Crystal form of a PARP1 inhibitor salt and preparation thereof

Abstract

A crystal form (Type A) of the bis-tartrate ((2R,3R)) salt of 7-((4-(2-fluoro-6- (methylcarbamoyl)pyridin-3-yl)piperazin-1-yl)methyl)-3,6-difluoropyrazolo[1,5- a]quinoxalin-4(5H)-one (Formula (I)), compositions comprising, methods of preparing and methods of treating therewith.

Description

[0001] CRYSTAL FORM OF A PARP1 INHIBITOR SALT AND PREPARATION THEREOF Cross reference to related applications

[0002] The present application claims the benefit of priority to Chinese Patent Application No. 202510295104.8, filed March 12, 2025, the contents of which are hereby incorporated by reference in their entirety.

[0003] Technical Field

[0004] The present disclosure relates to crystal forms of the bis-tartrate salt of the PARP1 inhibitor 7-((4-(2-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazin-l-yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one and preparation thereof.

[0005] Background of the Invention

[0006] Poly(ADP-ribose) polymerase (PARP) 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 PARP inhibitors.

[0007] The catalytic domain of PARP2 is very similar to that of PARP1 PARP2 is also found 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 PARP 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 PARP 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 PARP inhibitors (PARPi) 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 / p-catenin signaling. Targeting PARPs other than PARPI may be the reason why PARP inhibitors cause off-targeted toxicity, such as hair loss and diarrhea. In addition, inhibition of PARP2 activity has been found to lead to hematotoxicity (Farres et al., 2013 Blood 122: 44-54; Farres et al., 2015Cell Death and Differentiation 22: 1144-1157). The toxicity of these PARP inhibitors limits their clinical application as well as their combination with other targeted drugs.

[0008] Therefore, the development of highly selective PARP1 inhibitors may reduce both mechanism-related and non-mechanism-related toxi cities. Currently, several PARP1 selective inhibitors are in clinical development.

[0009] WO2023169226 discloses the following compound of Formula (II), which has the chemical name 7 -((4-(2-fluoro-6-(methylcarbamoyl)pyri din-3 -yl)piperazin-l -yl)methyl)-3,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one, alternatively 5-(4-((3,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide, as a PARP 1 selective inhibitor and its preparation method, the contents of which are incorporated herein by reference.

[0010]

[0011] Certain salts of the compound of Formula (II), and crystal forms of such salts, may have beneficial properties, for example, solubility, stability, bioavailability, impurity profile, filtration properties, dry ing properties, and lack of hygroscopicity, and may be easier to handle, micronize and tablet.

[0012] Summary of the Invention

[0013] The present disclosure provides a crystal form (Type A) of the compound of Formula (1), which is the bis-tartrate ((27?, 37?)) salt diagrammed below, compositions comprising and processes for preparing the same, and methods of using it to treat various conditions.

[0014]

[0015] In a first aspect, the present disclosure provides a crystal form, Type A, of a compound of Formula (I),

[0016]

[0017] In some embodiments, the crystal form is characterized by an X-ray powder diffraction (XRPD) spectrum that exhibits peaks at the following positions: 12.8 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, and 17.6 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20. 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, and 19.1 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that further exhibits peaks at 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, 19.1 ± 0.2° 20, 21.4 ± 0.2° 20, 23.1 ± 0.2° 20, 24.1 ± 0.2° 20, and 24.7 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at any 5, 6, 7 or 8 of the following positions: 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, and 19.1 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that further exhibits peaks at 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, 19.1 ± 0.2° 20, 21.4 ± 0.2° 20, 23.1 ± 0.2° 20, 24.1 ± 0.2° 20, and 24.7 ± 0.2° 20. In some embodiments, the cry stal form is characterized by an XRPD spectrum that exhibits peaks at any five, six, seven, eight, nine or ten of the following positions: 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, 19.1 ± 0.2° 20, 21.4 ± 0.2° 20, 23.1 ± 0.2° 20, 24.1 ± 0.2° 20, and 24.7 ± 0.2° 20.

[0018] In some embodiments, the crystal form is characterized by an X-ray powder diffraction (XRPD) spectrum that is substantially the same as that shown in Figure 1, or that is substantially the same as that shown in Figure 1 between the positions of 7.5° 20 and 20° 20, or that is substantially the same as that shown in Figure 1 between the positions of 7.5° 20 and 25° 20.

[0019] In some embodiments of crystal Type A, the cry stal form has a thermogravimetric analysis (TGA) curve substantially the same as that shown in Figure 2A. In some embodimentsof crystal Type A, the crystal form has a TGA curve that exhibits a weight loss of 1.58 percent between the temperatures of24.9°C and 150°C.

[0020] In some embodiments of crystal Type A, the crystal form has a differential scanning calorimetry' (DSC) curve substantially the same as that shown in Figure 2B.

[0021] In some embodiments of crystal Type A, the crystal form has at least one (e.g. one, two or all) of the following:

[0022] (a) an XRPD spectrum substantially the same as that shown in Figure 1;

[0023] (b) a TGA curve substantially the same as that show n in Figure 2A; and

[0024] (c) a DSC curve substantially the same as that shown in Figure 2B.

[0025] In some embodiments of the crystal form, the crystal form has a DSC curve that exhibits an endotherm peak onset at 193.5°C and / or an endotherm peak at 200.2°C. In some embodiments of the cry stal form, the crystal form has a DSC curve that exhibits an endotherm peak onset at 156.4°C and / or an endotherm peak at 199.2°C. In some embodiments of the crystal form, the crystal form has a DSC curve that exhibits an endotherm peak onset at 196.4°C and / or an endotherm peak at 202.4°C.

[0026] In some embodiments of crystal Type A, the crystal form is characterized by a powder X-ray diffraction (XRD) spectrum that exhibits peaks at at least four of, e.g. four, five, six, seven, eight, nine, ten, or more than ten of the following positions: 8.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 23.2 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ.

[0027] In some embodiments of crystal Type A, the crystal form is characterized by a powder X-ray diffraction (PXRD) spectrum that exhibits peaks at at least four of, e.g. four, five, six, seven, eight, nine, ten, or more than ten of the following positions: 8.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, and 24.7 ± 0.2° 2θ.

[0028] In some embodiments of cry stal Type A, the crystal form is characterized by a powder X-ray diffraction (XRD) spectrum substantially the same as that shown in Figure 4.

[0029] In a further aspect, the present disclosure provides a process for preparing a crystal form of a compound of Formula (I) disclosed herein. In some embodiments, the process comprises the following steps:

[0030] (a) suspending the compound of Formula (II)and tartaric acid in a solvent, stirring for 3 days at room temperature, and optionally collecting the solid material.

[0031] In some embodiments, to prepare the suspension, tartaric acid and the compound of Formula (II) are combined in a molar ratio of 3:1 tartaric acid to compound of Formula (II). In some embodiments, this ratio is from 2:1 to 3:1, e.g. the molar ratio is 2:1 or 3:1 tartaric acid:compound of Formula (II). In some embodiments, the solvent is acetonitrile and the molar ratio of tartaric acid to compound of Formula (II) is from 2:1 to 3:1. e.g. the molar ratio is 2:1 or 3: 1 tartaric acid:compound of Formula (II). In some embodiments, the solvent is acetone and the molar ratio of tartaric acid to compound of Formula (II) in the suspension is 3:1. In some embodiments, the process disclosed herein produces a crystal form of the compound of Formula (I) that has any of the X-ray diffraction, thermogravimetric analysis or differential scanning calorimetry features disclosed herein of the crystal form of the compound of Formula (I).

[0032] In an aspect, the present disclosure provides a composition or pharmaceutical (e.g. pharmaceutically acceptable) composition comprising a crystal form of the compound of Formula (I) disclosed herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises a crystal form disclosed herein of a compound of Formula (I), a pharmaceutically acceptable carrier or excipient, and at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is a known anticancer drug or a pharmaceutically acceptable salt thereof. In some embodiments, the at least one know n 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, bevacizumab, trastuzumab, rituximab, imatinib, gefitimb, 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), and sipuleucel-T (prostate cancer therapeutic vaccine).

[0033] In an aspect, the present disclosure provides a process for preparing a composition comprising combining crystal Type A disclosed herein and a pharmaceutically acceptable excipient or carrier.

[0034] In some embodiments, the method comprises combining cry stal Type A disclosed herein, 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, mvolumab, 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 therapeuticvaccine).

[0035] In an aspect, the present disclosure provides a composition prepared by a method for preparing a composition disclosed herein.

[0036] In an aspect, the present disclosure provides a method of treating or preventing a condition comprising administering a cry stal form of a compound of Formula (I) disclosed herein, or a composition disclosed herein comprising a crystal form of a compound of Formula (I) disclosed herein, to a subject e.g. to a subject in need of such treatment. In some embodiments, the condition is a condition that is responsive to the inhibition of PARP activity e.g. 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, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary' macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer or other brain cancer or other cancer of the central nervous system, malignant melanoma, small cell lung cancer, 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.

[0037] In some embodiments, the condition is a central nervous system (CNS) tumor. In some embodiments, the CNS tumor is selected from a meningioma, meningiosarcoma, ependymoma, astrocytoma, glioma, glioblastoma, pineal cell tumor, aggressive pituitary tumors, pituitary carcinomas, germ cell tumor, sarcoma, glioblastoma multiforme, medulloblastoma, oligodendroglioma, craniopharyngioma, retinoblastoma, schwannoma, primary' central nervous system lymphoma, brainstem glioma, pituitary adenoma, anaplastic astrocytoma, mixed glioma, primitive neuroectodermal tumor, hemangioblastoma, vestibular schwannoma, chordoma, spinal cord neurofibroma, lymphoma, optic nerve glioma, and dysembryoplastic neuroepithelial tumour.

[0038] In some embodiments, the condition is primary' brain cancer. In some embodiments, the condition is another brain cancer. In some embodiments, the condition is a brain tumor e.g. a brain tumor as disclosed herein. In some embodiments, the brain tumor is a high grade (fast growing) tumor. In some embodiments, the brain tumor is a low grade (slow growing) tumor. Insome embodiments, the brain tumor is a glioma, embryonal brain tumor (e.g. medulloblastoma), ependymoma, glioblastoma, primary central nervous system lymphoma, pineal region tumor (e.g. germ cell tumor or pineal cell tumor), pituitary tumor, meningioma, or acoustic neuroma (vestibular schwannoma).

[0039] 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) or of the 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.

[0040] In an aspect, the present disclosure provides a use of a crystal form of a compound of Formula (I) disclosed herein, or a composition disclosed herein comprising a crystal form of a compound of Formula (I) disclosed herein, in the treatment of a condition. In some embodiments, the condition is a condition that is responsive to the inhibition of PARP activity e.g. 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, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, 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 condition is primary brain cancer. In some embodiments, the condition is another brain cancer. In some embodiments, the condition is another cancer of the central nervous system. In some embodiments, the condition is a brain tumor or other CNS tumor identified in this disclosure, e.g., a CNS tumor selected from a meningioma, meningiosarcoma, ependymoma, astrocytoma, glioma, glioblastoma, pineal cell tumor, aggressive pituitary tumors, pituitary carcinomas, germ cell tumor, sarcoma, glioblastoma multiforme, medulloblastoma, oligodendroglioma, craniopharyngioma,retinoblastoma, schwannoma, primary central nervous system lymphoma, brainstem glioma, pituitary adenoma, anaplastic astrocytoma, mixed glioma, primitive neuroectodermal tumor, hemangioblastoma, vestibular schwannoma, chordoma, spinal cord neurofibroma, lymphoma, optic nerve glioma, and dysembryoplastic neuroepithelial tumour, or a brain tumor that is a high grade (fast growing) tumor, a low grade (slow growing) tumor, or is a glioma, embry onal brain tumor (e.g. medulloblastoma), ependymoma, glioblastoma, primary central nervous system lymphoma, pineal region tumor (e g. germ cell tumor or pineal cell tumor), pituitary' tumor, meningioma, or acoustic neuroma (vestibular schwannoma).

[0041] In an aspect, the present disclosure provides the use of a cry stal form 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 inhibition of PARP activity e.g. 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, nonHodgkin's lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary' macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, 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 condition is a brain tumor or other CNS tumor identified in this disclosure, e.g., as enumerated above.

[0042] In some embodiments, the medicament is prepared by combining a crystal form of a compound of Formula (I) disclosed herein with one or more excipients. In some embodiments, the condition is primary brain cancer. In some embodiments, the condition is another brain cancer. In some embodiments, the condition is another cancer of the central nervous system.

[0043] Brief Description of Figures

[0044] Figure 1 shows a powder X-ray diffraction (“PXRD” or “XRPD”) pattern of cry stal Type A of the compound of Formula (I).

[0045] Figure 2A shows a TGA of crystal Type A of the compound of Formula (I) in powderform.

[0046] Figure 2B shows a DSC of crystal Type A of the compound of Formula (I) in powder form.

[0047] Figure 3 shows a ¹H NMR spectrum of crystal Type A dissolved in DMSO-d₆ (crystal type A has a solubility in DMSO of greater than 44 mg / ml).

[0048] Figure 4 shows a XRPD pattern of crystal Type A of the compound of Formula (I), obtained from a ground powder of a crystal cluster sample.

[0049] Figure 5 shows an XRPD pattern of tartrate Type A.

[0050] Figure 6 shows TGA / DSC curves of tartrate Type A.

[0051] Figure 7 shows a ¹H NMR spectrum of tartrate Type A dissolved in DMSO-d₆.

[0052] Figure 8 shows an XRPD of a re-prepared (top) and first-prepared (see Figure 5) tartrate ty pe A.

[0053] Figure 9 shows TGA / DSC curves of a re-prepared tartrate Type A.

[0054] Detailed Description

[0055] I. General Description

[0056] In the following description, certain specific details are set forth in order 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.

[0057] II. Definition

[0058] Where an aspect or embodiment is described as comprising certain elements or features, 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.

[0059] Reference throughout this specification to "one embodiment" or "an embodiment" 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 thisspecification 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.

[0060] " Pharmaceutically acceptable excipients" include but are not limited to any adjuvants, 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.

[0061] " Pharmaceutical composition" refers to a formulation that comprises an active ingredient (e.g. the compound of Formula (I) and its crystal Type A 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.

[0062] Unless otherwise stated, the term "treating" a disease, disorder or condition in a subject (e.g. human, pet, domesticated or veterinary animal) as used herein refers to administering the compound or composition to a subject for the purpose of 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.

[0063] 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 for the purpose of causing 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.

[0064] 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.

[0065] Pharmaceutically acceptable: The term “pharmaceutically acceptable,” as used herein, 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 orinteracting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

[0066] When referring to, for example, XRD or XRPD patterns, DSC thermograms, DVS graphs or TGA, the term "substantially the same as that shown in..." includes patterns, 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.

[0067] In the present disclosure, for the characteristic powder X-ray diffraction peak position of the crystal form, the allowable error of the angular position (20) is ±0.2° unless specified otherwise. This error is used when comparing two powder X-ray diffraction patterns. If a diffraction peak in one image is designated as a certain angular position range of measured peak position ±0.2° (20), and a diffraction peak in another image is designated as the other angular position range of measured peak position ±0.2° (20), and if these peak ranges overlap, the two peaks are considered to have the same angular position (20). For example, if the diffraction peak of an image is determined to be at 5.20° 20, for comparison, the allowable error allows the peak to be specified in the range of 5.00° 20 -5.40° 20. If the control peak of the other diffraction pattern is determined to be at 5.35° 20, for comparison, the allowable error allows the peak to be specified in the range of 5.15° 2θ -5.55° 2θ. Because of the overlap between the two peak position ranges, the two compared peaks are considered to have the same angular position (20). In some embodiments, where specified, the allowable error of the angular position (20) is ±0.1°.

[0068] III. Crystal Form

[0069] In an aspect, the present disclosure provides a crystal form, Type A, of a compound of Formula (I),

[0070]

[0071] wherein the crystal form is characterized by an X-ray powder diffraction (XRPD) spectrum that exhibits peaks at the following positions: 12.8 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, and 17.6 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that exhibits peaks at: 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2°20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20, and 19.1 ± 0.2° 20. In some embodiments, the crystal form is characterized by an XRPD spectrum that further exhibits peaks at 8.7 ± 0.2° 20, 12.8 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20. 17.6 ± 0.2° 20, 19.1 ± 0.2° 20, 21.4 ± 0.2° 20, 23.1 ± 0.2° 20, 24.1 ± 0.2° 20, and 24.7 ± 0.2° 20. In some embodiments, the crystal form is characterized by an X-ray powder diffraction (XRPD) spectrum that is substantially the same as that shown in Figure 1. The XRPD spectrum of this material is shown in Figure 1. The following peak positions are present in the spectrum shown in Figure 1.

[0072] Table. XRPD pattern of tartrate Type A (822084-46-B)

[0073] Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 8.6792 424.29 0.1023 10.19 28.46 10.8289 97.60 0.1535 8.17 6.55 12.7936 1033.19 0.1023 6.92 69.31 13.5470 145.66 0.1535 6.54 9.77 14.2937 577.61 0.1279 6.20 38.75 14.6000 525.95 0.1023 6.07 35.28 15.9535 334.96 0.1023 5.56 22.47 17.1095 708.54 0.1023 5.18 47.53 17.3829 1490.67 0.1023 5.10 100.00 17.6471 810.82 0.1023 5.03 54.39 19.1478 414.95 0.1535 4.64 27.84 21.3974 361.93 0.1279 4.15 24.28 21.7542 139.61 0.1535 4.09 9.37 23.1303 426.55 0.1535 3.85 28.61 24.0799 645.74 0.1279 3.70 43.32 24.7336 639.73 0.2303 3.60 42.92 25.9122 553.59 0.1279 3.44 37.14 26.5011 474.03 0.1279 3.36 31.80 27.1229 112.60 0.2047 3.29 7.55

[0074]

[0075] Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 28.7273 263.21 0.2047 3.11 17.66 29.2030 272.55 0.1791 3.06 18.28 29.7566 139.81 0.1535 3.00 9.38 31.9114 110.36 0.1535 2.80 7.40

[0076]

[0077] 36.0589 92.74 0.5117 2.49 6.22

[0078] The crystal Type A of the present disclosure has properties suitable for medical or pharmaceutical uses, including but not limited to bioavailability, stability, purity, and / or manufacturabil ity.

[0079] In some embodiments, the crystal Type A of the compound of Formula (I) of the present disclosure has a thermogravimetric analysis (TGA) curve substantially the same as that shown in Figure 2A. In some embodiments of crystal Type A, the crystal form has a TGA curve that exhibits a weight loss of 1.58 percent between the temperatures of 24.9°C and 150°C.

[0080] In some embodiments of crystal Type A, the crystal form has a differential scanning calorimetry (DSC) curve substantially the same as that shown in Figure 2B.

[0081] In some embodiments of crystal Type A, the crystal form has at least one (e g. one, two or all) of the following:

[0082] (a) an XRPD spectrum substantially the same as that shown in Figure 1;

[0083] (b) a TGA curve substantially the same as that shown in Figure 2A; and

[0084] (c) a DSC curve substantially the same as that shown in Figure 2B.

[0085] In some embodiments of crystal Type A, the crystal form is characterized by a powder X-ray diffraction (XRD) spectrum substantially the same as that shown in Figure 4. The following peak positions are present in the spectrum shown in Figure 4.

[0086] Table. XRPD pattern of tartrate Type A (obtained from the crystal cluster sample-the same material from which Figure 4 was prepared)

[0087] Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 6.8047 366.48 0.1023 12.99 9.26 8.6973 1194.20 0.1279 10.17 30.18 10.8628 267.20 0.1279 8.14 6.75 12.8026 2225.69 0.1535 6.91 56.24 13.5816 507.76 0.1023 6.52 12.83 14.2957 1071.12 0.1023 6.20 27.07

[0088]

[0089] Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 14.6337 1326.90 0.1023 6.05 33.53 15.9850 682.74 0.1279 5.54 17.25 17.1331 1805.24 0.1023 5.18 45.62 17.4013 3957.24 0.1279 5.10 100.00 17.6746 1615.75 0.1023 5.02 40.83 18.3472 279.44 0.1023 4.84 7.06 19.1254 907.56 0.1023 4.64 22.93 20.3895 216.91 0.1279 4.36 5.48 21.1136 497.56 0.1279 4.21 12.57 21.3708 844.61 0.1279 4.16 21.34 21.7827 251.83 0.1023 4.08 6.36 22.8164 243.90 0.1023 3.90 6.16 23.1515 1135.70 0.1535 3.84 28.70 24.1069 901.72 0.1279 3.69 22.79 24.7670 1392.71 0.1535 3.59 35.19 25.5475 547.68 0.1023 3.49 13.84 25.9160 746.56 0.1023 3.44 18.87 26.5271 814.90 0.1279 3.36 20.59 27.2648 210.87 0.2558 3.27 5.33 27.8247 177.01 0.1535 3.21 4.47 28.3498 197.87 0.2558 3.15 5.00 28.6816 432.60 0.1023 3.11 10.93 29.1647 610.77 0.1791 3.06 15.43 29.7654 308.52 0.1535 3.00 7.80 31.3301 75.21 0.1535 2.86 1.90 31.9428 419.86 0.1279 2.80 10.61 32.4575 170.80 0.3070 2.76 4.32 33.6793 80.03 0.1535 2.66 2.02 34.7755 106.20 0.1535 2.58 2.68 35.1938 90.14 0.1535 2.55 2.28 36.0081 226.64 0.1535 2.49 5.73 36.7281 158.01 0.2047 2.45 3.99 37.5977 188.79 0.1535 2.39 4.77

[0090]

[0091] In some embodiments of crystal Type A, the crystal form is characterized by a powder X-ray diffraction (XRD) spectrum that exhibits peaks at four, five, six, seven, eight, nine, ten, or more than ten of the following positions: 8.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 17.7 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 23.2 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, and 24.8 ± 0.2° 2θ.

[0092] In some embodiments of crystal Type A, the crystal form is characterized by a powder X-ray diffraction (PXRD) spectrum that exhibits peaks at four, five, six, seven, eight, nine, ten, or more than ten of the following positions: 8.7 ± 0.2° 2θ, 12.8 ± 0.2° 2θ, 14.3 ± 0.2° 2θ, 14.6 ± 0.2° 2θ, 16.0 ± 0.2° 2θ, 17.1 ± 0.2° 2θ, 17.4 ± 0.2° 2θ, 17.6 ± 0.2° 2θ, 19.1 ± 0.2° 2θ, 21.4 ± 0.2° 2θ, 23.1 ± 0.2° 2θ, 24.1 ± 0.2° 2θ, and 24.7 ± 0.2° 2θ.

[0093] In some embodiments of the crystal form, the crystal form has a DSC curve that exhibits an endotherm peak onset at 193.5°C and / or an endotherm peak at 200.2°C. In some embodiments of the cry stal form, the cry stal form has a DSC curve that exhibits an endotherm peak onset at 156.4°C and / or an endotherm peak at 199.2°C. In some embodiments of the crystal form, the crystal form has a DSC curve that exhibits an endotherm peak onset at 196.4°C and / or an endotherm peak at 202.4°C.

[0094] The bis-tartrate Type A cry stal of the compound of Formula (I) disclosed herein may be prepared by methods disclosed herein. For example, L-tartaric acid and the compound of Formula (II) may be combined in a 3: 1 or approximately 3: 1 molar ratio (acid: compound of Formula (II)) in a suitable solvent (e.g. acetone) or mixture of solvents, slurried for a suitable period under suitable conditions (e.g. 3 days at room temperature optionally followed by slurrying at 50°C for 7 hours), and the bis-tartrate Type A crystal of the compound of Formula (I) isolated by standard methods such as, but not limited to, centrifugation and optionally dr ing the material obtained. For example, tartrate Type A was obtained via stirring the compound of Formula (11) and tartaric acid (molar ratio of 3:1, acid / free base) in acetone at room temperature for 4 days. The solid material is isolated by standard methods.

[0095] Alternatively, bis-tartrate Type A crystal of the compound of Formula (I) disclosed herein may be prepared by antisolvent addition. For example, about 20 mg of tartrate Type A (822084-46-B) was dissolved in 0.4-1.0 rnL solvent to obtain a clear solution and the solution was magnetically stirred (-1000 rpm) followed by addition of anti-solvent until precipitate appeared or the total amount of anti-solvent reached 10.0 mL. The samples without precipitate were transferred to slurry at 5 °C and then transferred to slurry at -20 °C. The clear samples were transferred to RT for evaporation. The solids were isolated for XRPD analysis. Results shown below showed that tartrate Type A was obtained under the following conditions.Table a. Summary of anti-solvent addition experiments

[0096] Solvent (v / v) Anti-solvent Result

[0097] MIBK Tartrate Type A

[0098] IPAc Tartrate Type A

[0099] MeOH / DCM

[0100] ACN Tartrate Type A

[0101] (1:1)

[0102] Toluene Tartrate Type A

[0103] DCM Tartrate Type A

[0104]

[0105] Alternatively, tartrate Type A may be prepared by salt formation. For example, about 20 mg of compound of Formula (II) and tartaric acid (molar ratio in following table) were suspended in 0.5 mL of solvent in an HPLC glass vial. After the suspension was stirred magnetically (1000 rpm) for 3 days at RT, the remaining solids were centrifuged for XRPD analysis. Results summarized below indicated that tartrate Type A was obtained under the following conditions.

[0106] Table b. Summary of salt formation experiments

[0107] MR

[0108] Experiment ID Solvent (v / v) Result

[0109] (Acid / API)

[0110] 1 ACN 2:1 Tartrate Type A

[0111]

[0112] Alternatively, tartrate Type A may be re-prepared by slurrying tartrate Type A under appropriate conditions. For example, about 20 mg of tartrate Type A (822084-46-B) was suspended in 0.5 mL of solvent in an HPLC glass vial. After the suspension was stirred magnetically (1000 rpm) for 3 days at RT, the remaining solids were centrifuged for XRPD analysis. Results summarized below indicated that tartrate Type A was obtained under the following conditions.

[0113] Table 0-1 Summary of slurry conversion experiments at RT

[0114] Solvent (v / v) Result

[0115] Acetone Tartrate Type A

[0116] EtOAc Tartrate Type A

[0117] MTBE Tartrate Type A

[0118] ACN Tartrate Type A

[0119] DCM Tartrate Type A n-Heptane Tartrate Type A

[0120] Toluene Tartrate Type A

[0121] Anisole Tartrate Type A

[0122] ACN / H2O (19:1) Tartrate Type A

[0123] NMP / IPAc (1:9) Tartrate Type AIV. Pharmaceutical Formulations and Routes of Administration

[0124] The compounds and compositions of the present invention can be delivered directly 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.

[0125] An effective amount of such compound, composition, or medicament can readily 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.

[0126] 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, intracistemal, 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.

[0127] Pharmaceutical dosage forms of a compound of the invention may be provided in 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.).

[0128] Pharmaceutical dosage forms of a compound of the present invention may be manufactured 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.

[0129] Proper formulation is dependent upon the desired route of administration. For intravenous 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.

[0130] Solid oral dosage forms can be obtained using excipients, which may include fillers, 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 organicsolvents 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.

[0131] In one embodiment, the compounds of the present invention can be administered 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.

[0132] For administration by inhalation, or administration to the nose, the compounds for 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.

[0133] Compounds and compositions formulated for parenteral administration by injection 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 otherswell known in the art. Other depot delivery systems may be presented in form of implants and pumps requiring incision.

[0134] Suitable carriers for intravenous injection for the compounds of the invention are 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 atonicity 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.

[0135] A therapeutically effective dose can be estimated initially using a variety of techniques 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.

[0136] 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.

[0137] The effective amount or therapeutically effective amount is the amount of the compound 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 w ithin 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.

[0138] Dosage amount and interval may be adjusted individually to provide plasma levels 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.

[0139] The amount of compound or composition administered may be dependent on a variety 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.

[0140] The present compounds and compositions may, if desired, be presented in a pack 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.

[0141] 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.

[0142] V. Preparation method

[0143] One method for preparing a compound of Formula (II) is described in WO 2023 / 169226, the contents of which are incorporated herein by reference.

[0144] VI. Method and application

[0145] The compound of the present disclosure is a PARP inhibitor. Therefore, the cry stal 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 PARP activity.

[0146] As used herein, clinical conditions responsive to the inhibition of PARP activity refer to diseases or conditions the pathogenesis and development of which could be treated or prevented by inhibiting activity of PARP.As used herein, clinical conditions responsive to the inhibition of PARP activity include cancers and other diseases responsive to the inhibition of PARP activity, such as excessive cell death, including central nervous system diseases such as stroke and neurodegenerative diseases.

[0147] The cancers responsive to the inhibition of PARP activity' include, but are not limited 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, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, 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.

[0148] Cancers and tumors responsive to the inhibition of PARP activity may further include CNS tumors, for example, a meningioma, meningiosarcoma, ependymoma, astrocytoma, glioma, glioblastoma, pineal cell tumor, aggressive pituitary' tumors, pituitary' carcinomas, germ cell tumor, sarcoma, glioblastoma multiforme, medulloblastoma, oligodendroglioma, craniopharyngioma, retinoblastoma, schwannoma, primary central nervous system lymphoma, brainstem glioma, pituitary adenoma, anaplastic astrocytoma, mixed glioma, primitive neuroectodermal tumor, hemangioblastoma, vestibular schwannoma, chordoma, spinal cord neurofibroma, lymphoma, optic nerve glioma, and dysembryoplastic neuroepithelial tumour. Cancers and tumors responsive to the inhibition of PARP activity may further include, in addition to primary brain cancer, another brain cancer, such as a brain tumor as enumerated in the present disclosure, for example, a high grade (fast growing) tumor, a low grade (slow growing) tumor, more specifically, a glioma, embryonal brain tumor (e.g. medulloblastoma), ependymoma, glioblastoma, primary central nervous system lymphoma, pineal region tumor (e.g. germ cell tumor or pineal cell tumor), pituitary tumor, meningioma, or acoustic neuroma (vestibular schwannoma).

[0149] Therefore, the present disclosure provides use of the compound of Formula (I) as disclosed herein (e.g., crystal Type A disclosed herein) in the preparation of a medicament for treatment or prevention of clinical conditions responsive to the inhibition of PARP activity, such as the cancers described herein. In some embodiments, the compound of Formula (I) as disclosed herein (e.g.,crystal Type A disclosed herein)

[0150] Also disclosed herein is a method for preparing a medicament, which includes the step of mixing the compound of Formula (I) (e.g. crystal Type A disclosed herein) according to the present disclosure, with a pharmaceutically acceptable carrier or excipient.

[0151] 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, including but not limited to intermediate compounds, can be obtained from commercial sources or prepared using methods known to those skilled in the art.

[0152] EXAMPLES

[0153] List of abbreviations

[0154] Abbreviation Meaning

[0155] 2-MeTHF 2-methyltetrahydrofuran

[0156] ACN acetonitrile

[0157] DCM dichloromethane

[0158] DMAc N, N-dimethylacetamide

[0159] DMSO dimethyl sulfoxide

[0160] EtOAc ethyl acetate

[0161] EtOH ethanol

[0162] IPA isopropanol

[0163] IPAc isopropyl acetate

[0164] MeOH methanol

[0165] MIBK 4-methyl-2-pentanone

[0166] MTBE methyl tert-butyl ether

[0167] NMP A-methyl-2-pyrrolidone

[0168] THF tetrahydrofuran

[0169]

[0170] Example 1: Preparation of the crystal Type A of the compound of Formula I Conditions for preparing a tartrate salt of the compound of Formula (II) (that is, crystal Type A of the compound of Formula I) are summarized in the following table. Using crystalline compound of Formula (II) as starting material, different conditions were evaluated to determinewhich yielded the tartrate salt. Two molar ratios were used of tartaric acid to compound of Formula (II) in 5 solvent systems. Around 20 mg of the compound of Formula (II) and the indicated amount of tartaric acid were added into 0.5 mL solvent, followed by slurry at room temperature for 4 days. The resulting suspension was centrifuged to retrieve the solids for XRPD test. The results were summarized in the following table. The salt hits were characterized by XRPD, TGA, DSC and ’H NMR or HPLC / IC.

[0171] Table 1. Tartrate salt formation conditions

[0172] A B D E Acid C

[0173] #

[0174] (acid / base) EtOH Acetone EtOAc THF ACN Crystalline Crystalline Crystalline Crystalline Crystalline 1 L-Tartaric acid

[0175] Formula (II) Formula (II) Formula (II) Formula (II) Formula (II) (1:1)

[0176] L-Tartaric acid Crystalline Tartrate Crystalline Tartrate 2 Tartaric acid

[0177] Formula (II) Type A Formula (II) Type A (3:1)

[0178]

[0179] In further detail, Tartrate Type A was obtained via stirring the crystalline compound of Formula (II) and tartaric acid (molar ratio of 3:1, acid:compound of Formula (II)) in acetone at room temperature for 4 days. The XRPD of the material obtained is shown in Figure 5. The TGA / DSC curves of the material obtained are displayed in Figure 6, which shows a weight loss of 2.37% up to 150° C and three endotherms at 156.4°C, 199.2°C and 298.0°C (peak). TheJH (proton) NMR result shown in Figure 7 shows the molar ratio of tartaric acid to compound of Formula (II) was 2.0 and the molar ratio of residual acetone / compound of Formula (II) was 0.1.

[0180] Example 2; Re-preparation of the crystal Type A of the compound of Formula I Tartrate Type A (822084-31-B)

[0181] Preparation steps:

[0182] 400.3 mg of the crystalline compound of Formula (II) and 382.3 mg L-tartaric acid were weighed out (822084-01 -A) and placed in a 20-mL vial followed by addition of 10.0 mL acetone to obtain a suspension.

[0183] The suspension was slurried at room temperature for 4 days, then centrifuged at 10,000 rpm for 2 minutes.

[0184] The resulting solid was dried under vacuum at 50°C for 4 hours. The resulting solid (625.0 mg) was collected and a test XRPD was performed (see Figure 8). This sample is referred to ‘Te-prepared tartrate Type A.”.

[0185] Characteristics of the material obtained:c i in TGA weight DSC..... Sample ID _l,, Molar ratio Purity zoiTnozi \ Salt form loss (%, endotherm..,™, <822084’> 150 C) (“C, peak) (ac'd / FB) (Are»%) 31-B Tartrate Type

[0186]

[0187] 202.4, 296.4 2.0 98.64 A

[0188] The XRPD patern of re-prepared tartrate Type A (822084-31-B) is shown in Figure 8 (top spectrum). The TGA / DSC curves are shown in Figure 9. which shows a weight loss of 1.16% up to 150 °C and two endotherms at 202.4 and 296.4 °C (peak). TherH NMR result (not shown) showed a molar ratio of acid / compound of formula (II) w as 2.0 and the molar ratio of residual acetone / compound of Formula (II) was 0.1. HPLC result (not shown) showed the purity was 98.64%. VH-XRPD result (not shown) showed no form change was observ ed after stored at 10~90%RH for 1 hr.

[0189] Hygroscopicity

[0190] In order to evaluate the hygroscopicity of tartrate Type A, DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH. XRPD characterization was performed for the samples after DVS test. The DVS results showed that the water uptake of tartrate Type A at 25°C and 80% relative humidity 1.469% (not shown). No form change was observed for tartrate Type A after the DV S test.

[0191] Solid Stability

[0192] Tartrate Type A was placed under the conditions of 80 °C for 24 hrs, 25 °C / 60% RH and 40 °C / 75% RH for 2. 4, 6 and 8 weeks. The physical and chemical stability were evaluated by XRPD and HPLC purity, respectively. The results are summarized in the following table. No form or purity’ change was observed for tartrate Type A after stored at 25 °C / 60%RH and 40 °C / 75%RH for 8 weeks (data not shown).

[0193] Table 2, Summary of solid stability

[0194] Starting material Conditions Time Purity (area%) Form change Initial - 98.17 - 80 °C 24 hrs 98.06 No

[0195] 2 weeks 98.13 No 4 weeks 98.05 No 25 °C / 60%RH

[0196] Tartrate Type A 6 weeks 98.17 - (822084-31-B) 8 weeks 98.14 No

[0197] 2 weeks 98.04 No 4 weeks 98.12 No 40 °C / 75%RH

[0198] 6 weeks 98.24 - 8 weeks 98.09 No

[0199]

[0200] In order to further evaluate the solid stability, a stability evaluation at 40 °C / 90% RH for 2, 4, 6 and 8 weeks was performed for tartrate crystal Type A. The physical and chemical stability were evaluated by XRPD and HPLC purity, respectively (not shown). The results are summarized in the following table. The results showed no purity decrease was observed for the re-prepared tartrate Type A after storage. No form change was observed for tartrate Type A after storage at 40 °C / 90% RH for 8 weeks.

[0201] Table 3. Summary of solid stability at 40 °C / 90%RH

[0202] Form Starting material Conditions Time Purity (area%)

[0203] change - - Initial 98.08

[0204] Ta 2 weeks 98.23

[0205] rtrate Type A No 4 weeks 98.10 No 40 °C / 90%RH (822084-31-B) - 98.15 6 weeks

[0206] 98.01 8 w eeks No

[0207]

[0208] Tableting Stability

[0209] Tableting stability evaluation was performed for 100 mg tartrate Type A with 50 MPa (1413 N), 100 MPa (2826 N), 350 MPa (10 kN) and 525 MPa (15 kN) pressure. The result (data not shown) showed no form change was observed after tableting (slight crystallinity decrease was obser ed at 350 MPa and 525 MPa).

[0210] Example 3; Standard preparation of the crystal Type A of the compound of Formula I Tartrate crystal Type A was prepared in a series of two procedures as follows:

[0211] A. 1002.3 mg compound of Formula (II) and 955.5 mg L-tartaric acid were weighed into a 20-rnL vial followed by addition of 20.0 mL Acetone to obtain a suspension. The suspension was slurried for 3 days at room temperature followed by slurrying at 50°C for 7 hours. The suspension was then centrifuged at 10,000 rpm for 2 minutes. The solid was evaluated by XRPD. Crystal Type A of the compound of Formula I was obtained.

[0212] B. 7902.2 mg compound of Formula (II) and 7554.1 mg L-tartaric acid was w eighed into a 500-mL reactor followed by addition of 200.0 mL Acetone to obtain a suspension. All of the material prepared in part A w as added to the suspension as seed. The resulting suspension was stirred at 30°C for 16 hours. The suspension was filtered under vacuum, then washed three times with 30 mL acetone. The resulting cake was dried at 50°C under vacuum for 6 hours. The solidswere collected and weighed (14.3 g). then evaluated by XRPD. Crystal Type A of the compound of Formula I was obtained.

[0213] The XRPD spectrum of this material is shown in Figure 1. The following peak positions are present in the spectrum:

[0214] Table 4 XRPD pattern of tartrate Type A (822084-46-B)

[0215] Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%] 8.6792 424.29 0.1023 10.19 28.46 10.8289 97.60 0.1535 8.17 6.55 12.7936 1033.19 0.1023 6.92 69.31 13.5470 145.66 0.1535 6.54 9.77 14.2937 577.61 0.1279 6.20 38.75 14.6000 525.95 0.1023 6.07 35.28 15.9535 334.96 0.1023 5.56 22.47 17.1095 708.54 0.1023 5.18 47.53 17.3829 1490.67 0.1023 5.10 100.00 17.6471 810.82 0.1023 5.03 54.39 19.1478 414.95 0.1535 4.64 27.84 21.3974 361.93 0.1279 4.15 24.28 21.7542 139.61 0.1535 4.09 9.37 23.1303 426.55 0.1535 3.85 28.61 24.0799 645.74 0.1279 3.70 43.32 24.7336 639.73 0.2303 3.60 42.92 25.9122 553.59 0.1279 3.44 37.14 26.5011 474.03 0.1279 3.36 31.80 27.1229 112.60 0.2047 3.29 7.55 28.7273 263.21 0.2047 3.11 17.66 29.2030 272.55 0.1791 3.06 18.28 29.7566 139.81 0.1535 3.00 9.38

[0216]

[0217] 31.9114 110.36 0.1535 2.80 7.40Pos. [°2θ] Height [cts] FWHM Left [°2θ] d-spacing [Å] Rel. Int. [%]

[0218]

[0219] 36.0589 92.74 0.5117 2.49 6.22 Thermogravimetric analysis of this material is presented in Figure 2A and shows a weight loss of 1.58% up to 150 °C. Due to the small TGA weight loss, tartrate Type A was postulated to be an anhydrate. DSC analysis of this material is presented in Figure 2B and shows an endotherm at 200.2 °C having an onset at 193.5°C.

[0220] solution nuclear magnetic resonance (XH NMR) result for this material is presented in Figure 3, which shows the molar ratio of acid / compound of Formula (II) was 2.0 and the molar ratio of acetone / compound of Formula (II) was 0.1.

[0221] High performance liquid chromatography (HPLC) (not shown) showed the purity of the material obtained was 98.27 area%.

[0222] Instruments and Methods

[0223] XRPD

[0224] For XRPD analysis, PANalytical X-ray powder diffractometers were used. The XRPD parameters used are listed in the following table.

[0225] Table 5. Parameters for XRPD

[0226] Parameters Empyrean and X’ Pert3

[0227] Cu, Ka;

[0228] Kai (A): 1.540598,

[0229] X-Ray wavelength

[0230] Ka2 (A): 1.544426

[0231] intensity ratio Ka2 / Kal: 0.50

[0232] X-Ray tube setting 45 kV. 40 mA

[0233] Divergence slit 1 / 8°

[0234] Scan mode Continuous Scan range (20 / °) 3~40

[0235] Step size (20 / °) 0.0263

[0236] Scan step time (s) 46.7

[0237] Test time ~5 min

[0238]

[0239] TGA and DSC

[0240] TGA data were collected using TA Discovery 5500 TGA from TA Instruments. DSC was performed using TA Discovery' 2500 DSC from TA Instruments. Detailed parameters used are listed in the following table.

[0241] Table 6. Parameters for TGA and DSC test

[0242]

[0243] Parameters TGA DSCMethod Ramp Ramp Sample pan Aluminum, open Aluminum, crimped 25° C- Target Temperature RT- Target temperature

[0244] temperature Heating rate 10° C / min 10° C / min Purge gas N

[0245]

[0246] N2 2

[0247] Solution NMR

[0248] Solution NMR was collected on Bruker 400M NMR Spectrometer using DMS0-<.

[0249] HPLC

[0250] Thermo Vanquish Core HPLC was utilized and detailed chromatographic conditions are listed in the following table.

[0251] Table 7. Parameters for HPLC

[0252] Parameters Thermo Vanquish Core with DAD detector Column Xselect CSH C18, 4.6 mm / 150 mm / 3.5 urn A: 0.1%TFAinH2O

[0253] Mobile phase

[0254] B: MeOH

[0255] Time (min) %B

[0256] 0.0 10

[0257] 5.0 30

[0258] 20.0 60 Gradient

[0259] 27.0 95

[0260] 30.0 95

[0261] 30.1 10

[0262] 35.0 10

[0263] Run time 35.0 min

[0264] Flow rate 1.0 mL / min

[0265] Injection volume 5 pL

[0266] Detector wavelength UV at 306 nm

[0267] Column temperature 20 °C

[0268] Sampler temperature RT

[0269] Diluent ACN / H2O (1:1, v / v) (0.05% TFA)

[0270]

[0271] Example 4. Single Crystal Growth and Structure Determination of Tartrate Type A

[0272] Summary.The purpose of this single crystal study is to cultivate a single crystal of tartrate Type A and perform single crystal X-ray diffraction (SCXRD) characterization on it, to determine the single crystal structure of the tartrate Type A.

[0273] The tartrate Type A single crystal was obtained by solvothermal synthesis of the compound of Formula (II) and L-tartaric acid in acetonitrile (ACN) solvent. SCXRD characterization indicated the single crystal belonged to monoclinic crystal system and P21space group. The unit cell dimensions were determined as {a = 7.56770(10) A, b = 16.1333(2) A, c = 13.07170(10) A, a = 90°, p = 92.4080(10)°, y = 90°, V = 1594.54(3) A3}. Single crystal structure determination showed that the asymmetric unit of the tartrate Type A crystal structure contained a cation (+1 charge) and a “hydrogen tartrate anion--proton--hydrogen tartrate anion” dimer (-1 charge) formed by short strong hydrogen bond (SSHB). There was no crystalline water molecule or other solvent molecule in the crystal structure, which confirmed the tartrate Type A was an anhydrate, and the acid / base molar ratio of this salt form is 2: 1.

[0274] Single Crystal Growth.

[0275] The tartrate Type A single crystal sample tested by SCXRD was obtained by solvothermal synthesis method. The experiment details are elaborated below.

[0276] 5.1 mg compound of Formula (II) and 5.0 mg L-tartaric acid (the base / acid molar ratio was 1:2) was weighed into a 3 mL glass vial with the addition of 0.5 mL ACN to make a suspension of reactant. The 3 mL vial was enclosed in a 10 mL Teflon lined hydrothermal autoclave. The autoclave was then placed in an oven to conduct solvothermal synthesis by 5h keep 12h 46h

[0277] running the heating and cooling program (RT->80°C >80°C — >25°C). After the heating and cooling program was completed, it was observed that crystal cluster sample was obtained in the reaction solution (not shown). XRPD characterization result is shown in Figure 4 and indicates that the obtained crystal cluster sample was tartrate Type A. This XRPD spectrum has the peak positions shown in the following table:

[0278] Table 8. XRPD pattern of tartrate Type A (obtained from the crystal cluster sample-the same material from which Figure 4 was prepared)

[0279] Pos. [°20] Height [cts] FWHM Left [°20] d-spacing [A] Rel. Int. [%] 6.8047 366.48 0.1023 12.99 9.26 8.6973 1194.20 0.1279 10.17 30.18 10.8628 267.20 0.1279 8.14 6.75 12.8026 2225.69 0.1535 6.91 56.24 13.5816 507.76 0.1023 6.52 12.83

[0280]

[0281] Pos. [°20] Height [cts] FWHM Left [°20] d-spacing [A] Rel. Int. [%] 14.2957 1071.12 0.1023 6.20 27.07 14.6337 1326.90 0.1023 6.05 33.53 15.9850 682.74 0.1279 5.54 17.25 17.1331 1805.24 0.1023 5.18 45.62 17.4013 3957.24 0.1279 5.10 100.00 17.6746 1615.75 0.1023 5.02 40.83 18.3472 279.44 0.1023 4.84 7.06 19.1254 907.56 0.1023 4.64 22.93 20.3895 216.91 0.1279 4.36 5.48 21.1136 497.56 0.1279 4.21 12.57 21.3708 844.61 0.1279 4.16 21.34 21.7827 251.83 0.1023 4.08 6.36 22.8164 243.90 0.1023 3.90 6.16 23.1515 1135.70 0.1535 3.84 28.70 24.1069 901.72 0.1279 3.69 22.79 24.7670 1392.71 0.1535 3.59 35.19 25.5475 547.68 0.1023 3.49 13.84 25.9160 746.56 0.1023 3.44 18.87 26.5271 814.90 0.1279 3.36 20.59 27.2648 210.87 0.2558 3.27 5.33 27.8247 177.01 0.1535 3.21 4.47 28.3498 197.87 0.2558 3.15 5.00 28.6816 432.60 0.1023 3.11 10.93 29.1647 610.77 0.1791 3.06 15.43 29.7654 308.52 0.1535 3.00 7.80 31.3301 75.21 0.1535 2.86 1.90 31.9428 419.86 0.1279 2.80 10.61 32.4575 170.80 0.3070 2.76 4.32 33.6793 80.03 0.1535 2.66 2.02 34.7755 106.20 0.1535 2.58 2.68 35.1938 90.14 0.1535 2.55 2.28 36.0081 226.64 0.1535 2.49 5.73 36.7281 158.01 0.2047 2.45 3.99

[0282]

[0283] Pos. [°20] Height [cts] FWHM Left [°20] d-spacing [A] Rel. Int. [%] 37.5977 188.79 0.1535 2.39 4.77

[0284]

[0285] Single Crystal Diffraction Data Collection

[0286] A single crystal with suitable size and good diffraction quality was isolated from the obtained cluster-like crystal sample (CP ID: 8268160-05-A4) and wrapped with Santovac Cryo Oil (an oil based cryoprotectant). The selected single crystal was mounted on a Cryoloop and fixed on the goniometer head with a random orientation. The single crystal was immersed in a stream of nitrogen at 120 K. Preliminary examination and data collection were performed on a Rigaku XtaLAB Synergy R (Cu / Kα X-ray radiation, lambda = 1.54184 Å) diffractometer at 120 K.

[0287] Cell parameters and orientation matrixes for data collection were retrieved and refined (T-vector algorithm) by CrysAlisPro (version: 1.171.42.89a) software using the setting angles of 14199 reflections in the range 3.3730° < 0 < 75.2800°. The data were collected to a minimum diffraction angle (0) of 3.384° and a maximum diffraction angle (0) of 75.664°. The completeness of data collection is 100%. The mean I / o of the collected data is 42.8 and the highest resolution is truncated at 0.80 A.

[0288] Instruments and Parameters

[0289] The single crystal X-ray diffraction data was collected at 120 K with Rigaku XtaLAB Synergy R (Cu / Ka radiation, X = 1.54184 A) diffractometer. The XRPD data was collected by PANalytical Empyrean X-ray diffractometer. The SCXRD and the XRPD instrument parameters are shown in the following tables.

[0290] Table 9. SCXRD instrument parameters

[0291] Instrument Rigaku XtaLAB SynergyR PhotonJet R (Cu) X-ray Source X-ray sources generator

[0292] (Cu / Ka: 1.54184 A) Detector Hypix 6000C detector Goniometer Four-circle Kappa Goniometer Cryostream-800 Pluse

[0293] Low Temperature Devices

[0294] (80-500K)

[0295]

[0296] Software package CrysAlisPro

[0297] Table 10. XRPD instrument parameters

[0298] Instrument PANalytical Empyrean Model Reflection mode

[0299] CuKα,

[0300] X-Ray wavelength

[0301]

[0302] Xai(A): 1.540598Instrument PANalytical Empyrean Kα2(Å): 1.544426 Kα2 / Kα1intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit (°) 1 / 8 Scan mode Continuous Scan range (° 2Theta) 3~40 Counting time (s) 46.665 Step size (° 2Theta) 0.0263

[0303]

[0304] Test time (h:m:s) About 5 min

Claims

What is claimed is:

1. A crystal form of a compound of Formula (I),(I)wherein the cry stal form is characterized by an X-ray powder diffraction (XRPD) spectrum that exhibits peaks at at least four of the following positions:8.7 ± 0.2° 29, 12.8 ± 0.2° 29, 14.3 ± 0.2° 29, 14.6 ± 0.2° 29. 16.0 ± 0.2° 29. 17.1 ± 0.2° 29, 17.4 ± 0.2° 29, 17.7 ± 0.2° 29, 19.1 ± 0.2° 29, 21.4 ± 0.2° 29, 23.2 ± 0.2° 29, 24.1 ± 0.2° 29, and 24.8 ± 0.2° 29orwherein the crystal form is characterized by a powder X-ray diffraction (PXRD) spectrum that exhibits peaks at at least four of the following positions:8.7 ± 0.2° 29, 12.8 ± 0.2° 29, 14.3 ± 0.2° 29, 14.6 ± 0.2° 29. 16.0 ± 0.2° 29, 17.1 ± 0.2° 29, 17.4 ± 0.2° 29, 17.6 ± 0.2° 29, 19.1 ± 0.2° 29, 21.4 ± 0.2° 29, 23.1 ± 0.2° 29, 24.1 ± 0.2° 29, and 24.7 ± 0.2° 29.

2. The crystal form of a compound of Formula (I) of claim 1, wherein the XRPD spectrum further exhibits peaks at the following positions:12.8 ± 0.2° 20, 17.1 ± 0.2° 20, 17.4 ± 0.2° 20, 17.6 ± 0.2° 20; and optionally also at 8.7 ± 0.2° 20, 14.3 ± 0.2° 20, 14.6 ± 0.2° 20, 16.0 ± 0.2° 20, and 19.1 ± 0.2° 20.

3. The crystal form of a compound of Formula (I) of claim 2, wherein the XRPD spectrum further exhibits peaks at the following positions:21.4 ± 0.2° 20, 23.1 ± 0.2° 20, 24.1 ± 0.2° 20, and 24.7 ± 0.2° 20.

4. A crystal form of a compound of Formula (I):wherein the crystal form is characterized by an X-ray powder diffraction (XRPD) spectrum that is substantially the same as that shown in Figure 1.

5. A crystal form of a compound of Formula (I):(I)wherein the crystal form has a thermogravimetric analysis (TGA) curve substantially the same as that shown in Figure 2A.

6. A crystal form of a compound of Formula (I):wherein the crystal form has a differential scanning calorimetry (DSC) curve substantially the same as that shown in Figure 2B.

7. A crystal form of a compound of Formula (I):(I)wherein the crystal form has at least one 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 2A;(c) a DSC curve substantially the same as that shown in Figure 2B.

8. A crystal form of a compound of Formula (I):(Dwherein the crystal form has a DSC curve that exhibits an endotherm peak onset at 193.5°C and / or an endotherm peak at 200.2°C.

9. A crystal form of a compound of Formula (I):(0wherein the crystal form has a TGA curve that exhibits a weight loss of 1.58 percent between the temperatures of 24.7°C and 150°C.

10. A composition comprising the crystal form of the compound of formula (I) of any one of claims 1-9 and a pharmaceutically acceptable carrier or excipient.

11. The composition of claim 10. wherein the composition further includes at least one known anticancer drug or pharmaceutically acceptable salt thereof,optionally wherein 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, 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), and sipuleucel-T (prostate cancer therapeutic vaccine).

12. A process for preparing a composition comprising combining the crystal form of any one of claims 1-9 and a pharmaceutically acceptable excipient or carrier.

13. A composition prepared by the method of claim 12.

14. The composition of claim 13, wherein the composition further includes at least one known anticancer drug or pharmaceutically acceptable salts thereof,optionally wherein the at least one known anti cancer 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, 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).

15. A process for preparing a crystal form of a compound of Formula (I),wherein the process comprises the following steps:(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 a solvent and causing the crystal form to precipitate by adding an anti-solvent, wherein:the solvent is MeOH / DCM (1:1) and the antisolvent is MIBK, IP Ac. ACN, toluene, or DCM, optionally wherein the addition of anti-solvent is followed by one or more of the following steps to cause crystallization: cooling the mixture to 5°C, cooling the mixture to -20°C, then warming the mixture to room temperature and permitting the solvent to evaporate.

16. A process for preparing a crystal form of a compound of Formula (I),wherein the process comprises the following steps:(b) suspending the compound of formula (II)and tartaric acid in a solvent, stirring for 3 days at room temperature, and optionally collecting the solid material,wherein:the solvent is acetonitrile, and the molar ratio of tartaric acid to compound of formula (II) is 3: 1.

17. A method of treating or preventing a condition comprising administering the crystal form of a compound of Formula (I) of any one of claims 1-9, or the composition of any one of claims 10, 11, 13 and 14, to a subject in need of such treatment.

18. The method of treating or preventing of claim 17, wherein the condition is a cancer or tumor, optionally wherein the condition is a cancer selected from 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, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer or other brain cancer or other cancer of the central nervous system, malignant melanoma, small cell lung cancer, 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.

19. The method of treating or preventing of claim 17, wherein the condition is a central nervous system (CNS) tumor.

20. The method of treating or preventing of claim 19, wherein the CNS tumor is selected from a meningioma, meningiosarcoma, ependymoma, astrocytoma, glioma, glioblastoma, pineal cell tumor, aggressive pituitary tumors, pituitary carcinomas, germ cell tumor, sarcoma, glioblastoma multiforme, medulloblastoma, oligodendroglioma,craniopharyngioma, retinoblastoma, schwannoma, primary central nervous system lymphoma, brainstem glioma, pituitary adenoma, anaplastic astrocytoma, mixed glioma, primitive neuroectodermal tumor, hemangioblastoma, vestibular schwannoma, chordoma, spinal cord neurofibroma, lymphoma, optic nerve glioma, and a dysembryoplastic neuroepithelial tumour.

21. The method of treating or preventing of claim 17, wherein the condition is a brain cancer, optionally wherein the brain cancer is a primary brain cancer.

22. The method of treating or preventing of claim 17, wherein the condition is a brain tumor, optionally either a high grade (fast growing) tumor or a low grade (slow growing) tumor.

23. The method of treating or preventing of claim 22, wherein the brain tumor is a glioma, embryonal brain tumor (e.g. medulloblastoma), ependymoma, glioblastoma, primary central nervous system lymphoma, pineal region tumor (e.g. germ cell tumor or pineal cell tumor), pituitary tumor, meningioma, or acoustic neuroma (vestibular schwannoma).

24. The method of treating or preventing any one of claims 17 to 23, wherein the method comprises administering an additional therapeutic agent in conjunction with the administration of the crystal form of a compound of Formula (I) or with the administration of the composition.

Images