by an XRPD spectrum that exhibits peaks at least four (e.g.4, 5, 6, 7 or all 8) of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, and 23.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, and 26.8 ± 0.2° 2θ. In some embodiments, the XRPD spectrum exhibits peaks at least four (e.g.4, 5, 6, 7 or all 8) of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ, and further exhibits a peak at least one of the following positions: 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ.

[0020] In some embodiments of the third aspect, crystal Form B is a hydrate, e.g. crystalForm B of the third aspect is a dihydrate.

[0021] In some embodiments, crystal Form B has an XRPD spectrum substantially thesame as that shown in Figure 9A.

[0022] In some embodiments, crystal Form B has an XRPD spectrum substantially thesame as that shown in Figure 9B.

[0023] In some embodiments, crystal Form B has a TGA curve substantially the same asthat shown in Figure 10A.

[0024] In some embodiments, crystal Form B has a DSC curve substantially the same asthat shown in Figure 10A.

[0025] In some embodiments, crystal Form B has a DSC curve substantially the same asthat shown in Figure 10B.

[0026] In some embodiments, crystal Form B has a TGA curve substantially the same asthat shown in Figure 10C.

[0027] In some embodiments of crystal Form B, the crystal form has at least one (e.g. one,two or all) of the following: (a) an XRPD substantially the same as that shown in Figure 9A or Figure 9B (after 16 hours drying); (b) a TGA curve substantially the same as that shown in Figure 10A; (c) a DSC curve substantially the same as that shown in Figure 10A; (d) a DSC curve substantially the same as that shown in Figure 10B (after 16 hours drying); and (e) a TGA curve substantially the same as that shown in Figure 10C (after 16 hours drying).

[0028] In some embodiments of the third aspect, the crystal form has a DSC curve that exhibits endotherm peaks at any one or more of (e.g. one, two or all three of) 101°C ± 5°C, 288°C ± 5°C and 309°C ± 5°C and / or endotherm onset temperatures of any one or more of (e.g. one, two or all three of) 57°C ± 5°C, 280°C ± 5°C, and 295°C ± 5°C. In some embodiments of the third aspect, after the crystal has been dried e.g. for 16 hours under a heat lamp, the crystal form has a DSC curve that exhibits DSC endotherm peaks at either or both of 83°C ± 5°C and 318°C ± 5°C and / or endotherm onset temperatures at either or both of 21°C ± 5°C and 296°C ± 5°C.

[0029] In a further aspect, the present disclosure provides a process for preparing any of thecrystal forms of a compound of Formula (I) disclosed herein or amorphous compound of Formula (I). In some embodiments, the process comprises dissolving a compound of Formula (I) in a solvent or mixture of solvents as disclosed herein, then causing the compound of Formula (I) to precipitate under conditions disclosed herein. In some embodiments, the starting material is a crystal form or a mixture of crystal forms of the compound of Formula (I) e.g. those disclosed herein, or is amorphous e.g. as disclosed herein, or is a mixture of any combination of these.

[0030] In an aspect, the present disclosure provides a process for preparing the compoundof Formula (I) disclosed herein. In an embodiment, the process comprises the steps of: (a) reducing a compound of Formula (SM1) to obtain a compound of Formula (VI): ; (b) preparing a compound of Formula (V) from a compound of Formula (VI) and acompound of Formula (SM2) in the presence of alkalis and coupling reagent in the organic solvent: ; (c) solvent to get acompound of Formula (IV): ; (d) reacting a comp presence of palladiumcatalyst to get a compound of Formula (III): ; (e) preparing a of Formula (III) and aacylation reagent: ; (f) preparing a between acompound of Formula (II) and a compound of Formula (SM3) in the presence of alkali and solvent: .

[0031] formof the second aspect disclosed herein, wherein the process is recrystallizing the compound of Formula (I) in a solvent to obtain the crystal form. In one embodiment, the solvent is a mixture of acetic acid and methanol.

[0032] In an aspect, the present disclosure provides a process for preparing the crystal formof the third aspect disclosed herein, wherein the process comprises the steps of:(a) providing the compound of Formula (I) in solid form;(b) optionally washing the compound of Formula (I);(c) dissolving the compound of Formula (I) in an acid, optionally wherein the acidis hydrochloric acid, 1.0 N hydrochloric acid, sulfuric acid, aqueous sulfuric acid, or 0.25 M aqueous sulfuric acid; (d) optionally washing the solution with an organic solvent, optionally whereinthe organic solvent is dichloromethane, and / or extracting the solution, optionally wherein the extraction solvent is ethyl acetate; (e) causing the compound of Formula (I) to precipitate by combining the solutionwith a base, optionally wherein the base is sodium bicarbonate in solid or solution form, sodium carbonate in solid or solution form, ammonia, or aqueous ammonia; (f) optionally drying the precipitate, optionally wherein the drying comprises, forexample, drying under an infrared lamp for up to 16 hours at, for example, 40°C.

[0033] In an aspect, the present disclosure provides a process for preparing the crystal formof the third aspect disclosed herein.

[0034] In some embodiments, the process comprises the following steps:1. Optionally washing the compound of Formula (I), which may be amorphousor crystalline or a mixture thereof, with e.g. dichloromethane, methanol, and ethyl acetate, optionally in that order; with each wash, optionally stirring or mixing to expose the solid compound to the wash solvent prior to removing the solvent; 2. collecting the solid material and adding acid e.g. 1.0 N hydrochloric acid untildissolved (e.g. approximately 1 mL acid per 26.5 mg compound of Formula (I) free base), 3. extracting e.g. three times with about 4 times as much ethyl acetate as acidwas used (v / v), 4. adding saturated sodium bicarbonate (NaHCO3) solution dropwise whilestirring to cause the crystalline form B to precipitate; 5. optionally isolating the solid material by filtration.

[0035] In some embodiments, the process comprises the following steps:1. dissolving the compound of Formula (I), which may be amorphous orcrystalline or a mixture thereof, in acid e.g.1.0 N hydrochloric acid until dissolved (e.g. approximately 1 mL acid per 45-50 mg compound of Formula (I) free base), 2. adding sodium carbonate (Na2CO3) dropwise with stirring until precipitationcomplete (about 1 mL Na2CO3per 90-95 mg compound of Formula (I)); 3. optionally isolating the solid material by filtration.

[0036] In some embodiments, the process comprises dissolving the compound of Formula(I) in sulfuric acid e.g. aqueous sulfuric acid e.g.0.25 M, for example at ambient temperature (e.g.15°C to 30°C, 18°C to 28°C, 20°C to 25°C), washing the solution with dichloromethane and adding the aqueous solution to aqueous ammonia (e.g.1.5 M) to form a slurry. The slurry is stirred at ambient temperature for 1 hour, filtered and dried e.g. under an infrared lamp to provide the crystal form of the compound of Formula (I).

[0037] In some embodiments, the process comprises dissolving the compound of Formula(I) (e.g.1g) in sulfuric acid e.g. aqueous H2SO4 (e.g.0.25 M, 10 mL). The resulting clear solution is combined with aqueous ammonia (e.g. 1.5 M, 5 mL) at ambient temperature. The resulting suspension is stirred for e.g. about 1 hour, filtered, washed with H2O (e.g.5 mL), and dried under an infrared lamp to yield the crystal form of the third aspect disclosed herein. The material can be dried for 16 hours. The resulting material has a water content of 7.3wt% by Karl Fischer test. XRPD shows a spectrum consistent with the crystal form of the third aspect disclosed herein (In a hydrate molecule comprising of one molecule of the compound Formula (I) and close to two water molecules). If heated for 40 hours, the material converts to the crystal form of the second aspect disclosed herein, as assessed by XRPD and TGA, with water content of 1.5wt% by KF.

[0038] In some embodiments, a process disclosed herein yields a crystal form with any ofthe following properties: the crystal form is characterized by an XRPD spectrum that exhibits peaks at least four (e.g.4, 5, 6, 7 or all 8) of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, and 23.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, and 26.8 ± 0.2° 2θ. In some embodiments, the XRPD spectrum exhibits peaks at least four (e.g.4, 5, 6, 7 or all 8) of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ, and further exhibits a peak at least one of the following positions: 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ; the crystal form has an XRPD spectrum substantially the same as that shown in Figure 9A or Figure 9B; the crystal form has a TGA curve substantially the same as that shown in Figure 10A or Figure 10C; the crystal form has a DSC curve substantially the same as that shown in Figure 10A or Figure 10B; the crystal form has at least one of the following: (a) an XRPD substantially the same as that shown in Figure 9A or Figure 9B, (b) a TGA curve substantially the same as that shown in Figure 10A or Figure 10C, and (c) a DSC curve substantially the same as that shown in Figure 10A or Figure 10B; the crystal form has a DSC curve that exhibits DSC endotherm peaks at at 101°C ± 5°C, 288°C ± 5°C and 309°C ± 5°C; the crystal form has a DSC curve that exhibits endotherm onset temperatures at 57°C ± 5°C, 280°C ± 5°C, and 295°C ± 5°C; after the crystal has been dried e.g. for 16 hours under an infrared heat lamp (e.g. at about 40°C), the crystal form has a DSC curve that exhibits DSC endotherm peaks at either or both of 83°C ± 5°C and 318°C ± 5°C and / or endotherm onset temperatures at either or both of 21°C ± 5°C and 296°C ± 5°C. In some embodiments, the process yields a mixture of crystal forms of the compound of Formula (I) or a mixture of amorphous and one or more crystal forms of the compound of Formula (I).

[0039] In an aspect, the present disclosure provides a composition or pharmaceutical (e.g.pharmaceutically acceptable) composition comprising any of the crystal forms of Formula (I) disclosed herein, or a combination of any of the crystal forms of Formula (I) disclosed herein, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises, in addition to any of the crystal forms of Formula (I) disclosed herein, or a combination of any of the crystal forms of Formula (I) disclosed herein, and a pharmaceutically acceptable carrier or excipient, at least one additional therapeutic agent, such as at least one known anticancer drug or a pharmaceutically acceptable salt thereof. In some embodiments, the at least one known anticancer drug is selected from the group consisting of: abiraterone, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, darolutamide, enzalutamide, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5- fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, prednisone, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, dinutuximab, blinatumomab, ipilimumab, Avastin (bevacizumab), Herceptin (trastuzumab), MabThera (rituximab), imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib lafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pratinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin, recombinant human interleukin-2, sipuleucel-T, prostate cancer therapeutic vaccine.

[0040] In an aspect, the present disclosure provides a method for preparing a composition(e.g. a pharmaceutical composition or pharmaceutically acceptable composition) comprising combining a crystal form of the compound of Formula (I) disclosed herein, or a combination of crystal forms of the compound of Formula (I) disclosed herein, optionally together with the amorphous form of the compound of Formula (I) disclosed herein, with a pharmaceutically acceptable excipient or carrier. In some embodiments, the method comprises combining a crystal form disclosed herein, or a combination of crystal forms disclosed herein, with an additional therapeutic agent, for example at least one known anticancer drug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the at least one known anticancer drug is selected from the group consisting of: abiraterone, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, darolutamide, enzalutamide, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5- azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy- uridine, fludarabine, nelarabine, ara-C, pralatrexate, prednisone, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, dinutuximab, blinatumomab, ipilimumab, Avastin (bevacizumab), Herceptin (trastuzumab), MabThera (rituximab), imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib lafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pratinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin, recombinant human interleukin-2, sipueucel-T, prostate cancer therapeutic vaccine.

[0041] In an aspect, the present disclosure provides a composition prepared by a method forpreparing a composition disclosed herein.

[0042] In an aspect, the present disclosure provides a method of treating or preventing acondition comprising administering a crystal form of a compound of Formula (I) disclosed herein, or a combination of crystal forms of a compound of Formula (I) disclosed herein, or a composition disclosed herein, to a subject in need of such treatment or prevention. In some embodiments, the condition is a condition that is responsive to the selective inhibition of PARP1 activity relative to PARP2 activity. In some embodiments, the condition is a cancer or tumor. In some embodiments, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (including, e.g. small cell lung cancer) (including, e.g. small cell lung cancer), Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, granuloma fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenal cortical cancer, skin cancer and prostate cancer. In some embodiments, the method of treating or preventing disclosed herein further comprises administering an additional therapeutic agent in conjunction with, e.g. before, simultaneously with or after the administration of the crystal form of a compound of Formula (I), combination of crystal forms of a compound of Formula (I), or composition. “In conjunction with” includes, but is not limited to, a circumstance in which the compound of Formula (I) and the additional therapeutic agent are prescribed for use in coordination with each other even if not administered simultaneously or in the same composition.

[0043] In an aspect, the present disclosure provides a use of a crystal form of a compoundof Formula (I) disclosed herein, or a combination of crystal forms of a compound of Formula (I) disclosed herein, or a composition disclosed herein, in the treatment of a condition. In some embodiments, the condition is a condition that is responsive to the selective inhibition of PARP1 activity relative to PARP2 activity. In some embodiments, the condition is a cancer or tumor. In some embodiments, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (including, e.g. small cell lung cancer) (including, e.g. small cell lung cancer), Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, granuloma fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenal cortical cancer, skin cancer and prostate cancer.

[0044] In an aspect, the present disclosure provides the use of a crystal form of a compoundof Formula (I) disclosed herein, or a combination of crystal forms of a compound of Formula (I) disclosed herein, or a composition disclosed herein, in the manufacture of a medicament for treating a condition. In some embodiments, the condition is a condition that is responsive to the selective inhibition of PARP1 activity relative to PARP2 activity. In some embodiments, the condition is a cancer or tumor. In some embodiments, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (including, e.g. small cell lung cancer), Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, granuloma fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenal cortical cancer, skin cancer and prostate cancer. In some embodiments, the medicament is prepared by combining a crystal form of a compound of Formula (I) disclosed herein, or a combination of crystal forms of a compound of Formula (I) disclosed herein, with one or more excipients. BRIEF DESCRIPTION OF FIGURES

[0045] Figure 1 shows an XRPD of a crystal form A.

[0046] Figure 2 shows a DSC of a crystal form A.

[0047] Figure 3 shows a TGA of a crystal form A.

[0048] Figure 4 shows an overlay of XRPDs of a sample of crystal form A before andafter storage at high temperature (60oC). Bottom diffractogram: taken before storage at 60oC; middle diffractogram: taken after storage at 60oC for 10 days; top diffractogram: taken after storage at 60oC for 30 days.

[0049] Figure 5 shows an overlay of XRPDs of a sample of crystal form A before andafter storage at high humidity (25oC / 92.5%RH). Bottom diffractogram: taken before storage at 25oC / 92.5%RH; middle diffractogram: taken after storage at 25oC / 92.5%RH for 10 days; top diffractogram: taken after storage at 25oC / 92.5%RH for 30 days.

[0050] Figure 6 shows an overlay of XRPDs of a sample of crystal form A before andafter strong light irradiation (photostability assay). Bottom diffractogram: taken before exposure to strong light irradiation; middle diffractogram: taken after exposure to strong light irradiation; top diffractogram: taken after exposing aluminum foil-wrapped sample to strong light irradiation.

[0051] Figure 7 shows an overlay of XRPDs of the crystal form A after acceleratedstability evaluation (40oC / 75%RH). From bottom to top, the Figure shows XRPDs of the initial sample (Init.), of the sample taken after storage at 40oC / 75%RH for 1 month (1M), of the sample taken after storage at 40oC / 75%RH for 3 months (3M), of the sample taken after storage at 40oC / 75%RH for 6 months (6M).

[0052] Figure 8 shows an overlay of XRPDs of the crystal form A after long-term stability evaluation (25oC / 60%RH). From top to bottom, the Figure shows XRPDs of the sample taken after storage at 25oC / 60%RH for 1 month (1M), of the sample taken after storage at 25oC / 60%RH for 3 months (3M), of the sample taken after storage at 25oC / 60%RH for 6 months (6M), of the sample taken after storage at 25oC / 60%RH for 9 months (9M), and of the initial sample (Init.).

[0053] Figure 9A shows XRPD of the crystal form B in the absence of drying.

[0054] Figure 9B shows XRPD of the crystal form B after 16 hours drying underinfrared lamp.

[0055] Figure 10A shows DSC (lower (green) line) and TGA (upper (blue) line) of thecrystal form B in the absence of drying.

[0056] Figure 10B shows DSC (blue line) of the crystal form B after 16 hours dryingunder infrared lamp.

[0057] Figure 10C shows TGA of the crystal form B after 16 hours drying underinfrared lamp.

[0058] Figure 11 shows the asymmetric unit of the anhydrate crystal form A singlecrystal structure model.

[0059] Figure 12 shows the molecular packing structure diagram of the anhydratecrystal form A single crystal structure model (viewed along crystallographic a-axis).

[0060] Figure 13 shows the asymmetric unit of the hydrate crystal form A singlecrystal structure model.

[0061] Figure 14 shows the molecular packing structure diagram of the hydrate crystalform A single crystal structure model (viewed along crystallographic a-axis).

[0062] Figure 15 shows simulated XRPD from single-crystal experiments of anhydrate(Top: red diffractogram) and hydrate (Bottom: blue diffractogram) of the crystal form A.

[0063] Figure 16 shows XRPD comparison at 22-31degrees of anhydrate (Reddiffractogram) and hydrate (Blue diffractogram) of the crystal form A.

[0064] Figure 17 shows differences in structure between the fully dehydrated form andthe partially dehydrated form.

[0065] Figure 18 shows the XRPD spectrum of amorphous compound of formula (I).

[0066] Figure 19 shows the polarized light microscopy (PLM) of amorphouscompound of formula (I).

[0067] Figure 20 shows an XRPD of the crystal form A.DETAILED DESCRIPTIONI. General Description

[0068] In the following description, a certain amount of specific details are set forth inorder to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will understand that the present disclosure can be practiced without these details. The following description of several embodiments is based on the understanding that the present disclosure is regarded as an example of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments shown. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. The embodiment shown under any heading can be combined with the embodiment shown under any other heading. II. Definition

[0069] Where an aspect or embodiment is described as comprising certain elements orfeatures, the present disclosure should be understood to also disclose, as alternative aspects or embodiments, the corresponding aspects or embodiments that consist of or consist essentially of those same elements or features.

[0070] Reference throughout this specification to "one embodiment" or "anembodiment" means that a specific feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present disclosure. Therefore, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. In addition, specific features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0071] "Pharmaceutically acceptable excipients" include but are not limited to anyadjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, which have been approved by the United States Food and Drug Administration (U.S. FDA) or Chinese National Medical Products Administration (CN NMPA) or other relevant agencies as acceptable for use in humans or livestock.

[0072] "Pharmaceutical composition" refers to a formulation that comprises an activeingredient (e.g. the compound of Formula (I) and its various forms (amorphous and crystal forms) of the present disclosure), and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (such as a human). Such vehicles include all pharmaceutically acceptable excipients for this purpose.

[0073] Unless otherwise stated, the term "treating" a disease, disorder or condition in asubject (e.g. human, pet, domesticated or veterinary animal) as used herein refers to reversing, reducing, or inhibiting progression in the subject of a disease, disorder or condition or one or more symptoms of the disease, disorder or condition in the subject.

[0074] The term "preventing" a disease, disorder or condition in a subject (e.g. human,pet, domesticated or veterinary animal) as used herein refers to any treatment of a subject that causes one or more clinical symptoms of the disease, disorder or condition not to develop in the subject, or that causes a disease, disorder or condition not to develop in the subject.

[0075] References herein to "about" a value or parameter include (and describe)implementations for the value or parameter itself. For example, description referring to "about X" includes description of "X". In addition, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0076] Pharmaceutically acceptable: The term “pharmaceutically acceptable,” as usedherein, refers to substances that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Accordingly, pharmaceutically acceptable relates to substances that are not biologically or otherwise undesirable, i.e., the substance can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0077] When referring to, for example, XRD or XRPD spectrums, DSC thermograms,DVS graphs or TGA, the term "substantially the same as that shown in..." includes spectrums, thermograms, or graphs which are not necessarily the same as those described herein, but fall within the limits of experimental error or deviation when considered by the person skilled in the art.

[0078] In the present disclosure, for the characteristic powder X-ray diffraction peakposition of the crystal form, the allowable error of the angular position (2θ) is ±0.2°. This error is used when comparing two powder X-ray diffraction spectrums. If a diffraction peak in one image is designated as a certain angular position range of measured peak position ±0.2° (2θ), and a diffraction peak in another image is designated as the other angular position range of measured peak position ±0.2° (2θ), and if these peak ranges overlap, the two peaks are considered to have the same angular position (2θ). For example, if the diffraction peak of an image is determined to be at 5.20°, for comparison, the allowable error allows the peak to be specified in the range of 5.00°-5.40°. If the control peak of the other diffraction spectrum is determined to be at 5.35°, for comparison, the allowable error allows the peak to be specified in the range of 5.15°-5.55°. Because of the overlap between the two peak position ranges, the two compared peaks are considered to have the same angular position (2θ). In some embodiments, the allowable error of the angular position (2θ) is ±0.1°. III. Crystal Form

[0079] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I) as follow: . wherein the diffraction (XRPD) spectrum that exhibits peaks at least four of the following positions: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, and 21.8 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at:10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

[0080] The present disclosure provides crystal forms of the following compound ofFormula (I) (5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7- yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide). The crystal form of the present disclosure has properties suitable for medical or pharmaceutical uses, including but not limited to bioavailability, stability, purity, and / or manufacturability. Specifically, the present disclosure provides the crystal form A of the compound of Formula (I).

[0081] In some of Formula (I) of the present disclosure spectrum including diffraction peaks (characteristic peaks) at least four of the following positions: 5.4±0.2° 2θ, 9.9±0.2° 2θ, 10.8±0.2° 2θ, 11.4±0.2° 2θ, 13.2±0.2° 2θ, 16.2±0.2° 2θ, 17.7±0.2° 2θ, 20.2±0.2° 2θ, 20.5±0.2° 2θ, 22.6±0.2° 2θ, and 24.3±0.2° 2θ. In some embodiments, the XRPD spectrum of the crystal form includes diffraction peaks at positions: 2θ=5.4±0.2°, 10.8±0.2°, 16.2±0.2° and 20.2±0.2°. In some embodiments, the XRPD spectrum of the crystal form further includes at least one of the diffraction peaks at positions of 13.2±0.2°, 20.5±0.2°, and 22.6±0.2°. In some embodiments, the XRPD spectrum of the crystal form further includes at least one of the diffraction peaks at positions of 9.9±0.2°, 11.4±0.2° and 17.7±0.2°.

[0082] In some embodiments, the crystal form A of the compound of Formula (I) hasan XRPD spectrum that includes diffraction peaks at 2θ=5.4°±0.2°, 9.9±0.2°, 10.8±0.2°, 11.4±0.2°, 13.2°±0.2°, 16.2±0.2°, 17.7±0.2°, 20.2±0.2°, 20.5±0.2°,22.6±0.2°, and 24.3±0.2° 2θ.

[0083] In some embodiments, the said diffraction peak at the position of 16.2±0.2°includes the two diffraction peaks at positions of 16.2±0.04° and 16.3±0.04°.

[0084] In some embodiments, the crystal form A of the compound of Formula (I)further includes any one, any two, or all three diffraction peaks at positions of 21.0±0.2°, 26.1±0.2°and 29.0±0.2°.

[0085] In some embodiments, the crystal form A of the compound of Formula (I) hasan XRPD spectrum substantially the same as that shown in Figure 1.

[0086] In some embodiments, the crystal form A of the compound of Formula (I) hasthe diffraction peaks at 2θ substantially the same as that shown in Table 6.

[0087] In some embodiments, the crystal form A of the compound of Formula (I) has aDSC thermogram substantially the same as that shown in Figure 2.

[0088] In some embodiments, the crystal form A of the compound of Formula (I) has aTGA substantially the same as that shown in Figure 3. In an embodiment, the crystal form A of the compound of Formula (I) of the present disclosure has at least one, any two, or all three of the following (a) to (c): (a) an XRPD spectrum substantially the same as that shown in Figure 1; (b) a DSC thermogram substantially the same as that shown in Figure 2; and (c) a TGA substantially the same as that shown in Figure 3.

[0089] In an aspect, the present disclosure provides a crystal form of compound ofFormula (I), , wherein the crystal form (crystal Form B) is characterized by an XRPD spectrum that exhibits peaks at least four of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, and 23.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ and 24.8 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, and 26.8 ± 0.2° 2θ. In some embodiments, the XRPD spectrum exhibits peaks at least four (e.g.4, 5, 6, 7 or all 8) of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ, and further exhibits a peak at least one of the following positions: 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ. In some embodiments, crystal Form B is characterized by an XRPD spectrum that exhibits peaks at: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 12.7 ± 0.2° 2θ, 13.4 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 15.4 ± 0.2° 2θ, 16.1 ± 0.2° 2θ, 20.1 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, 24.8 ± 0.2° 2θ, 26.8 ± 0.2° 2θ, 29.0 ± 0.2° 2θ, and 29.5 ± 0.2° 2θ.

[0090] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I): (I) wherein the crystal form has as that shown in Figure 9A or in Figure 9B .

[0091] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I): wherein the crystal same as that shown in Figure 10A or Figure 10C (after drying).

[0092] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I): wherein the the same as that shown in Figure 10A or Figure 10B (after drying).

[0093] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I): , wherein the crystal form has at least one of the following: (a) an XRPD substantially the same as that shown in Figure 9A (no drying) or Figure 9B (after drying with IR lamp 16 hours); (b) a TGA curve substantially the same as that shown in Figure 10A; (c) a DSC curve substantially the same as that shown in Figure 10A; (d) a DCS curve substantially the same as that shown in Figure 10B (after drying with IR lamp 16 hours); and (e) a TGA curve substantially the same as that shown in Figure 10C (after drying with IR lamp 16 hours).

[0094] In an aspect, the present disclosure provides a crystal form of a compound ofFormula (I): wherein the endotherm peaks at any one or more of (e.g. one, two or all three of) 101°C ± 5°C, 288°C ± 5°C and 309°C ± 5°C and / or any one or more of (e.g. one, two or all three of) endotherm onset temperatures of 57°C ± 5°C, 280°C ± 5°C, and 295°C ± 5°C. In some embodiments, after the crystal has been dried e.g. for 16 hours under a heat lamp, the crystal form has a DSC curve that exhibits DSC endotherm peaks at either or both of 83°C ± 5°C and 318°C ± 5°C and / or endotherm onset temperatures at either or both of 21°C ± 5°C and 296°C. IV. Pharmaceutical Formulations and Routes of Administration

[0095] The compounds and compositions of the present invention can be delivereddirectly or in pharmaceutical compositions or medicaments along with suitable carriers or excipients, as is well known in the art. Present methods of treatment can comprise administration of an effective amount of a compound of the invention to a subject in need. In a preferred embodiment, the subject is a mammalian subject, and in a most preferred embodiment, the subject is a human subject.

[0096] An effective amount of such compound, composition, or medicament canreadily be determined by routine experimentation, as can the most effective and convenient route of administration, and the most appropriate formulation. Various formulations and drug delivery systems are available in the art. See, e.g., Gennaro, A.R., ed. (1995) Remington's Pharmaceutical Sciences, supra.

[0097] Suitable routes of administration may, for example, include oral, rectal, topical,nasal, pulmonary, ocular, intestinal, and parenteral administration. Primary routes for parenteral administration include intravenous, intramuscular, and subcutaneous administration. Secondary routes of administration include intraperitoneal, intra- arterial, intra-articular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine, and intraventricular administration. The indication to be treated, along with the physical, chemical, and biological properties of the drug, dictate the type of formulation and the route of administration to be used, as well as whether local or systemic delivery would be preferred.

[0098] Pharmaceutical dosage forms of a compound of the invention may be providedin an instant release, controlled release, sustained release, or target drug-delivery system. Commonly used dosage forms include, for example, solutions and suspensions, (micro-) emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols, and lyophilized formulations. Depending on route of administration used, special devices may be required for application or administration of the drug, such as, for example, syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. Pharmaceutical dosage forms are often composed of the drug, an excipient(s), and a container / closure system. One or multiple excipients, also referred to as inactive ingredients, can be added to a compound of the invention to improve or facilitate manufacturing, stability, administration, and safety of the drug, and can provide a means to achieve a desired drug release profile. Therefore, the type of excipient(s) to be added to the drug can depend on various factors, such as, for example, the physical and chemical properties of the drug, the route of administration, and the manufacturing procedure. Pharmaceutically acceptable excipients are available in the art and include those listed in various pharmacopoeias. See, e.g., the U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP), and British pharmacopeia (BP); the U.S. Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, e.g., Inactive Ingredient Guide (1996); Ash and Ash, Eds. (2002) Handbook of Pharmaceutical Additives, Synapse Information Resources, Inc., Endicott NY; etc.).

[0099] Pharmaceutical dosage forms of a compound of the present invention may bemanufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tabletting, suspending, extruding, spray-drying, levigating, emulsifying, (nano / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of the present invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0100] Proper formulation is dependent upon the desired route of administration. Forintravenous injection, for example, the composition may be formulated in aqueous solution, if necessary using physiologically compatible buffers, including, for example, phosphate, histidine, or citrate for adjustment of the formulation pH, and a tonicity agent, such as, for example, sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid formulations, or patches may be preferred, possibly containing penetration enhancers. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms, and as instant or controlled / sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions. The compounds may also be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0101] Solid oral dosage forms can be obtained using excipients, which may includefillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherants, cationic exchange resins, wetting agents, antioxidants, preservatives, coloring, and flavoring agents. These excipients can be of synthetic or natural source. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatine, magnesium carbonate, magnesium / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicium dioxide, sodium benzoate, sorbitol, starches, stearic acid or a salt thereof, sugars (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated), and waxes. Ethanol and water may serve as granulation aides. In certain instances, coating of tablets with, for example, a taste- masking film, a stomach acid resistant film, or a release-retarding film is desirable. Natural and synthetic polymers, in combination with colorants, sugars, and organic solvents or water, are often used to coat tablets, resulting in dragees. When a capsule is preferred over a tablet, the drug powder, suspension, or solution thereof can be delivered in a compatible hard or soft shell capsule.

[0102] In one embodiment, the compounds of the present invention can beadministered topically, such as through a skin patch, a semi-solid, or a liquid formulation, for example a gel, a (micro-) emulsion, an ointment, a solution, a (nano / micro)-suspension, or a foam. The penetration of the drug into the skin and underlying tissues can be regulated, for example, using penetration enhancers; the appropriate choice and combination of lipophilic, hydrophilic, and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and use of complexing agents. Other techniques, such as iontophoresis, may be used to regulate skin penetration of a compound of the invention. Transdermal or topical administration would be preferred, for example, in situations in which local delivery with minimal systemic exposure is desired.

[0103] For administration by inhalation, or administration to the nose, the compoundsfor use according to the present invention are conveniently delivered in the form of a solution, suspension, emulsion, or semisolid aerosol from pressurized packs, or a nebuliser, usually with the use of a propellant, e.g., halogenated carbons derived from methane and ethane, carbon dioxide, or any other suitable gas. For topical aerosols, hydrocarbons like butane, isobutene, and pentane are useful. In the case of a pressurized aerosol, the appropriate dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin, for use in an inhaler or insufflator, may be formulated. These typically contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0104] Compounds and compositions formulated for parenteral administration byinjection are usually sterile and can be presented in unit dosage forms, e.g., in ampoules, syringes, injection pens, or in multi-dose containers, the latter usually containing a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as buffers, tonicity agents, viscosity enhancing agents, surfactants, suspending and dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the vehicle may contain water, a synthetic or vegetable oil, and / or organic co-solvents. In certain instances, such as with a lyophilized product or a concentrate, the parenteral formulation would be reconstituted or diluted prior to administration. Depot formulations, providing controlled or sustained release of a compound of the invention, may include injectable suspensions of nano / micro particles or nano / micro or non-micronized crystals. Polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can serve as controlled / sustained release matrices, in addition to others well known in the art. Other depot delivery systems may be presented in form of implants and pumps requiring incision.

[0105] Suitable carriers for intravenous injection for the compounds of the inventionare well- known in the art and include water-based solutions containing a base, such as, for example, sodium hydroxide, to form an ionized compound; sucrose or sodium chloride as a tonicity agent; and a buffer, for example, a buffer that contains phosphate or histidine. Co-solvents, such as, for example, polyethylene glycols, may be added. These water-based systems are effective at dissolving compounds of the invention and produce low toxicity upon systemic administration. The proportions of the components of a solution system may be varied considerably, without destroying solubility and toxicity characteristics. Furthermore, the identity of the components may be varied. For example, low-toxicity surfactants, such as polysorbates or poloxamers, may be used, as can polyethylene glycol or other co-solvents, biocompatible polymers such as polyvinyl pyrrolidone may be added, and other sugars and polyols may substitute for dextrose.

[0106] A therapeutically effective dose can be estimated initially using a variety oftechniques well- known in the art. Initial doses used in animal studies may be based on effective concentrations established in cell culture assays. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain some embodiments, a compound of the disclosure is formulated for oral administration. An exemplary dose of a compound of the disclosure in a pharmaceutical formulation for oral administration is from about 0.5 to about 10 mg / kg body weight of subject. In some embodiments, a pharmaceutical formulation comprises from about 0.7 to about 5.0 mg / kg body weight of subject, or alternatively, from about 1.0 to about 2.5 mg / kg body weight of subject. A typical dosing regimen for oral administration would be administration of the pharmaceutical formulation for oral administration three times per week, two times per week, once per week or daily.

[0107] An effective amount or a therapeutically effective amount or dose of an agent,e.g., a compound of the invention, refers to that amount of the agent or compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50 % of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Agents that exhibit high therapeutic indices are preferred.

[0108] The effective amount or therapeutically effective amount is the amount of thecompound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Dosages particularly fall within a range of circulating concentrations that includes the ED50 with little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and / or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject's condition.

[0109] Dosage amount and interval may be adjusted individually to provide plasmalevels of the active moiety that are sufficient to achieve the desired effects; i.e., the minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data and animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0110] The amount of compound or composition administered may be dependent on avariety of factors, including the sex, age, and weight of the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0111] The present compounds and compositions may, if desired, be presented in apack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack; or glass and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0112] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein and are specifically contemplated. IV. Preparation method

[0113] The present disclosure provides a preparation method of the compound ofFormula (I) 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7- yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide. The method herein does not require any chromatographic column separation and purification with a high yield, making it particularly suitable for large-scale industrial production.

[0114] Specifically, the compound of Formula (I) is prepared using a methodcomprising the following step (6): reacted in the presence of alkali and solvent to carry out the substitution reaction to obtain the compound of Formula (I).

[0116] In the above reaction, the said alkali includes inorganic alkali, organic alkali, orthe mixture of inorganic alkali and organic alkali. The suitable inorganic alkali is selected from one or more of KI, NaI, Na2CO3, K3PO4, NaOH, and NaOAc, and the suitable organic alkali is selected from one or more of Et3N (triethylamine), pyridine, DBU (1,8-diazabicycloundecano-7ene), TMG (tetramethylguanidine), DABCO (triethylenediamine), DIEA (N, N-diisopropylethylamine), and NMM (methylmorpholine). In some embodiments, the molar ratio of the inorganic alkali to organic alkali is 1:(10 to 30). In some embodiments, the said alkali is a mixture of KI and DIEA. In some embodiments, the molar ratio of KI to DIEA is 1:(23 to 28).

[0117] In the above reaction, in some embodiments, the molar ratio of the compoundof Formula II to the alkali is 1:(3 to 7). In some embodiments, 1 mole compound of Formula II uses about 0.1 to 0.3 moles of KI and 4.8 to 5.2 moles of DIEA. In some embodiments, 1 mole compound of Formula II uses about 0.2 moles of KI and about 5.0 moles of DIEA.

[0118] In the above reaction, the said solvent in some embodiments is selected from one or more of 1,4-dioxane, water and N-methyl-2-pyrrolidone (NMP), for example, a mixture of 1,4-dioxane, water and NMP. In some embodiments, the volume ratio of 1,4- dioxane, water to NMP is (3.0 to 4.0):1:(3.0 to 4.0), for example (3.4 to 3.6):1:(3.2 to 3.4).

[0119] In the above reaction, in some embodiments the temperature is 95 to 105℃.

[0120] In the above reaction, in some embodiments the molar ratio of the compound ofFormula II and the compound of Formula SM3 or its salt is 0.6 to 1.0, for example 0.78 to 0.87. In some embodiments, the salt of the compound of Formula SM3 is hydrochloride.

[0121] The present invention finds that in the presence of the aforementioned solvent,such as, for example, 1,4-dioxane, water and NMP, and, for example, at the reaction temperature mentioned above, the compound of Formula II can be completely transformed. In some embodiments, the time of the Substitution reaction may be 10 to 30 hours.

[0122] In the above reaction, the mixture of the compound of Formula II and thecompound of Formula SM3 is heated and refluxed to allow the Substitution reaction and complete conversion.

[0123] In some embodiments, purification can be carried out after the reaction iscompleted. In some embodiments, the purification steps include: the temperature of the reaction is reduced to 45-55oC, water (the amount of water can be 20-30 V of the compound of Formula II) is added, the mixture is stirred at room temperature for 3-7 hours and filtered to obtain the compound of Formula (I). Furthermore, in some embodiments, in the purification step, after stirring at room temperature for 3-7 hours and filtering, the filter cake is washed with water and the wet product is dissolved at 85- 95oC in DMSO (the amount can be 35-45V of the compound of Formula II, such as, for example, 35.5V), and then cooled to 45-55oC, methanol (the amount can be 31.5-40.5V of the compound of Formula II, such as, for example, 34-37V) is added, and the mixture is stirred at room temperature for 2-5 hours, filtered, the filter cake is washed with methanol to obtain the compound of Formula (I). In some embodiments, the volume ratio of DMSO and methanol used in the cooling step is (2 to 1): 1. In some embodiments, the filter cake is washed with methanol and then vacuum dried under reduced pressure to obtain purified compound of Formula (I).

[0124] In some embodiments, step (6) comprises adding 1,4-dioxane, water, N,N-diisopropylethylamine, the compound hydrochloride of Formula SM3, potassium iodide, the compound of Formula II, and NMP to a reactor, heating and reflux until the reaction is completed, reducing the temperature of the reaction solution to 50 ± 5oC, adding water to the reaction solution, and further reducing the temperature to room temperature. After stirring at room temperature for 3-7 hours, filter and wash the filter cake with water, Dissolve the wet product in DMSO at 90 ± 2°C, cool to 50 ± 5°C, add methanol, continue to cool to room temperature, stir for 2-5 hours, filter, wash the filter cake with methanol, and dry the wet product under reduced pressure at 50 ± 5oC to obtain the compound of Formula (I). In some embodiments, the amount and ratio of each substance in the reaction system, as well as the amount of each purified substance used in the purification step, are as described in any of the previous embodiments.

[0125] The compound of Formula III and the acylation reagent are reacted to get thecompound of Formula II by using the following step (5):

[0126] In the from one ormore of oxaloyl chloride, sulfoxide chloride, trimethylchlorosilane, phosphorus oxychloride and sulfonyl chloride, e.g. sulfoxide chloride. In some embodiments, the molar ratio of the acylation reagent to the compound of Formula III is from 2.5 to 3.5. In some embodiments, the molar ratio is from 2.8 to 3.1.

[0127] In the above step (5), the suitable organic solvent is selected from one or moreof dichloromethane, acetonitrile and tetrahydrofuran. In some embodiments, the organic solvent is dichloromethane.

[0128] In some embodiments, activator such as N,N-dimethylformamide is added tothe reaction in step (5). In some embodiments, the molar ratio of the activator and the compound of Formula III is from 1.8 to 2.3.

[0129] In the reaction of step (5), the reaction temperature is 5°C to 15°C. The reactiontime is 10 to 30 hours. In some embodiments, the acylation reagent is added at -5°C to 5℃ and the mixture is stirred for 30 min to 5 hours, then heated to 5°C to 15℃ for reaction.

[0130] After the reaction is completed, water is used to quench the reaction, the mixture is filtered, and the filter cake is washed with dichloromethane and water in turn to obtain the compound of Formula II. In some embodiments, after the end of the reaction, 1V to 5V of water is added to the reaction solution, the mixture is stirred for 6 to 14 hours, filtered and the filter cake is washed with dichloromethane and water successively to obtain the compound of Formula II. In this reaction, column chromatography was no longer used for post-treatment.

[0131] In some embodiments, step (5) includes adding the compound of Formula III,dichloromethane, and N,N-dimethylformamide to the reactor, dropwise adding sulfoxide chloride at -5°C to 5° C and stirring for 45 minutes to 3 hours, heating to 10 ± 5oC and stirring until the reaction is completed, adding water, stirring for 8-12 hours, filtering, washing the filter cake with dichloromethane and water sequentially, drying the wet product under reduced pressure at 50 ± 5oC, and obtaining the compound of Formula II.

[0132] According to the present disclosure, the compound of Formula IV and theorganotin are reacted in the presence of palladium catalyst to obtain the compound of Formula III by using the following step (4):

[0133] In the above more of 1,4-dioxane,tetrahydrofuran, acetonitrile, DMF, dimethoxyethane and diglyme; the organotin is tributyltin methanol; the catalyst is selected from one or more of Xphos Pd G2, Ruphos Pd G2, Brettphos Pd G1 and Xantphos Pd G3.

[0134] In some embodiments, step (4) includes reacting the compound of Formula IVwith organotin reagent in the presence of organic solvents and catalysts at 75-85 ℃ for 12 to 30 hours, the organic solvent and silica thiol are added, and stirred for 3 to 8 hours at 75-85 ℃, the mixture is filtered, silica thiol is added to the filtrate, stirred for 3 to 10 hours at 75-85 ℃, the mixture is filtered, the filtrate is concentrated, methyl tert-butyl ether is added, the temperature is cooled to room temperature and the mixture is stirred form 5 to 20 hours, filtered to obtain the compound of Formula III. The invention finds that the purity of the compound of Formula III can reach 97% and the loss of mother liquor can be controlled at about 5% when 1,4-dioxane and methyl tert-butyl ether are used for crystallization. In the above reaction, the volume ratio of the 1,4-dioxane and methyl tert-butyl ether is (2.5 to 3.5):1.

[0135] In some embodiments, of the molar ratio of the compound of Formula IV andorganotin reagent is 1:(1 to 1.2).

[0136] According to the present disclosure, the compound of Formula V is reacted inbasic condition in the organic solvent to get the compound of Formula IV by using the following step (3):

[0137] Inorganic the alkaline condition;for example, the said inorganic alkali may be K2CO3, Na2CO3, K3PO4or NaOH, e.g. K2CO3; the said organic alkali is selected from one or more of Et3N (triethylamine), pyridine, DBU (1,8-diazabicycloundecano-7-ene), TMG (tetramethylguanidine), DABCO (triethylenediamine) and DIEA (N,N-diisopropylethylamine).

[0138] In some embodiments, the molar ratio of the inorganic alkali and the compoundof Formula V is (8 to 10):1.

[0139] In the above reaction, the said organic solvent may be selected from one ormore of THF, dioxane, IPA, CH3CN, DMSO or NMP. In some embodiments, the organic solvent is NMP.

[0140] In the above reaction, the compound of Formula V is added in batches, forexample, in 2 to 5 batches with an interval of 3 to 6 hours between each addition. Before the addition, the temperature of the reaction solution can be reduced to 45-55℃, and then the temperature can be raised to the reaction temperature after the addition.

[0141] In the above reaction, the reaction temperature can be 115-125 ℃ and thereaction time can be 3-30 hours.

[0142] In the above reaction, after the reaction is completed, the temperature isreduced, water is added, the mixture is filtered, the pH of the filtrate is adjusted with acid (such as hydrochloric acid) to precipitate the compound of Formula IV. In some embodiments, the temperature is reduced to room temperature, then water is added (with a water content of 60 V the total amount of compound V), and the mixture is stirred for 8 to 18 hours, and filtered to obtain the filtrate. The pH of the filtrate can be adjusted to 5-6, and then stirred and filtered to obtain the compound of Formula IV.

[0143] In some embodiments, step (3) includes: the compound of Formula V is putinto a reactor, potassium carbonate and NMP are added, and stirred at 115-125 ℃ for 3- 6 hours. The temperature is cooled to 45-55 ℃, then the compound of formula V is put into the reaction kettle, the temperature is raised to 115-125℃ and stir for 3-6 hours, then the temperature is cooled to 45-55℃, and then the compound of Formula V is put into the reaction kettle, the temperature is raised to 115-125℃ and the mixture is stirred for 10-16 hours. The temperature is reduced to room temperature, then water is added, the mixture is stirred for 8 to 18 hours, and filtered to obtain the filtrate. The pH of the filtrate can be adjusted to 5-6, and then stirred and filtered to obtain the compound of Formula IV.

[0144] According to the present disclosure, with the participation of alkalis andcoupling agent, the compound of Formula VI and the compound of Formula SM2 are reacted in the organic solvent to get the compound of Formula V by using the following step (2):

[0145] In the diisopropylethylamine), DBU or K2CO3. In some embodiments, the alkali is DIEA. The said coupling reagent may be HATU, HBTU, HOBT and EDCI, or CDI. In some embodiments, the coupling reagent is CDI. The said organic solvent may be CH3CN or DMAc. In some embodiments, the compound of Formula VI and the compound of Formula SM2 are reacted in the presence of DIEA and CDI in CH3CN to get the compound of Formula V.

[0146] The reaction temperature for the above reaction can be 75-85℃, and thereaction time can be 10-30 hours.

[0147] In some embodiments, the molar ratio of the compound of Formula SM2 to thecompound of Formula VI is 2 to 3. After the reaction is completed, the temperature is reduced to room temperature, water is added to the reaction solution, the mixture is stirred for 10 to 20 hours, filtered to obtain the compound of Formula V. When needed, the filter cake can be washed with water and dried at 45-55oC under vacuum to obtain a dry compound of Formula V.

[0148] According to the present disclosure, the Formula SM1 is reduced to obtain theFormula VI compound by using the following step (1):

[0149] Under a certain hydrogen pressure, Formula SM1 andplatinum catalyst in the organic solvent are reacted to obtain the compound of Formula VI. The said hydrogen pressure may be from 0.27 to 0.3MPa, inclusive. In some embodiments, the hydrogen pressure is 0.3MPa. The said platinum catalyst may be Pt- V / C. The said organic solvent may be THF (tetrahydrofuran). In some embodiments, the weight ratio of platinum catalyst (such as Pt-V / C) to the compound of Formula SM1 is about 0.05 to 0.20.

[0150] After the reaction is completed, the temperature is reduced, filtered bydiatomite, washed with THF, and the filtrate is concentrated under reduce pressure, replaced twice with ACN, concentrated to obtain the acetonitrile solution of the compound of Formula VI.

[0151] The present invention also includes methods for preparing compounds ofFormulas I, II, III, IV, V, and VI as described in the previous sections.

[0152] The present invention also includes the compounds themselves of Formulas I,II, III, IV, V, and VI of the present application.

[0153] The present invention also includes the application of compounds SM1, SM2,SM3, I, II, III, IV, V, and VI of the present application in the preparation of compounds of Formula (I).

[0154] The present invention also includes products containing compounds of FormulaII, III, IV, V, and VI obtained in the above preparation steps, including but not limited to various solutions, filtrates, filter cakes, etc.

[0155] In some embodiments, the present disclosure also provides a preparationmethod for the crystal form of the compound of Formula I, which includes: recrystallizing the compound of Formula (I) in a solvent to obtain the crystal form, wherein the solvent is a mixture of acetic acid and methanol.

[0156] In the above method, the compound of Formula (I) is dissolved in acetic acid,methanol is added dropwise, seed crystals are added, stirred, and filtered to obtain the crystal form A of the compound of Formula (I). The compound of Formula (I) and acetic acid can be mixed at a temperature of 35-45oC.

[0157] In the above method, the amount of acetic acid is sufficient to completelydissolve the compound of Formula (I). In some embodiments, the volume of acetic acid to compound of Formula (I) can be (4-6): 1. The volume ratio of acetic acid to methanol can be 1: (2.5-3.5), e.g. 1:3. The amount of seed crystals added can be 0.2-2.5% by weight of the compound of Formula (I).

[0158] In some embodiments, the compound of Formula (I) is dissolved in acetic acid,then methanol is added dropwise, crystal seeds are added, stirred for 1-3 hours, and then methanol is added dropwise. The stirring is continued for 2-4 hours, dropped to room temperature, and stirred for 4-10 hours. After filtration, crystal form A can be obtained. The volume ratio of methanol added twice can be 1: (2-4).

[0159] In some embodiments, the crystallization method includes adding acetic acidand the compound of Formula (I) to a reactor, dissolving at 35-45°C and then methanol is added dropwise, then crystal seeds are added, the mixture is stirred for 1-3 hours and then methanol is added dropwise, the mixture is continued to stir for 2-3 hours, then the temperature is reduced to room temperature and the mixture is still stirred for 4-10 hours, filtered, washed with methanol, dried to obtain the crystal form of the compound of Formula (I).

[0160] In some embodiments, the crystallization method also includes the step ofpreparing a compound of Formula (I) using any of the methods described herein. Preparation of Form B Methods for preparing crystal Form B as disclosed herein of the compound of Formula (I), including exemplary reagents, quantities and proportions, are provided herein. For example, crystal Form B may be prepared by a process comprising the steps of: (a) providing the compound of Formula (I) in solid form, e.g. any solid formdisclosed herein; (b) optionally washing the compound of Formula (I);(c) dissolving the compound of Formula (I) in an acid, optionally wherein the acidis hydrochloric acid, 1.0 N hydrochloric acid, sulfuric acid, aqueous sulfuric acid, or 0.25 M aqueous sulfuric acid;(d) optionally washing the solution with an organic solvent, optionally whereinthe organic solvent is dichloromethane, and / or extracting the solution, optionally wherein the extraction solvent is ethyl acetate; (e) causing the compound of Formula (I) to precipitate by combining the solutionwith a base, optionally wherein the base is sodium bicarbonate in solid or solution form, sodium carbonate in solid or solution form, ammonia, or aqueous ammonia; (f) optionally drying the precipitate, optionally wherein the drying comprises, forexample, drying under an infrared lamp for up to 16 hours. Crystal Form B may be prepared by a process comprising the following steps: 1. Optionally washing the compound of Formula (I), which may be amorphousor crystalline or a mixture thereof, with e.g. dichloromethane, methanol, and ethyl acetate, optionally in that order; with each wash, optionally stirring or mixing to expose the solid compound to the wash solvent prior to removing the solvent; 2. collecting the solid material and adding acid e.g. 1.0 N hydrochloric acid untildissolved (e.g. approximately 1 mL acid per 26.5 mg compound of Formula (I) free base), 3. extracting e.g. three times with about 4 times as much ethyl acetate as acidwas used (v / v), 4. adding saturated sodium bicarbonate (NaHCO3) solution dropwise whilestirring to cause the crystalline form B to precipitate; 5. optionally isolating the solid material by filtration.Crystal Form B may be prepared by a process that comprises the following steps: 1. dissolving the compound of Formula (I), which may be amorphous orcrystalline or a mixture thereof, in acid e.g.1.0 N hydrochloric acid until dissolved (e.g. approximately 1 mL acid per 45-50 mg compound of Formula (I) free base), 2. adding sodium carbonate (Na2CO3) dropwise with stirring until precipitationcomplete (about 1 mL Na2CO3per 90-95 mg compound of Formula (I)); 3. optionally isolating the solid material by filtration.

[0161] In some embodiments, the process comprises dissolving the compound ofFormula (I) in sulfuric acid e.g. aqueous sulfuric acid e.g. 0.25M, for example at ambient temperature (e.g. 15°C to 30°C, 18°C to 28°C, 20°C to 25°C), washing the solution with dichloromethane and adding the aqueous solution to aqueous ammonia (e.g. 1.5M) to form a slurry. The slurry is stirred at ambient temperature for 1 hour, filtered and dried e.g. under an infrared lamp to provide the crystal form of the compound of Formula (I).

[0162] In some embodiments, the process comprises dissolving the compound ofFormula (I) (e.g. 1g) in sulfuric acid e.g. aqueous H2SO4(e.g. 0.25M, 10mL). The resulting clear solution is combined with aqueous ammonia (e.g. 1.5M, 5mL) at ambient temperature. The resulting suspension is stirred for e.g. about 1 hour, filtered, washed with H2O (e.g. 5mL), and dried under an infrared lamp to yield the crystal form of the third aspect disclosed herein. The material can be dried for 16 hours. The resulting material has a water content of 7.3wt% by Karl Fischer test. XRPD shows a spectrum consistent with the crystal form of the third aspect disclosed herein (In a hydrate molecule comprising of one molecule of the compound Formula (I) and close to two water molecules). If heated for 40 hours, the material converts to the crystal form of the second aspect disclosed herein, as assessed by XRPD and TGA, with water content of 1.5wt% by KF. V. Method and application

[0163] The compound of the present disclosure is a PARP1 selective inhibitor, that is,the inhibitory effect of the compound of the present invention on PARP1 is stronger or more significant than that on PARP2 (or other PARPs). Therefore, the crystal form of the compound of the present disclosure can be used for manufacture of a medicament for treatment or prevention of clinical conditions responsive to the inhibition of PARP1 activity.

[0164] As used herein, clinical conditions responsive to the inhibition of PARP1activity refer to diseases or conditions the pathogenesis and development of which could be treated or prevented by inhibiting activity of PARP1.

[0165] As used herein, clinical conditions responsive to the inhibition of PARP1activity include cancers and other diseases responsive to the inhibition of PARP1 activity, such as excessive cell death, including central nervous system diseases such as stroke and neurodegenerative diseases.

[0166] The cancers responsive to the inhibition of PARP1 activity includes, but is notlimited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (including, e.g. small cell lung cancer), Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, granuloma fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumor disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocytosis, adrenal cortical cancer, skin cancer and prostate cancer.

[0167] Therefore, the present disclosure provides use of the compound of Formula (I)in the preparation of a medicament for treatment or prevention of clinical conditions responsive to the inhibition of PARP1 activity, such as the cancers described herein.

[0168] In some embodiments, the present disclosure provides use of a crystal form ofthe compound of Formula (I) (e.g. crystal form A or crystal Form B) according to the present disclosure, or a mixture of two or more such crystal forms, in the preparation of a medicament for treatment or prevention of clinical conditions responsive to the inhibition of PARP1 activity, such as the cancers described herein.

[0169] In some embodiments, the present disclosure provides use of a crystal form ofthe compound of Formula (I) (e.g. crystal form A or crystal Form B) according to the present disclosure, or a mixture of two or more such crystal forms, as a drug substance in the preparation of a medicament for treatment or prevention of clinical conditions responsive to the inhibition of PARP1 activity, such as the cancers described herein. A crystal form or a mixture of crystal forms may further comprise the compound of Formula (I) in amorphous form.

[0170] Also disclosed herein is a method for preparing a medicament, which includesthe step of mixing a crystal form of the compound of Formula (I) (e.g. crystal form A or crystal Form B) according to the present disclosure, or a mixture of two or more such crystal forms, with a pharmaceutically acceptable carrier or excipient. A crystal form or a mixture of crystal forms may further comprise the compound of Formula (I) in amorphous form.

[0171] A preparation of the compound of Formula (I) may be crystal Form A or crystalForm B or pure amorphous material as disclosed herein or may comprise a mixture of two or more of these.

[0172] The following examples further illustrate the embodiments herein, which should not be construed as limiting the scope of the embodiments described herein. Compounds, starting materials and reagents useful in the processes described herein, such as compounds of formulae SM1, SM2 and SM3, can be obtained from commercial sources or prepared using methods known to those skilled in the art. Example 1: Polymorph Screening and Suspension Competitive Experiments

[0173] The starting material of the compound of Formula (I) used for polymorphscreening was prepared as follows: about 6g of the compound of Formula (I) was dissolved in DMSO (100mL), stirred at 80°C for 1 hour, cooled to room temperature and poured into ice water (1 L) to precipitate the solids. The solid was collected by filtration and slurried with H2O (100 mL) at 100 °C for 1 hour, and the mixture was filtered. The solid obtained by filtration was lyophilized to give the starting material. The X-ray powder diffraction (XRPD) result showed the starting material was crystalline, which was named as Crystal form A as shown in Figure 20.

[0174] Using the above starting material, 100 polymorph screening experiments wereperformed under different conditions, using methods of slow evaporation, vapor-solid permeation, vapor-solution permeation, temperature cycling heating and cooling, suspension stirring (RT and 50ºC), slow cooling, anti-solvent addition and grinding. Based on the X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) characterization results, no new solid form was obtained.

[0175] Another crystal form of the compound of Formula I was obtained by thefollowing method: a sample of the compound of Formula I was dissolved in 1N aqueous HCl adjusted to pH 1 to 2. The solution was extracted with EtOAc. The aqueous phase was collected and adjusted to pH 7 to 9 with NaHCO3 aqueous phase and solid precipitated out. The mixture was filtered and the filter cake was dried to give the product. It had an XRPD diffraction peak basically consistent with that of crystal form A, but additional diffraction peaks presented, and additional diffraction peaks disappeared after heating the sample to 170°C and cooling to room temperature.

[0176] Slurry competitive experiments were performed for the crystal form A and theother crystal form of the preceding paragraph to investigate the inter-conversion relationship under different temperatures / solvents, room temperature and water activity conditions. The test operation was as follows: approximately 5 mg of compound crystal form A of Formula I was weighed in each solvent, stirred and balanced at room temperature / 50 ºC for 2 hours, and then filtered. The filtrate was transferred to a small bottle containing compound crystal form A of Formula I and other crystal forms, and continue to suspend and stir at room temperature / 50 ºC before testing XRPD. The different conditions and results of the slurry competitive experiments are shown in Table 1. Table 1. Results of slurry competitive experiments Solvent (v / v) Temp. Time Result Acetone RT 2 days Form A EtOAc RT 2 days Form A Acetone 50 ºC 2 days Form A EtOAc 50 ºC 2 days Form A EtOH RT 2 days Form A EtOH / H2O (97:3) RT 2 days Form A EtOH / H2O (93:7) RT 2 days Form A EtOH / H2O (86:14) RT 2 days Form A EtOH / H2O (70:30) RT 2 days Form A H2O RT 2 days Form A The results showed that all obtained are crystal form A. XRPD was tested using the parameters in the following table:

[0002] Parameters Reflection Mode Cu, kα Kα1 (Å): 1.540598, X-Ray wavelength Kα2 (Å): 1.544426, Kα2 / Kα1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Fixed 1 / 8º Scan mode Continuous Scan range 3~40 (º 2TH) Scan step time [s] 0.0263 Step size 46.7 (º 2TH) Test Time about 5 min Example 2: Solubility of the crystal form A

[0177] The solubility of the crystal form A in different single solvent systems weretested at 25 ℃ and 50 ℃, respectively. The results are shown in Table 2. Table 2: Solubility of the crystal form A in single solvent systems Solubility (mg / mL) Solvent at 25℃ at 50℃Methanol (MeOH) 1 1 Ethanol (EtOH) 0 1 Isopropanol (iPrOH) 0 0 n-Propanol 0 1 Ethyl Acetate (EA) 1 3 Isopropyl Acetate (IPA) 0 1 Acetone 1 3 2-Butanone 1 2 4-Methyl-2-pentanone 0 1 Methyl tert-butyl ether 1 1 (MTBE) n-Heptane 0 1 Acetonitrile 0 1 Toluene 1 3 Dichloromethane (DCM) 1 4 Tetrahydrofuran (THF) 1 3 2-Methyltetrahydrofuran 2 2 (2-Me THF) Cyclohexane 0 1 Dimethyl sulfoxide 1 1 (DMSO) Water 0 1 Acetic acid (AcOH) > 200 > 200 Hexafluoroisopropanol > 200 > 200 Trifluoroethanol ≤ 100 ≤ 100

[0178] The solubility of the crystal form A in different binary solvents systems weretested at 25℃ and 50 ℃, respectively. The results are shown in Table 3. Table 3: Solubility of Crystal Form A in Binary Solvents Systems Solubility (mg / mL) Solvent at 25℃ at 50℃Ethanol / Water (9V / 1V) 0 1 Ethanol / Water (1V / 1V) 0 1 Ethanol / Water (1V / 9V) 0 0 Isopropanol / Water (9V / 1V) 0 1 Isopropanol / Water (1V / 1V) 0 1 Isopropanol / Water (1V / 9V) 0 0 Methanol / Dichloromethane 1 ND (9V / 1V) Methanol / Dichloromethane 8 ND (1V / 1V) Methanol / Dichloromethane 12 ND (1V / 9V) Methanol / Tetrahydrofuran 0 1 (9V / 1V) Methanol / Tetrahydrofuran 2 4 (1V / 1V) Methanol / Tetrahydrofuran 2 4 (1V / 9V) Dichloromethane / 2 ND Tetrahydrofuran (9V / 1V) Dichloromethane / 1 ND Tetrahydrofuran (1V / 1V) Dichloromethane / 1 ND Tetrahydrofuran（1V / 9V) Methanol / Water (9V / 1V) ND 0 Methanol / Water (1V / 1V) ND 0 Methanol / Water (1V / 9V) ND 0 Acetonitrile / Water (9V / 1V) ND 1 Acetonitrile / Water (1V / 1V) ND 1 Acetonitrile / Water (1V / 9V) ND 0 Tetrahydrofuran / Water ND 6 (9V / 1V) Tetrahydrofuran / Water ND 3 (1V / 1V) Tetrahydrofuran / Water ND 0 (1V / 9V) Methanol / 2-Methyltetrahydrofuran ND 1 (9V / 1V) Methanol / 2-Methyltetrahydrofuran ND 2 (1V / 1V) Methanol / 2-Methyltetrahydrofuran ND 2 (1V / 9V) Ethyl Acetate / Water (98V / 2V) ND 1

[0179] The results showed that the crystal form A has relatively low solubility in mostsingle and binary solvent systems tested, except in acetic acid and hexafluoroisopropanol. Example 3: Crystallization method by using hexafluoroisopropanol / other solvents

[0180] The solubility of the crystal form A in hexafluoroisopropanol was high (morethan 200 mg / mL at 25℃) (as shown in Example 2). Based on that result, hexafluoroisopropanol was used as a solvent, and crystal form A was recrystallized with methyl tert-butyl ether, water and methanol as counter solvents, respectively. The steps for the recrystallization experiment of hexafluoroisopropanol / water system were as follows: the crystal form A was dissolved in hexafluoroisopropanol and the solution was stirred at 30oC. Water and crystal seeds were added, and the mixture was stirred. Additional water was added and the mixture was continuously stirred. Then the mixture was cooled down to 10oC, stirred, filtered, washed and dried to give the product.

[0181] The recrystallization experiment steps of hexafluoroisopropanol / methyl tert-butyl ether system and hexafluoroisopropanol / methanol system were similar to those of the above hexafluoroisopropanol / water system. The experimental results are shown in Table 4 below. Table 4: Crystallization results of hexafluoroisopropanol / other solvent systems Yield / Crystallization System XRPD Purity Residual solvent Mother liquid loss crystal form A hexafluoroisopropanol / water 100% / with additional 99.91% / (1V / 3V) 0.4% diffraction peaks hexafluoroisopropanol / methyl 88% / MTBE: crystal form A 99.21% tert-butyl ether (1V / 3V) 0.1% 7500 ppm Methanol: 1772 ppm hexafluoroisopropanol / methanol 97.9% / crystal form A 99.96% (1V / 3V) 0.3% Hexafluoro- isopropanol: 20419 ppm

[0182] The XRPD of the product obtained from the crystallization ofhexafluoroisopropanol / water system indicates that crystal form A was obtained, but the XRPD contains additional diffraction peaks. The product crystallized in the system of hexafluoroisopropanol / methyl tert-butyl ether is the crystal form A, and the methyl tert- butyl ether residue in the product is high. The product obtained by crystallization in the hexafluoroisopropanol / methanol system is crystal form A, but the content of the residual hexafluoroisopropanol in the product is high. Example 4: Crystallization method by using acetic acid / other solvents

[0183] The solubility of the crystal form A in acetic acid was high (more than 200mg / mL at 25℃) (as shown in Example 2). Based on that result, acetic acid was used as a solvent, and crystal form A was recrystallized with methyl tert-butyl ether and methanol as counter solvents, respectively. The steps for the recrystallization experiments of acetic acid / methyl tert-butyl ether system, and acetic acid / methanol system were similar to those described in Example 3. The experimental results are shown in Table 5 below. Table 5: Crystallization results of acetic acid / other solvent systems Yield / Crystallization System XRPD Purity Residual solvent Mother liquid loss Methyl tert-butyl ether: 700 ppm Acetic acid / methyl tert-butyl 95.8% / Crystal form A 99.78% ether (1V / 3V) 4.74% Acetic acid: 2191 ppm Methanol: 300 ppm 81.9% / Acetic acid / methanol (1V / 3V) Crystal form A 99.87% 15.84% Acetic acid: 400 ppm

[0184] The products obtained by crystallization in the acetic acid / methyl tert-butylether system and acetic acid / methanol system are both crystal form A, and the content of each residual solvent in the product is minimal. Example 5: Preparation of the crystal form A of the compound of Formula I Step 1: Preparation of 5-bromo-2,3-difluoroaniline (the compound of Formula VI) 5-bromo-2,3-difluoronitrobenzene (the compound of Formula SM1, 14.8 kg, 62.2 mol),tetrahydrofuran (195.5 kg, 15 V) and Pt-V / C (1.47 kg) were added into a hydrogenation kettle. The reaction system was replaced with hydrogen three times keeping the pressure at 0.3 MPa, and the mixture was stirred for 20 hours at 50oC. The mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, then replaced twice with acetonitrile, and finally concentrated under reduced pressure to obtain 32.6 kg of acetonitrile solution of 5-bromo-2,3- difluoroaniline (the compound of Formula VI, brown liquid, purity 98.2%, yield 94%). HPLC(std): 6.75 min; MS(ESI): m / z=207.96[M+H]+;1H NMR(400MHz, DMSO-d6): 6.77 (d, J = 6.8 Hz, 1H), 6.70–6.66 (m, 1H), 5.66 (s, 2H). Step 2: Preparation of N-(5-bromo-2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (the compound of Formula V) 1H- kg, 144.5 mol), N,N'-carbonyl diimidazole (18.68 kg, 115.2 mol) and acetonitrile (76 kg, 8.0 V) were added into a kettle, the mixture was stirred for 5 hours at 25oC. Then to the mixture was added 5- bromo-2,3-difluoroaniline (the compound of Formula VI, 12.0 kg, 57.7 mol) and N,N- diisopropylethylamine (14.88 kg, 115.1 mol) and stirred for 18 hours at 80oC. The reaction mixture was cooled, diluted with water (300 kg, 25.0 V) and stirred for 16 hours at room temperature. The final mixture was filtered, and the cake was washed with process water. The cake was dried under vacuum condition at 50oC for 24 hours to obtain N-(5-bromo-2,3- difluorophenyl)-1H-pyrazole-5-carboxamide (the compound of Formula V, 15.5 kg, white solid, purity 99.7%, yield 89%). HPLC(std): 10.23 min; MS(ESI): m / z=301.97[M+H]+;1H NMR(400MHz, DMSO-d6): 13.55 (s, 1H), 9.95 (s, 1H), 7.94 (d, J = 2 Hz, 1H), 7.88-7.87 (m, 1H), 7.66-7.63 (m, 1H), 6.81 (d, J = 2 Hz 1H). Step 3: Preparation of 7-bromo-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula IV) N-(5-bromo-2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (the compound of Formula V, 5.2 kg, 17.2 mol) was added into a kettle, then potassium carbonate (22 kg, 157 mol) and NMP (491 kg, 31 V) was added, and the mixture was stirred for 5 hours at 120oC. The mixture was cooled down to 50oC, to which was added N-(5-bromo-2,3-difluorophenyl)-1H-pyrazole- 5-carboxamide (the compound of Formula V, 5.2 kg, 17.2 mol), and the reaction system was heated to 120oC and stirred for 5 hours. Then the reaction system was cooled down to 50oC, to which was added N-(5-bromo-2,3-difluorophenyl)-1H-pyrazole-5-carboxamide (the compound of Formula V, 5.1 kg, 16.9 mol), and the resulting mixture was heated to 120oC and stirred for 13 hours. The mixture was cooled down to room temperature, diluted with process water (929 kg, 60.0 V) and stirred for 13 hours. The resulting mixture was filtered, and the filtrate was collected. The pH of filtrate was adjusted to 5 to 6 with concentrated hydrochloric acid (28 kg, 1.5 V). The resulting mixture was stirred and filtered, and the wet product was dried under reduced pressure at 60oC for 44 hours to obtain 7-bromo-9-fluoropyrazolo[1,5- a]quinoxalin-4(5H)-one (the compound of Formula IV, 12.38 kg, white solid, purity 97.3%, yield 81%). HPLC(std): 6.74 min；MS(ESI): m / z=281.97[M+H]+;1H NMR(400MHz, DMSO-d6): 12.09 (s, 1H), 8.13 (d, J = 2 Hz, 1H), 7.54-7.51 (dd, J = 2, 11.5 Hz, 1H), 7.35 (t, J = 2 Hz, 1H), 7.20 (d, J = 2 Hz, 1H). Step 4: Preparation of 9-fluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula III) 1,4-dioxane (190 quinoxalin-4(5H)-one (the compound of Formula IV, 9.0 kg, 31.9 mol), Xphos Pd G2 (1.09 kg, 1.60 mol) and (tributylstannyl)methanol (12 kg, 36.4 mol) were added into a kettle, and the mixture was stirred for 16 hours at 80oC. To the reaction mixture was added 1,4-dioxane (285 kg, 30.5 V) and silica thiol (4.6 kg) and stirred for 5 hours at 80oC. The reaction mixture was filtered and washed with 1,4-dioxane. To the filtrate was added silica thiol (2.7 kg) and stirred for 8 hours at 80oC. The resulting filtrate was filtered and washed with 1,4-dioxane. The final filtrate was concentrated under reduced pressure and stirred for 3 hours at 80oC, which was added tert- butyl methyl ether (111 kg, 16.5 V), cooled down to room temperature and stirred for 13 hours. The final mixture was filtered, and the cake was washed with tert-butyl methyl ether. The wet product was dried under reduced pressure at 50oC for 20 hours to obtain 9-fluoro-7- (hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula III, 7.34 kg, off-white solid, purity 96%, yield 80%). HPLC(std): 4.82 min；MS(ESI): m / z=234.07[M+H]+;1H NMR(400MHz, DMSO-d6): 12.07 (s, 1H), 8.10(d, J = 2 Hz, 1H), 7.21 (s, 1H), 7.17 (d, J =2 Hz, 1H), 7.13-7.10 (d, J = 13.2 Hz, 1H), 5.49 (s, 1H), 4.55 (s, 2H). Step 5: Preparation of 7-(chloromethyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula II) 9-fluoro-7- (the compound of Formula III, 5.73 kg, 24.6 mol), dichloromethane (220 kg, 29 V) and N,N-dimethylformamide (2.8 kg, 49.4 mol) were added into a kettle, to the mixture thionyl chloride was added dropwise (15 kg, 72.1 mol) and stirred for 1 hours at 0oC, then the resulting mixture was heated to 10oC and stirred for 18 hours. The resulting mixture was diluted with water (11 kg, 2V), stirred for 10 hours and filtered, and the cake was washed with dichloromethane and water in sequence. The wet product was dried under reduced pressure at 50oC for 20 hours to obtain 7- (chloromethyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula II, 6.3 kg, white solid, purity 96.0%, yield 91%). HPLC(std): 7.64 min；MS(ESI): m / z=252.03[M+H]+;1H NMR(400MHz, DMSO-d6): 12.12 (s, 1H), 8.12 (d, J = 1.76 Hz, 1H), 7.32-7.29 (d, J = 12.5 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 1.76 Hz, 1H), 4.84 (s, 2H). Step 6: Preparation of 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7- yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (the compound of Formula I) , , diisopropylethylamine (11.6 kg, 90.1 mol), N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride (the compound hydrochloride of Formula SM3, 5.1 kg, 21.5 mmol), potassium iodide (0.6 kg, 3.5 mol), 7-(chloromethyl)-9-fluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (the compound of Formula II, 4.5 kg, 17.8 mol) and NMP (47 kg, 10 V) were added into a kettle, the mixture was refluxed and stirred for 16 hours. The mixture was cooled down to 50oC and water (112 kg, 25 V) was added dropwise, then the resulting mixture was cooled down to room temperature, stirred for 5 hours, filtered and washed with water. The wet product was dissolved in DMSO (176 kg, 35.5 V) at 90oC, then the solution was cooled down to 50oC and methanol (126 kg, 35.5 V) was added dropwise. The resulting solution was cooled down to room temperature, stirred for 3 hours and filtered, and the cake was washed with methanol. The wet product was dried under reduced pressure at 50oC for 20 hours to obtain 5-(4-((9-fluoro-4-oxo- 4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (the compound of Formula I, 5.8 kg, white solid, purity 99.9%, yield 72%). Recrystallization: Acetic acid (20.5 kg, 5 V) and 5-(4-((9-fluoro-4-oxo-4,5- dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-6-methylpyridine-2- carboxyformamide (the compound of Formula I, 4.0 kg, 8.9 mol) were added into a kettle and dissolved at 40oC. To the solution was added methanol (12.7 kg, 4 V) and crystal seeds (80g), stirred for 1 to 3 hours and added methanol (35 kg, 11 V). The resulting solution was stirred for 2 to 3 hours at 40oC and 7 hours at room temperature, filtered and washed with methanol. The wet product was dried under reduced pressure at 50oC for 21 hours to obtain 5-(4-((9-fluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-6 -methylpyridine-2-carboxyformamide (the crystal form A of the compound of Formula I, 3.44 kg, off-white solid, 100% purity, 86% yield). HPLC(std): 11.60 min; MS(ESI): m / z=450.21[M+H]+;1H NMR(400MHz, DMSO-d6): 12.00 (s, 1H), 8.42–8.39 (q, J = 5.2, 4.4 Hz, 1H), 8.10 (d, J = 2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.20-7.17 (m, 2H), 3.62 (s, 2H), 2.97 (b,4H), 2.80 (d, J = 4.8 Hz,3H), 2.60 (b,4H), 2.50 (s,3H). Example 6: Charaterization of the crystal form A The crystal form A produced in Example 5 was characterized by XRPD, TGA and DSC.1. Instruments and Methods1) X-ray powder diffractometer (XRPD)The XRPD was detected on the X-ray powder diffraction analyzer produced by Bruker, and the testing parameters used are listed below. Parameters Bruker D8 Advance Kα1 (Å): 1.5406, X-Ray wavelength Kα2 (Å): 1.54439 Kα2 / Kα1 :0.50 Parameters Bruker D8 Advance Cu: K-Alpha1 (A=1.54060 A) X-Ray tube setting 40 kV, 40 mA Divergence slit 0.60 mm Scan mode Continuous Scan range (°2θ) 4-40 Scan step time (s) 0.12 Step size (°2θ) 0.02 deg2) Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)TGA and DSC were collected on TA TA550 thermogravimetric analyzer and TA DSC250 differential scanning calorimeter, respectively. The testing parameters used are listed below. Parameters TGA DSC Method Ramp Ramp Sample pan Platinum, open Aluminum, crimped Temperature 30 to 350 ℃ 30 to 400 ℃ Heating rate (ºC / min) 10 10 Purge gas N2 N22. Characterization

[0185] An example of an XRPD spectrum obtained for the crystal form A is shown inFigure 1, and the corresponding XRPD diffraction peak is shown in Table 6. XRPD peak positions can vary by plus or minus 0.2° 2θ. Table 6: XRPD data of the crystal form A No. °2θ Rel. Intensity 1 5.4 80% 2 9.9 19% 3 10.8 100% 4 11.2 36% 5 11.4 40% 6 12.1 4% 7 13.2 45% No. °2θ Rel. Intensity 8 14.4 9% 9 14.6 3% 10 14.8 5% 11 16.2 91% 12 16.3 17% 13 17.2 7% 14 17.7 16% 15 18.5 6% 16 19.0 2% 17 20.2 43% 18 20.5 45% 19 21.0 9% 20 21.1 6% 21 21.8 15% 22 22.6 30% 23 22.9 4% 24 23.6 10% 25 23.9 11% 26 24.3 29% 27 25.0 6% 28 25.2 2% 29 26.1 31% 30 27.0 4% 31 27.4 6% 32 28.0 4% 33 29.0 23% 34 29.5 2% 35 29.8 3% 36 30.8 5% 37 30.9 2% 38 31.6 3% No. °2θ Rel. Intensity 39 32.3 2% 40 32.6 5% 41 33.1 2% 42 34.5 2% 43 34.8 2% 44 37.4 1% 45 39.2 2% The TGA curve was displayed in Figure 2, which showed the TGA thermogram of the crystal form A. The DSC curve was displayed in Figure 3, which showed the DSC thermogram of the crystal form A. The DSC thermogram shows one endothermic peak at 320.7 ºC (onset temperature). Example 7: Stability of the crystal form A

[0186] Evaluation of the stability of crystal form A was carried out under hightemperature (60oC) for 10 and 30 days. The XRPD of the sample was detected by using the method described above. The XRPD overlay of the crystal form A after high temperature stability evaluation is shown as in Figure 4. The results showed that the XRPD of the sample did not show significant changes after 10 and 30 days, indicating that the sample remained in crystal form A.

[0187] Evaluation of the stability of crystal form A was carried out under highhumidity (25oC / 92.5%RH) for 10, and 30 days. The XRPD of the sample was detected by using the method described above. The XRPD overlay of the crystal form A after high humidity stability evaluation is shown as in Figure 5. The results showed that the XRPD of the sample did not show significant changes after 10, and 30 days, indicating that the sample remained in crystal form A.

[0188] Evaluation of the stability of crystal form A was carried out under strong lightirradiation (1^ICH). The XRPD of the sample was detected by using the method described above. The XRPD overlay of the crystal form A after strong light irradiation stability evaluation is shown as in Figure 6. The results showed that the XRPD of the sample did not show significant changes under strong light irradiation, indicating that the sample remained in crystal form A.

[0189] This procedure was carried out as follows:0.5 g sample was placed in a clean quartz petri dish. Two replicates were prepared in parallel and placed into a photo stability chamber. The samples were exposed to light according to the current edition of the Chinese pharmacopoeia. When the total energy reached 1.2 million lux·hr and 200 W·hr per square meter (1 ^ ICH), the two copies of samples were removed from the illumination chamber for testing.

[0190] Two parallel controls were treated the same way. The control samples wereprepared by the same procedure, and the sample was wrapped completely by aluminum foil. These were exposed to light as described above, then tested. These samples are called “1 ^ ICH-dark.”

[0191] Evaluation of the stability of crystal form A was carried out under the conditionof accelerated (40oC / 75%RH) for 1, 3, and 6 months. The XRPD of the sample was detected by using the method described above. The XRPD overlay of the crystal form A of accelerated stability evaluation is shown as in Figure 7. The results showed that the XRPD of the sample did not show significant changes after 1, 3, and 6 months, indicating that the sample remained in crystal form A.

[0192] Evaluation of the stability of crystal form A was carried out under the conditionof long-term (25oC / 60%RH) for 1, 3, 6 and 9 months. The XRPD of the sample was detected by using the method described above. The XRPD overlay of the crystal form A after long-term stability evaluation is shown as in Figure 8. The results showed that the XRPD of the sample did not show significant changes after 1, 3, 6 and 9 months, indicating that the sample remained in crystal form A. Example 8: Preparation of amorphous compound of Formula (I)

[0193] Amorphous compound of Formula (I) was prepared as follows: 9.0g of thecompound of Formula (I) was dissolved in 960g dichloromethane and 240mL methanol and spray dried on a Buchi B-290 Advanced Spray Drier according to the parameters in Table 7. This spray drying resulted in amorphous material, as assessed by X-ray powder diffraction (XRPD) and polarized light microscopy (PLM), as shown in Figures 18 and 19. For example, the XRPD shows no resolved diffraction peaks, which indicates amorphous material. Table 7 Parameter Target Actual Nozzle size 1.4 mm 1.4 mm Inlet Temp Record actual 65°C Outlet Temp 40-45°C 47°C Aspirator 100% 100% Spray Air Setting 30 mm 30 mm Peristaltic Pump Rate 5 g / min 5 g / min Example 9: First Preparation of Form B of the Compound of Formula (I)

[0194] 105.6 mg of the compound of Formula (I) was placed into a fritted glass filterby using with water. Solids washed with 10 mL dichloromethane (DCM), 5 mL MeOH, and 10 mL of ethyl acetate (EtOAc) in sequence. Solids stirred with glass rod into each solvent to mix and allow exposure before pulling vacuum. After addition of ethyl acetate, the mixture was stirred into a suspension. Solids collected and 1.0 N HCl added until dissolved (~4 mL). Ethyl acetate added to extract (3^ 15 mL), with turbidity clearing up between washes. Saturated sodium bicarbonate solution added dropwise while stirring to precipitate.

[0195] Solids were isolated by filtration and were tested by XRPD, which showed thatthey were Form B crystals.

[0196] An example of an XRPD spectrum of Form B is shown in Figure 9A, and thecorresponding XRPD peak positions are shown in Table 8. Each listed XRPD peak position can vary by plus or minus 0.2° 2θ. An example of an XRPD spectrum of Form B after 16 hours drying under an IR lamp is shown in Figure 9B. Table 8. XRPD data of the crystal Form B No. Pos. (°2θ) 1 4.56 ± 0.2 2 9.25 ± 0.2 3 10.75 ± 0.2 4 12.68 ± 0.2 5 13.37 ± 0.2 6 13.88 ± 0.2 7 15.4 ± 0.2 8 16.13 ± 0.2 9 20.13 ± 0.2 10 21.25 ± 0.2 11 21.89 ± 0.2 12 23.52 ± 0.2 13 24.84 ± 0.2 14 26.83 ± 0.2 15 29.01 ± 0.2 16 29.46 ± 0.2 XRPD may be tested using the following parameters: Table 9. Parameters for XRPD Parameters Reflection Mode Cu, kα Kα1 (Å): 1.540598, X-Ray wavelength Kα2 (Å): 1.544426, Kα2 / Kα1 intensity ratio: 0.50 X-Ray tube setting 40 kV, 15 mA Divergence slit Fixed 1 / 8º Scan mode Continuous Scan range 3-40 (º 2-theta) Scan step time [s] 17.595 Step size 0.0109 (º 2-theta) Test Time 4.5 min Example 10: Second Preparation of Form B of the Compound of Formula (I)

[0197] Crystal Form B of the compound of Formula (I) was prepared as follows: 93.7mg of the compound of Formula (I) was dissolved in approximately 2 mL of 1.0 N HCl. While stirring, saturated Na2CO3 was added dropwise, with 1 mL added after precipitation appeared complete. Stirred for less than 5 minutes. Solids were isolated by filtration and tested by XRPD and found to be Form B.

[0198] Form B was characterized by TGA and DSC. The TGA showed a rapid weightloss of at least 4.75% beginning at ambient temperatures, while the DSC showed a large desolvation endotherm with a peak at 100.65 ºC and a sharper endotherm with an onset near 296 ºC (Figure 10A).

[0199] TGA data was collected using a TA Discovery 550 TGA (CPNJ-E3) from TAInstrument. DSC was performed using a TA 2500 DSC (CPNJ-E27) from TA Instrument. DSC was calibrated with indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 10.

[0003] Table 10. Parameters for TGA and DSC measurements Parameters TGA DSC Method Ramp Ramp Sample pan Platinum, open Aluminum, crimped Temperature RT – desired temperature Heating rate 10 ºC / min Purge gas N2

[0200] Analogous procedures are used to analyze the same material after drying thematerial for 16 hours using e.g. an infrared lamp. The results are shown in Figures 10B (DSC) and 10C (TGA). Example 11: Third Preparation of Form B of the Compound of Formula (I)

[0201] The compound of Formula (I) (1g) was dissolved in aqueous sulfuric acid(0.25M, 10mL) at ambient temperature, and the resulting solution was then washed with dichloromethane (DCM) (10mL). The aqueous solution was added to aqueous ammonia (1.5M, 5mL) to carry out slurry. The resulting solid-liquid mixture was stirred at ambient temperature for 1 hour, filtered and dried under an IR lamp to provide the compound of Formula (I) (~0.95g). An example of the XRPD of Form B is shown in Figure 9A. An example of an XRPD spectrum of Form B after 16 hours drying under an IR lamp is shown in Figure 9B. Example 12: Single crystal cultivation and structure analysis of the crystal form A Anhydrate: The single crystals of the crystal form A were obtained from acetic acid (solvent) / 2-MeTHF (anti-solvent) solvent system via liquid-vapor permeation. The single crystal X-ray diffraction SCXRD characterization result indicated the single crystal of the crystal form A belonged to triclinic crystal system and P1̅ space group. The unit cell parameters were determined as {a = 7.5277(2) Å, b = 9.1395(2) Å, c = 16.2025(2) Å, α = 90.5230(10)º, β = 90.508(2)º, γ = 105.180(2)º, V = 1075.71(4) Å3}. Single crystal structure analysis showed the asymmetric unit of the crystal structure was comprised of only one molecule of the compound of Formula (I) as shown in Figure 11, which indicated the single crystal of the crystal form A was an anhydrate. The molecular packing diagrams viewed along the crystallographic a-axis is shown as in Figure 12. There is a small cavity in the lattice that does not contain any crystalline water molecules or other solvent molecules. Hydrate: The single crystals of the crystal form A were obtained from DMSO (solvent) / 2- MeTHF (anti-solvent) solvent system via liquid-vapor permeation and slow evaporation. SCXRD characterization result indicated the single crystal of the crystal form A belonged to triclinic crystal system and P1̅ space group. The unit cell parameters were determined as {a = 7.58340(10) Å, b = 9.1224(2) Å, c = 16.1236(3) Å, α = 90.4750(10)º, β = 90.2170(10)º, γ = 104.760(2)º, V = 1078.55(4) Å3}. Single crystal structure analysis showed the asymmetric unit of the crystal structure was comprised of one molecule of the compound of Formula I, and a crystalline water molecule with a chemical occupancy of about 0.2 in the lattice void as shown in Figure 13, which indicated the single crystal of the crystal form A was a non-stoichiometric hydrate (the molar ratio of the freebase molecule to crystalline water molecule in the single crystal structure is 1:0.2). The molecular packing diagrams viewed along the crystallographic a-axis is shown as in Figure 14.

[0202] The above hydrate and anhydrate have only minuscule differences in structurebut show minor peak drift due to those differences (Figure 15 and Figure 16). The hydrate structure only has 20% occupancy on one water - inferring that a monohydrate would present, but that it was not successfully captured in this structure. The hydrogen- bonding observed in the structure would be viable as a monohydrate. The anhydrate structure is almost identical, with a difference of 0.26% in volume, and nearly identical orientations and packing (Figure 17). Example 13: PARP1 and PARP2 chemiluminescent Assay

[0203] The diluent of recombinant poly (ADP-ribose) polymerase 1 and 2 (PARP1 andPARP2) (40 ng enzyme / well) and the compounds to be tested were mixed, respectively. The solutions were added to a 96-well plate coated with recombinant protein mixture, incubated at room temperature for 1 h, then 50 μL 0.3ng / mL Streptavidin-HRP of horseradish peroxidase was added to each well. The plates were incubated for 30 minutes at room temperature. Finally, the plates were treated with streptavidin-HRP followed by addition of the ELISA ECL substrate to produce chemiluminescence that can be measured using a chemiluminescence reader. Inhibition of the tested compound to PARP1 / 2 enzyme activity was calculated according to the following formula. IC50 value is obtained by fitting the s-shaped dose response curve equation by using XL Fit software. The curve equation is Y=100 / (1+10^(logC-logIC50)), C is the compound concentration.

[0204] The results showed that the inhibitory effect (IC50) of the compound of thepresent disclosure on PARP1 and PARP2 enzyme were 1.71 nM and 868 nM, respectively. Compared with PARP2, the compound of the present disclosure has selective inhibitory effect on PARP1 enzyme activity. Example 14: Assay of the inhibitory activity of the compound of Formula (I) on the growth of cells of BRCA mutant human breast cancer MDA-MB-436

[0205] The compound of Formula (I) was assayed for its inhibitory activity on thegrowth of cells of the BRCA mutant human breast cancer MDA-MB-436 cell line. MDA-MB-436 cells were cultured in complete medium (DMEM medium +10% FBS + Insulin + glutathione). When the confluence reached about 80%, cells were digested and gently dislodged from the bottom of the dish with a 1 mL pipette. Cell suspension was collected and centrifuged at 500rpm for 3min. The supernatant was discarded, and the cell pellet were re-suspended in complete medium. The cells were seeded into a culture dish at an appropriate proportion, and then cultured in a 5% CO2incubator at 37℃. The assay was carried out when the cells were in optimum condition and the confluence was reached 80%. Cells in the logarithmic growth phase were taken to centrifugate, and the culture supernatant was removed. The cells were resuspended in refresh complete medium and counted. The resuspended cells were seeded at 3000 / well in a 96-well plate and incubated at 37℃, 5% CO2incubator overnight. The compound was prepared as below: 1000^ dilution tested compound solution to 40^ test compound solution by adding 5μL 1000^ compound solution to 120 μL Medium (25-fold dilution). The solution was mixed by oscillation. 0.1% DMSO was used as the control.

[0206] The next day, the 96-well plate inoculated with cells was taken out from theincubator, and the culture supernatant was removed. Then fresh medium of 195 uL / well and 5μL / well of 40^ test compound solution as mentioned above were added into the 96 well plate, respectively. Finally, the plate was incubated for 7 days in a 37℃ 5% CO2 incubator. The medium containing compound was changed on the fourth day. After 7 days, 20μL of CCK-8 was added to each well and shaken gently, then was cultured for 4 hours. The plate was shaken for 5min after incubation. the absorbance values of 450nm or 650nm wavelengths were recorded respectively (OD = absorbance value of 450nm - absorbance value of 650nm) by using the multifunction readout instrument.

[0207] Data were analyzed by software GraphPad Prism 6.0. The inhibitory activity of compounds on cell proliferation was plotted using cell survival rate against the compound concentration as coordinates. Cell survival rate %= (ODcompound- ODbackground) / (ODDMSO-ODbackground) ×100. The IC50 value was fitted by the s-shaped dose response curve equation: Y=100 / (1+10^(logC-logIC50)), and C was the compound concentration.

[0208] The results showed that the compound of the present disclosure has a goodinhibitory effect on the growth of MDA-MB-436 cells with BRCA mutation (IC50 = 1.20 nM).

Claims

What is claimed is:

1. A crystal form of a compound of Formula (I),, X-ray powder diffraction (XRPD) spectrum thatpositions: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

2. The crystal form of claim 1, wherein the crystal form is characterized by an XRPDspectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

3. The crystal form of claim 1, wherein the crystal form is characterized by an XRPDspectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, and 21.8 ± 0.2° 2θ.

4. The crystal form of claim 1, wherein the crystal form is characterized by an XRPDspectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

5. The crystal form of claim 1, wherein the crystal form is characterized by an XRPDspectrum that exhibits peaks at: 10.8 ± 0.2° 2θ, 13.2 ± 0.2° 2θ, 16.2 ± 0.2° 2θ, 20.2 ± 0.2° 2θ, 21.8 ± 0.2° 2θ, and 29.0 ± 0.2° 2θ.

6. A crystal form of a compound of Formula (I):, wherein, a diffraction peaks at least four of thefollowing positions: 5.4±0.2° 2θ, 9.9±0.2° 2θ, 10.8±0.2° 2θ, 11.4±0.2° 2θ 13.2±0.2° 2θ, 16.2±0.2° 2θ, 17.7±0.2° 2θ 20.2±0.2° 2θ, 20.5±0.2° 2θ, 22.6±0.2° 2θ, and 24.3±0.2° 2θ.

7. A crystal form of a compound of Formula (I):, wherein thethe same as that shown inFigure 1.

8. A crystal form of a compound of Formula (I):, wherein the (TGA) curve substantially thesame as that9. A crystal form of a compound of Formula (I):, wherein the (DSC) curve substantially thesame as that shown in Figure 3.

10. A crystal form of a compound of Formula (I):, wherein the(a) an XRPD spectrum substantially the same as that shown in Figure 1; (b) a TGA curve substantially the same as that shown in Figure 2; and (c) a DSC curve substantially the same as that shown in Figure 3.

11. A crystal form of a compound of Formula (I):,exhibits a peak at 322.4°C ± 5° C.

12. A crystal form of a compound of Formula (I),I), whe an XRPD spectrum that exhibits peaks at least four of the following positions: 4.6 ± 0.2° 2θ, 9.3 ± 0.2° 2θ, 10.8 ± 0.2° 2θ, 13.9 ± 0.2° 2θ, 21.3 ± 0.2° 2θ, 21.9 ± 0.2° 2θ, 23.5 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ.

13. A crystal form of a compound of Formula (I):, wherein thethe same as that shown in Figure 9A or Figure 9B.

14. A crystal form of a compound of Formula (I):, wherein thethe same as that shown in Figure 10A or Figure 10C.

15. A crystal form of a compound of Formula (I):I), wherein the c y the same as that shown in Figure 10A or Figure 10B.

16. A crystal form of a compound of Formula (I):, following:(a) an same as in Figure 9A or Figure 9B; (b) a TGA curve substantially the same as that shown in Figure 10A or Figure 10C; and (c) a DSC curve substantially the same as that shown in Figure 10A or Figure 10B.

17. A crystal form of a compound of Formula (I):, wherein theDSC endotherm peaks at any one, two or all three of 101°C ± 5° C, 288°C ± 5°C and 309°C ± 5°C and / or endotherm onset temperatures of any one, two or all three of 57°C ± 5°C, 280°C ± 5°C, and 295°C ± 5°C, or has a DSC curve that exhibits DSC endotherm peaks at either or both of 83°C ± 5°C and 318°C ± 5°C and / or endotherm onset temperatures at either or both of 21°C ± 5°C and 296°C ± 5°C.

18. A composition comprising the crystal form of any one of claims 1-17 and apharmaceutically acceptable carrier or excipient.

19. The composition of claim 18, wherein the composition further includes at least oneknown anticancer drug or pharmaceutically acceptable salt thereof.

20. The composition of claim 19, wherein the at least one known anticancer drug isselected from the group consisting of: abiraterone, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, darolutamide, enzalutamide, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, prednisone, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, dinutuximab, blinatumomab, ipilimumab, bevacizumab, trastuzumab, rituximab, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib lafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pratinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine).

21. A method for preparing a composition comprising combining the crystal form of anyone of claims 1-17 and a pharmaceutically acceptable excipient or carrier.

22. A composition prepared by the method of claim 21.

23. The composition of claim 22, wherein the composition further includes at least oneknown anticancer drug or pharmaceutically acceptable salts thereof.

24. The composition of claim 23, wherein the at least one known anticancer drug isselected from the group consisting of: abiraterone, busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin, carboplatin, camptothecin, irinotecan, topotecan, doxorubicin, darolutamide, enzalutamide, epirubicin, aclarubicin, mitoxantrone, methylhydroxy ellipticine, etoposide, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, methotrexate, 5-fluoro-2'-deoxy-uridine, fludarabine, nelarabine, ara-C, pralatrexate, prednisone, pemetrexed, hydroxyurea, thioguanine, colchicine, vinblastine,vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, docetaxel, panitumumab, necitumumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, elotuzumab, T-DM1, , dinutuximab, blinatumomab, ipilimumab, bevacizumab, trastuzumab, rituximab, imatinib, gefitinib, erlotinib, ostinib, afatinib, ceritinib, alectinib, crizotinib, erlotinib, lapatinib, solutinib lafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pratinib, brutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabitinib, axitinib, temsirolimus, idelalisib, pazopanib, everolimus, tamoxifen, letrozole, fulvestrant, mitoguanhydrazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), sipueucel-T (prostate cancer therapeutic vaccine).

25. A process for preparing a compound of Formula (I), wherein the process comprisesthe steps of: (a) reducing a compound of Formula (SM1) to obtain a compound of Formula (VI):; (b) preparing a compound of Formula (V) from a compound of Formula (VI) and acompound of Formula (SM2) in the presence of alkalis and coupling reagent in the organic solvent: ; (c)to get acompound of Formula (IV):; (d) reacting a comp presence of palladiumcatalyst to get a compound of Formula (III): ; (e) preparing aof Formula (III) and aacylation reagent: ; (f) preparing abetween acompound of Formula (II) and a compound of Formula (SM3) in the presence of alkali and solvent:.

26. A process for preparing a crystal form of a compound of Formula (I) as follows,wherein the process is recrystallizing the compound of Formula (I) in a mixture of acetic acid and methanol.(I).

27. A process for prepa rmula (I) as follows,(I) wherein the process (a) providing the(b) optionally washing the compound of Formula (I);(c) dissolving the compound of Formula (I) in an acid, optionally wherein the acidis hydrochloric acid, 1.0 N hydrochloric acid, sulfuric acid, aqueous sulfuric acid, or 0.25 M aqueous sulfuric acid; (d) optionally washing the solution with an organic solvent, optionally whereinthe organic solvent is dichloromethane, and / or extracting the solution, optionally wherein the extraction solvent is ethyl acetate; (e) causing the compound of Formula (I) to precipitate by combining the solutionwith a base, optionally wherein the base is sodium bicarbonate in solid or solution form, sodium carbonate in solid or solution form, ammonia, or aqueous ammonia; (f) optionally drying the precipitate, optionally wherein the drying comprisesdrying under an infrared lamp for up to 16 hours.

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