Crystalline forms, compositions containing same, and methods of use thereof

Abstract

A crystalline form of a compound of structure (I): JPEG2024520141000060.jpg53170 or its sulfate, hemisulfate, or hydrogen sulfate salts, or its hydrates are disclosed. Also disclosed are the sulfate, hemisulfate, and hydrogen sulfate salts of the compound of formula (I), as well as their hydrates.

Description

[Technical field]

[0001] The present invention relates to crystalline forms, pharmaceutical compositions and their use in the treatment of diseases or conditions, such as cancer, in particular ataxia telangiectasia and diseases or conditions (e.g., cancer) that depend on the activity of RAD-3-related protein (ATR) kinase. [Background technology]

[0002] DNA damage occurs continuously in cells as a result of environmental insults, including ultraviolet light, X-rays, and endogenous stressors (e.g., reactive oxygen and base hydrolysis). Cancer cells experience higher rates of DNA damage, which is inherently induced by a higher rate of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to aid in the repair of DNA damage and act as cellular checkpoints to halt replication of cells with damaged DNA, allowing repair functions to occur before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways senses and repairs distinct, yet overlapping, types of DNA damage.

[0003] One major DDR protein that acts as a critical cell cycle checkpoint is the ataxia telangiectasia mutated rad3-related (ATR) kinase, which is related to the family of phosphoinositide 3-kinase-related protein kinases (PIKKs). ATR is activated by single-stranded (ss) DNA damage caused by stalled replication forks or during nucleotide excision repair, but also by double-strand breaks following DNA end resection during homologous recombination.

[0004] ATR has been identified as an important cancer target because it is essential for dividing cells. Thus, cancer cells with high levels of replication stress due to oncogenic mutations, dysfunctional G1 / S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM), or affected by DNA damaging agents, such as radiation therapy or chemotherapy, are more dependent on ATR for DNA repair and survival. Taken together, these results highlight the rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential for a therapeutic window over healthy proliferating cells. Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need for new anti-cancer therapies, particularly those based on ATR inhibitors. [Means for solving the problem]

[0006] The invention features crystalline forms, salts, pharmaceutical compositions, and their use in treating ataxia telangiectasia and diseases or conditions dependent on the activity of RAD-3 related protein (ATR) kinase (e.g., cancer).

[0007] In one aspect, the present invention relates to a crystalline form of a compound of formula (I),

[0008] [ka]

[0009] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 9.6°2θ±0.2°2θ and 15.8°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 8.9°2θ±0.2°2θ and 20.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 19.8°2θ±0.2°2θ and 20.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 18.2°2θ±0.2°2θ and 19.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.8°2θ±0.2°2θ, 22.2°2θ±0.2°2θ, and 23.9°2θ±0.2°2θ.

[0010] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 243°C and 247°C. In another aspect, the present invention provides a crystalline form of a compound of formula (I),

[0011] [ka]

[0012] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 8.1°2θ±0.2°2θ and 20.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 9.1°2θ±0.2°2θ, 15.9°2θ±0.2°2θ, and 23.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, and 19.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 16.1°2θ±0.2°2θ and 21.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having a peak at 12.3° 2θ±0.2° 2θ.

[0013] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 82° C. and 109° C. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 245° C. and 248° C.

[0014] In another aspect, the present invention provides a crystalline form of a compound of formula (I),

[0015] [ka]

[0016] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 7.2°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, and 29.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 10.2°2θ±0.2°2θ, 14.4°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.6°2θ±0.2°2θ and 27.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 12.5°2θ±0.2°2θ and 30.9°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 15.4°2θ±0.2°2θ and 18.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 19.7°2θ±0.2°2θ.

[0017] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 245° C. and 249° C. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 111° C. and 154° C.

[0018] In another embodiment, the present invention provides a crystalline form of the hydrogen sulfate salt of the compound of formula (I),

[0019] [ka]

[0020] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 13.0°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 25.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 14.8°2θ±0.2°2θ and 16.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 20.1°2θ±0.2°2θ and 24.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, and 18.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 19.3°2θ±0.2°2θ and 21.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 24.6°2θ±0.2°2θ and 25.6°2θ±0.2°2θ.

[0021] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 183°C and 218°C. In another embodiment, the present invention provides a crystalline form of a hydrate of the hydrogen sulfate salt of the compound of formula (I),

[0022] [ka]

[0023] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 5.9°2θ±0.2°2θ and 11.8°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 14.9°2θ±0.2°2θ and 20.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.2°2θ±0.2°2θ and 21.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 13.3°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, and 22.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 16.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 24.1°2θ±0.2°2θ and 29.5°2θ±0.2°2θ.

[0024] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 91°C and 116°C. In another aspect, the present invention provides a crystalline form of a compound of formula (I),

[0025] [ka]

[0026] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 5.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 2.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 8.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 16.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 19.0°2θ±0.2°2θ and 21.1°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 12.0°2θ±0.2°2θ and 17.1°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 9.5°2θ±0.2°2θ and 14.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 18.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 18.4°2θ±0.2°2θ.

[0027] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 252°C-253°C. In another embodiment, the present invention provides a crystalline form of the hemisulfate salt of the compound of formula (I),

[0028] [ka]

[0029] Provided is a crystalline form, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 8.3°2θ±0.2°2θ and 15.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 15.1°2θ±0.2°2θ and 23.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.9°2θ±0.2°2θ.

[0030] In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 171°C and 183°C. In a further aspect, the present invention relates to the hydrogen sulfate salt of the compound of formula (I),

[0031] [ka]

[0032] or a hydrate thereof. In a still further aspect, the present invention provides a hemisulfate salt of a compound of formula (I):

[0033] [ka]

[0034] In a still further aspect, the present invention provides a sulfate salt of a compound of formula (I):

[0035] [ka]

[0036] In yet another aspect, the present invention provides a pharmaceutical composition comprising any one of the crystalline forms described herein or any one of the salts described herein. In a further aspect, the invention provides a method of inhibiting ATR kinase in a cell expressing ATR kinase, comprising contacting the cell with an effective amount of any one of the crystalline forms described herein, the pharmaceutical compositions described herein, or any one of the salts described herein. In some embodiments, the cell is in a subject.

[0037] In yet a further aspect, the present invention provides a method of treating a subject in need thereof, comprising administering to the subject an effective amount of any one of the crystalline forms described herein, the pharmaceutical compositions described herein, or any one of the salts described herein. In some embodiments, the subject is diagnosed with a disease or condition having symptoms of cellular hyperproliferation (e.g., cancer (e.g., carcinoma (e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armorial carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, fibroblast ... Dense carcinoma, Embryonal carcinoma, Cerebro-like carcinoma, Epidermoid carcinoma, Tonsillar carcinoma, Exophytic carcinoma, Ulcer carcinoma, Fibrous carcinoma, Gelatinous carcinoma, Colloid adenocarcinoma, Giant cell carcinoma, Adenocarcinoma, Granulosa cell carcinoma, Hair matrix carcinoma, Hematopoietic carcinoma, Hepatocellular carcinoma, Hürthle cell carcinoma, Glassy carcinoma, Adrenal-like carcinoma, Infantile embryonal carcinoma, Carcinoma in situ, Carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, Large cell carcinoma, Lenticular carcinoma, Lentiform carcinoma, Lipomatous carcinoma, Lymphoepithelial carcinoma, Medullary carcinoma, Medullary carcinoma carcinoma), melanoma, soft carcinoma, mucinous carcinoma, mucinous secretory carcinoma, mucous cell carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, globular cell carcinoma, spindle cell carcinoma, porous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, nodular carcinoma (carcinomatuberosum), nodular carcinoma, verrucous carcinoma, and choriocarcinoma), sarcomas (e.g., chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chlorosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhages sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal osteosarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, telangiectatic sarcoma), adenocarcinoma, leukemia (e.g., nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblast ... Lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Reeder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia have and need treatment for chronic myeloma (e.g., acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, superficial spreading melanoma)

[0038] In some embodiments, the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer.

[0039] In some embodiments, the cancer is Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0040] In some embodiments, the subject is suffering from and in need of treatment for a pre-malignant condition. definition As used herein, the term "adenocarcinoma" refers to a malignant tumor arising from glandular cells that fill organs within an organism. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.

[0041] As used herein, the term "ATR kinase" refers to ataxia-telangiectasia- and RAD-3-related protein kinase. The term "cancer" as used herein refers to all types of cancer, neoplasms or malignant tumors found in mammals (e.g., humans), including leukemia, carcinoma and sarcoma.Non-limiting examples of cancers that can be treated by the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, and pancreatic cancer. Further non-limiting examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer.

[0042] The term "carcinoma" as used herein refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and give rise to metastases. Non-limiting examples of cancers that may be treated by the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basocellulare, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, compact carcinoma, etc. durum, embryonal carcinoma, encephalo-like carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullare, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucin-secreting carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinomaThese include globular cell carcinoma, spindle cell carcinoma, cellular carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, carcinoma tuberosum, nodular carcinoma, warty carcinoma, and choriocarcinoma.

[0043] As used herein, the term "crystalline form B" refers to a crystalline form of the compound of formula (I),

[0044] [ka]

[0045] The crystalline form is characterized by an X-ray powder diffraction pattern with peaks at 9.6°2θ±0.2°2θ and 15.8°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by an X-ray powder diffraction pattern with peaks at 8.9°2θ±0.2°2θ and 20.5°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by an X-ray powder diffraction pattern with peaks at 19.8°2θ±0.2°2θ and 20.7°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by an X-ray powder diffraction pattern with peaks at 18.2°2θ±0.2°2θ and 19.2°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a powder X-ray diffraction pattern with peaks at 17.8°2θ±0.2°2θ, 22.2°2θ±0.2°2θ, and 23.9°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset at 243°C-247°C.

[0046] As used herein, the term "crystalline form C" refers to a crystalline form of the compound of formula (I),

[0047] [ka]

[0048] The crystalline form is characterized by an X-ray powder diffraction pattern with peaks at 8.1°2θ±0.2°2θ and 20.3°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern with peaks at 9.1°2θ±0.2°2θ, 15.9°2θ±0.2°2θ, and 23.6°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern with peaks at 14.3°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, and 19.3°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern with peaks at 16.1°2θ±0.2°2θ and 21.3°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern with a peak at 12.3° 2θ±0.2° 2θ. In some embodiments, crystalline form C is characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 82° C. and 109° C. In some embodiments, crystalline form C is characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 245° C. and 248° C.

[0049] As used herein, the term "form F" refers to a crystalline form of the compound of formula (I),

[0050] [ka]

[0051] The crystalline form F is characterized by an X-ray powder diffraction pattern having peaks at 7.2°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, and 29.4°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by an X-ray powder diffraction pattern having peaks at 10.2°2θ±0.2°2θ, 14.4°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by an X-ray powder diffraction pattern having peaks at 17.6°2θ±0.2°2θ and 27.0°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by an X-ray powder diffraction pattern having peaks at 12.5°2θ±0.2°2θ and 30.9°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by an X-ray powder diffraction pattern with peaks at 15.4°2θ±0.2°2θ and 18.3°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by an X-ray powder diffraction pattern with peaks at 19.7°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 245°C and 249°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 111°C and 154°C.

[0052] As used herein, the term "form M" refers to a crystalline form of the compound of formula (I),

[0053] [ka]

[0054] The crystalline form is characterized by an X-ray powder diffraction pattern with peaks at 5.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern with peaks at 2.0°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 8.5°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 16.2°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 19.0°2θ±0.2°2θ and 21.1°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 12.0°2θ±0.2°2θ and 17.1°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 9.5°2θ±0.2°2θ and 14.7°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 18.7°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by an X-ray powder diffraction pattern with peaks at 18.4°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset at 252°C-253°C.

[0055] As used herein, the term "crystalline hydrogen sulfate salt Form A" refers to a crystalline form of the hydrogen sulfate salt of the compound of formula (I),

[0056] [ka]

[0057] The crystalline form is characterized by an X-ray powder diffraction pattern with peaks at 13.0°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 25.6°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate Form A is further characterized by an X-ray powder diffraction pattern with peaks at 14.8°2θ±0.2°2θ and 16.5°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate Form A is further characterized by an X-ray powder diffraction pattern with peaks at 20.1°2θ±0.2°2θ and 24.5°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form A is further characterized by a powder X-ray diffraction pattern with peaks at 14.3°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, and 18.2°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form A is further characterized by a powder X-ray diffraction pattern with peaks at 19.3°2θ±0.2°2θ and 21.4°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form A is further characterized by a powder X-ray diffraction pattern with peaks at 24.6°2θ±0.2°2θ and 25.6°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form A is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 183°C and 218°C.

[0058] As used herein, the term "crystalline hydrogen sulfate Form B" refers to a crystalline form of the hydrate of the hydrogen sulfate salt of the compound of formula (I),

[0059] [ka]

[0060] The crystalline form is characterized by an X-ray powder diffraction pattern with peaks at 5.9°2θ±0.2°2θ and 11.8°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate Form B is further characterized by an X-ray powder diffraction pattern with peaks at 14.9°2θ±0.2°2θ and 20.6°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate Form B is further characterized by an X-ray powder diffraction pattern with peaks at 17.2°2θ±0.2°2θ and 21.2°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate Form B is further characterized by an X-ray powder diffraction pattern with peaks at 13.3°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, and 22.0°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form B is further characterized by an X-ray powder diffraction pattern with peaks at 16.7°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form B is further characterized by an X-ray powder diffraction pattern with peaks at 24.1°2θ±0.2°2θ and 29.5°2θ±0.2°2θ. In some embodiments, the crystalline hydrogen sulfate salt Form B is further characterized by a differential scanning calorimetry thermogram with an endothermic event onset between 91°C and 116°C.

[0061] As used herein, the term "crystalline sulfate salt Form A" refers to a crystalline form of the hemisulfate salt of the compound of formula (I),

[0062] [ka]

[0063] The crystalline form is characterized by an X-ray powder diffraction pattern having peaks at 8.3°2θ±0.2°2θ and 15.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 15.1°2θ±0.2°2θ and 23.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by an X-ray powder diffraction pattern having peaks at 17.9°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset between 171°C and 183°C.

[0064] "Disease" or "Condition" refers to an existing or medical condition of a patient or subject that can be treated by the compounds or methods provided herein. The term "leukemia" as used herein broadly refers to a progressive malignant disease of the hematopoietic organs, generally characterized by distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally classified clinically based on (1) the duration and characteristics of the disease-acute or chronic, (2) the type of cells involved; bone marrow (myeloid), lymph (lymphatic), or monocytic, and (3) the increased or non-increased number of abnormal cells in the blood-leukemic or non-leukemic (subleukemic). Exemplary leukemias that may be treated by the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, and acute myeloid leukemia. leukemia), leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblast ... These include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0065] The term "lymphoma" as used herein refers to cancer originating from cells of immune origin.Non-limiting examples of T and B cell lymphoma include non-Hodgkin's lymphoma and Hodgkin's disease, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom macroglobulinemia, peripheral T cell lymphoma (PTCL), angioimmunoblastic T cell lymphoma (AITL) / follicular T cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T cell lymphoma (EATL), adult T cell leukemia / lymphoma (ATLL), or extranodal NK / T cell lymphoma, nasal type.

[0066] The term "melanoma" as used herein is intended to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated by the compounds or methods provided herein include, for example, acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0067] The term "pharmaceutical composition" as used herein refers to a composition that contains a compound described herein, is formulated with a pharma- ceutical acceptable excipient, and is manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a sterile solution that does not contain particulate embolic material and in a solvent system suitable for intravenous use), or in any other formulation described herein.

[0068] The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier", which is used interchangeably herein, refers to any component other than the compounds described herein (e.g., a vehicle that can suspend or dissolve active compounds), which has the properties of being non-toxic and non-inflammatory in patients. Excipients can include, for example, anti-adherents, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (coloring agents), emollients, emulsifiers, fillers (diluents), film-forming agents or coating agents, flavors, fragrances, glidants (gliding agents), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0069] The term "premalignant" or "precancerous" as used herein refers to a condition that is not malignant but is poised to become malignant. Non-limiting examples of precancerous conditions include myelodysplastic syndromes, colonic polyps, actinic keratosis of the skin, cervical dysplasia, pulmonary metaplasia, and leukoplakia.

[0070] The term "sarcoma" generally refers to tumors composed of a substance like embryonic connective tissue and generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Non-limiting examples of sarcomas that may be treated by the compounds or methods provided herein include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanotic sarcoma, myxoid sarcoma, osteosarcoma, urban sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, euthyroid sarcoma, and uterine sarcoma. These include Ing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic polypigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, astrocytic sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0071] The term "subject" as used herein refers to a human or non-human animal (e.g., a mammal) that is suffering from or at risk of a disease or condition, as determined by a qualified professional (e.g., a doctor or nurse) with or without laboratory tests known in the art of samples from the subject.Preferably, the subject is a human.Non-limiting examples of diseases and conditions include diseases that have symptoms of cell hyperproliferation, such as cancer.

[0072] As used herein, the terms "treatment" and "treating" refer to the medical management of a subject with the intent of improving, ameliorating, stabilizing, preventing, or curing a disease or condition. This term includes active treatment (treatment aimed at improving the disease or condition), causal treatment (treatment directed at the cause of the associated disease or condition), symptomatic treatment (treatment designed to reduce the symptoms of the disease or condition), preventive treatment (treatment aimed at minimizing or partially or completely inhibiting the onset of the associated disease or condition), and supportive treatment (treatment used to complement another therapy). [Brief description of the drawings]

[0073] [Figure 1] 1 is a microscopic image of crystals of crystalline form B of compound of formula (I) isolated from ethyl acetate. The image was made with polarized visible light. [Diagram 2] FIG. 1 is an XRPD diffractogram of crystalline form B of compound of formula (I) isolated from ethyl acetate. [Diagram 3] 1 is a plot showing the TG and DSC traces for crystalline form B of compound of formula (I) isolated from ethyl acetate. [Figure 4] 1 is a DVS plot of crystalline form B of compound of formula (I). [Figure 5A] Figures 5A and 5B are a series of microscopy images of crystalline form C of compound of formula (I). Figure 5A is an image of the solid (crystalline form C) prepared from acetone / water after drying under vacuum at room temperature. The images were made with polarized visible light. [Figure 5B] Figures 5A and 5B are a series of microscopic images of crystalline form C of the compound of formula (I). Figure 5B is an image of crystals isolated from ethanol / water (crystalline form C). The images were made with polarized visible light. [Figure 6] FIG. 1 is an XRPD diffractogram of crystalline form C of compound of formula (I) isolated from acetone / water. [Figure 7] 1 is a plot showing the TG and DSC traces for crystalline form C of compound of formula (I) isolated from acetone / water (Form C). [Figure 8] 1 is a DVS plot of crystalline form C of compound of formula (I) isolated from acetone-water. [Figure 9] 1 is an overlay of XRPD diffractograms comparing XRPD traces of crystalline form C of the compound of formula (I) (top diffractogram), crystalline form C of the compound of formula (I) after DVS (middle diffractogram), and crystalline form J of the compound of formula (I) (bottom diffractogram). [Figure 10]1 is a microscopic image of crystalline form F of compound of formula (I) previously isolated from aqueous ethanol at room temperature as crystalline form C which later transforms into cubic-like crystals of crystalline form F. The image was made with polarized visible light. [Figure 11] FIG. 1 is an XRPD diffractogram of crystalline form F of compound of formula (I) previously isolated from aqueous ethanol at room temperature as crystalline form C which later transforms into crystalline form F. [Figure 12] 1 is a plot showing the TG and DSC traces for crystalline form F of the compound of formula (I). [Figure 13] 1 is a DVS plot of crystalline form F of compound of formula (I). [Figure 14] 1 is a plot showing the open-pan DSC of crystalline form F of compound of formula (I). Dehydration was observed (first endotherm with onset at 105° C.), melting of the anhydrous phase (second endotherm with onset at 180° C.), followed by crystallization of the neat form (exotherm with onset at 204° C.) melting at 245° C.-248° C. [Figure 15] 1 is an overlay of XRPD diffractograms comparing an XRPD trace of a simulated pattern of crystalline form F of compound of formula (I) (from SCXRD, top diffractogram), an XRPD trace of crystalline form F after heating to 170° C. (second diffractogram from the top), an XRPD trace of crystalline form F after heating to 190° C. (third diffractogram from the top), an XRPD trace of crystalline form F after heating to 195° C. (fourth diffractogram from the top), an XRPD trace of crystalline form F after heating to 235° C. (fifth diffractogram from the top), and a reference XRPD trace of crystalline form B. [Figure 16] Microscopic image of crystalline form F after heating to 195° C., showing some particles that contain cracks or lack birefringence. The image was made with polarized visible light. [Figure 17] 1 is a plot showing a modulated DSC trace for crystalline form F of compound of formula (I) after heating to 195° C. A glass transition at 157° C. (midpoint) was observed. [Figure 18]1 is an overlay of XRPD diffractograms comparing crystalline form F of compound of formula (I) in water (top diffractogram), a simulated pattern (from SCXRD) of reference crystalline form F (second diffractogram from the top), an XRPD trace of crystalline form F after suspending a sample in water for 1 day (third diffractogram from the top), and an XRPD trace of a simulated pattern (from SCXRD) of the reference crystalline form C form. [Figure 19A] Figures 19A and 19B are a series of microscopic images of two crystalline forms of the compound of formula (I), crystalline forms B and F, respectively, after suspension in water at room temperature for 5 days. Figure 19A shows that crystalline form B has transformed into crystalline form C. The images were made with polarized visible light. [Figure 19B] Figures 19A and 19B are a series of microscopic images of two crystalline forms of the compound of formula (I) (forms B and F, respectively) after suspension in water at room temperature for 5 days. Figure 19B shows that form F was unchanged. The images were made with polarized visible light. [Figure 20] 1 is a microscopic image of the crystalline hydrogen sulfate salt form of compound of formula (I) isolated from ethanol / tetrahydrofuran (Crystalline Hydrogen Sulfate Form A). The image was made with polarized visible light. [Figure 21] FIG. 1 is an XRPD diffractogram of the crystalline hydrogen sulfate salt form of compound of formula (I) isolated from ethanol / tetrahydrofuran after oven vacuum drying at room temperature (Crystalline Hydrogen Sulfate Form A). [Figure 22] 1 is a plot showing the TG and DSC traces for the crystalline hydrogen sulfate salt form of the compound of formula (I) (Crystalline Hydrogen Sulfate Form A). [Figure 23] 1 is a DVS plot of the crystalline hydrogen sulfate salt form of compound of formula (I) (Crystalline Hydrogen Sulfate Form A). [Figure 24]FIG. 1 is an overlay of XRPD diffractograms comparing XRPD traces of the crystalline hydrogen sulfate salt form of compound of formula (I) after DVS (crystalline hydrogen sulfate Form A) (top diffractogram), crystalline hydrogen sulfate Form A before DVS, and a simulated pattern of the anhydrous hydrogen sulfate salt of compound of formula (I) from SCXRD. [Figure 25A] 1 is a series of microscope images of the crystalline hydrate of the hydrogen sulfate salt of compound of formula (I) (crystalline hydrogen sulfate Form B). The images were made with polarized visible light. [Figure 25B] 1 is a series of microscope images of the crystalline hydrate of the hydrogen sulfate salt of compound of formula (I) (crystalline hydrogen sulfate Form B). The images were made with polarized visible light. [Figure 26] FIG. 1 is an XRPD diffractogram of the crystalline hydrate of the hydrogen sulfate salt of compound of formula (I) (crystalline hydrogen sulfate form B). [Figure 27] 1 is a plot showing TG and DSC traces for a crystalline hydrate of the hydrogen sulfate salt of the compound of formula (I) (Crystalline Hydrogen Sulfate Form B). [Figure 28] 1 is a DVS plot of the crystalline hydrate of the hydrogen sulfate salt of compound of formula (I) (Crystalline Hydrogen Sulfate Form B). [Figure 29A] Figures 29A, 29B, 30A and 30B are a series of microscope images used to monitor the crystalline metastable form of the hydrogen sulfate salt of the compound of formula (I). The crystalline particles (Figures 29A and 29B) had a fine needle-like morphology and a distinct XRPD pattern compared to the crystalline hydrogen sulfate salt form A. [Figure 29B] Figures 29A, 29B, 30A and 30B are a series of microscope images used to monitor the crystalline metastable form of the hydrogen sulfate salt of the compound of formula (I). The crystalline particles (Figures 29A and 29B) had a fine needle-like morphology and a distinct XRPD pattern compared to the crystalline hydrogen sulfate salt form A. [Figure 30A]Figures 29A, 29B, 30A and 30B are a series of microscope images used to monitor the crystalline metastable form of the hydrogen sulfate salt of the compound of formula (I). After 4 hours while stirring in ethanol, some of the particles transformed into tetragonal-like crystals (Figure 30A). [Figure 30B] Figures 29A, 29B, 30A and 30B are a series of microscope images used to monitor the crystalline metastable form of the hydrogen sulfate salt of the compound of formula (I). After stirring in ethanol for 18 hours, the metastable form was completely transformed into the crystalline hydrogen sulfate salt form A, as confirmed by XRPD analysis (Figure 30B). [Diagram 31] FIG. 1 is an overlay of XRPD diffractograms comparing XRPD traces of the crystalline metastable form of the hydrogen sulfate salt of compound of formula (I) (top diffractogram), crystalline hydrogen sulfate salt Form A (middle diffractogram), and a simulated pattern (from SCXRD) of reference crystalline hydrogen sulfate salt Form A (bottom diffractogram). [Diagram 32] FIG. 1 is an overlay of XRPD diffractograms comparing XRPD traces of a crystalline dichloromethane solvate of compound of formula (I) after oven drying (48° C. overnight) (obtained after suspending compound of formula (I) in dichloromethane for 3 days) (top diffractogram), a crystalline dichloromethane solvate of compound of formula (I) after stirring in dichloromethane (middle diffractogram), and a simulated pattern (from SCXRD) of a crystalline dichloromethane solvate of compound of formula (I) (bottom diffractogram). [Diagram 33] FIG. 1 is an XRPD diffractogram of a crystalline tetrahydrofuran solvate of compound of formula (I). [Diagram 34] FIG. 1 is an XRPD diffractogram of the crystalline methanol solvate of compound of formula (I). [Diagram 35]FIG. 1 is an overlay of XRPD diffractograms comparing XRPD traces of a crystalline 2-methyltetrahydrofuran solvate of compound of formula (I) (obtained after suspending compound of formula (I) in 2-methyltetrahydrofuran) after oven drying (48° C. overnight) (top diffractogram), a reference crystalline 2-methyltetrahydrofuran (2-MeTHF) solvate of compound of formula (I) (second diffractogram from the top), a crystalline 2-MeTHF solvate after stirring in 2-MeTHF at 50° C. overnight and then at room temperature for an additional 2 days (third diffractogram from the top), and a crystalline 2-MeTHF solvate after stirring in 2-MeTHF at 50° C. overnight (bottom diffractogram). [Diagram 36] 1 is an overlay of XRPD diffractograms for a 7-day stability study of crystalline form F of compound of formula (I) in 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) at room temperature. No morphological changes were observed after 7 days by XRPD. [Figure 37] 1 is an overlay of XRPD diffractograms for the stability assessment of the crystalline hydrogen sulfate salt of compound of formula (I) (crystalline hydrogen sulfate form A). After 4 hours, crystalline form C was observed. [Figure 38] 1 is an overlay of XRPD diffractograms for the stability assessment of the crystalline hydrate of the hydrogen sulfate salt of compound of formula (I) (crystalline hydrogen sulfate form B). After overnight stirring in 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) in water, with and without citrate buffer, crystalline hydrogen sulfate form B was observed to convert to crystalline form C of compound of formula (I). [Figure 39] 1 is an overlay of XRPD diffractograms for the 7-day stability study of crystalline hydrogen sulfate salt Form A. [Diagram 40] 1 is an overlay of XRPD diffractograms for 7-day stability evaluation of crystalline form F. [Diagram 41]1 is an overlay of XRPD diffractograms for 14-day stability evaluation of crystalline form B. [Diagram 42] 1 is an overlay of XRPD diffractograms for a 14-day stability study of crystalline form F. [Diagram 43] 1 is an overlay of XRPD diffractograms for a 4-week stability study of crystalline hydrogen sulfate salt Form A. [Diagram 44] 1 is an overlay of DSC traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 7 days. [Diagram 45] 1 is an overlay of DSC traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open vial) after 7 days. [Figure 46] 1 is an overlay of DSC traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 14 days. [Figure 47] 1 is an overlay of DSC traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open vial) after 14 days. [Figure 48] 1 is an overlay of DSC traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 4 weeks. [Figure 49] 1 is an overlay of DSC traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) (open vial) and 40° C. / 75% RH (open and closed vials) after 4 weeks. [Figure 50] 1 is an overlay of TG traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 7 days. [Figure 51]1 is an overlay of TG traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open vial) after 7 days. [Figure 52] 1 is an overlay of TG traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 14 days. [Diagram 53] 1 is an overlay of TG traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open vial) after 14 days. [Figure 54] 1 is an overlay of TG traces of crystalline hydrogen sulfate salt form A before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open and closed vials) after 4 weeks. [Figure 55] 3 is an overlay of TG traces of crystalline form F before and after exposure to 25° C. / 60% relative humidity (RH) and 40° C. / 75% RH (open vial) after 4 weeks. [Figure 56] 1 is an overlay of solid-state XRPD diffractograms of the free form of the compound of formula (I). Crystalline form M is the free form (top diffractogram). Crystalline form L is a monomethanol solvate of the compound of formula (I) (second diffractogram from the top). Crystalline form K is a desolvated dichloromethane solvate of the compound of formula (I) (third diffractogram from the top). Crystalline form J is the free form of the compound of formula (I) (fourth diffractogram from the top). Crystalline form I is a mixture of crystal forms B and M. Crystalline form H is a solvated / desolvated form of the compound of formula (I). Crystalline form G is a dichloromethane solvate of the compound of formula (I). Crystalline form F is the free form of the compound of formula (I). Crystalline form E is a 2-methyltetrahydrofuran (2-MeTHF) solvate of the compound of formula (I). Crystalline form D is a monotetrahydrofuran solvate of the compound of formula (I). Crystalline form C is the free form of the compound of formula (I). Crystalline form B is a non-solvated form of the compound of formula (I). Crystalline form A is a mixture of crystalline form B and a solvate of the compound of formula (I). [Figure 57] 1 is an overlay of XRPD diffractograms of selected salts from salt screening and salt scale-up. ML-1 is the first crystalline form of the maleate salt of the compound of formula (I) (top diffractogram). SA-2 is the crystalline hydrogen sulfate salt form A (second diffractogram from the top). HCl-5, HCl-3, and HCl-1 are crystalline forms of the hydrochloride salt of the compound of formula (I) (third and fourth diffractograms from the top, respectively, and bottom diffractogram). [Figure 58] 1 is a microscopic image of the crystalline hemisulfate salt form of compound of formula (I) (crystalline sulfate form A) isolated from ethanol and sulfuric acid (0.55 equivalents). The image was made with polarized visible light. [Figure 59] FIG. 1 is an XRPD diffractogram of the crystalline hemisulfate salt form of compound of formula (I) (Crystalline Sulfate Form A). [Figure 60] 1 is an overlay of TG (top) and DSC (bottom) traces for the crystalline hemisulfate salt form of the compound of formula (I) (crystalline sulfate form A). [Figure 61A] Figures 61A and 61B are TG and DSC traces for the crystalline hemisulfate salt form (crystalline sulfate salt form A) of the compound of formula (I) isolated from a scale-up experiment (see Example 2). Figure 61A is an overlay of the TG (top) and DSC (bottom) traces for the crystalline sulfate salt form A isolated from a scale-up experiment. [Figure 61B] Figures 61A and 61B are TG and DSC traces for the crystalline hemisulfate salt form of compound of formula (I) (crystalline sulfate salt form A) isolated from a scale-up experiment (see Example 2). Figure 61B is a DSC trace of the scaled-up crystalline sulfate salt form A, showing two overlapping endotherms. [Figure 62] FIG. 1 is a 1H NMR spectrum (DMSO-d6) of the crystalline hemisulfate salt form of compound of formula (I) (crystalline sulfate salt form A). [Figure 63]1 is an overlay of XRPD diffractograms from a 7-day stability evaluation of crystalline sulfate salt Form A. Diffractogram (1) is a reference of crystalline sulfate salt Form A before humidity exposure (dry). Diffractogram (2) is a diffractogram of crystalline sulfate salt Form A plus another crystalline form of the sulfate salt of compound of formula (I) after exposure to 75% RH at 40° C. for 7 days. [Figure 64] FIG. 1 is an XRPD diffractogram of crystalline form M of compound of formula (I). [Figure 65] 1 is a DSC trace of crystalline form M of compound of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0074] Generally, the present invention provides a compound of formula (I) and its hydrogen sulfate, hemisulfate, and sulfate crystalline forms. The compound of formula (I) has the following structure:

[0075] [ka]

[0076] The crystalline form of the compound of formula (I) may be, for example, crystalline form B, crystalline form C, crystalline form F, crystalline form M. The crystalline form of the hydrogen sulfate salt of the compound of formula (I) may be, for example, crystalline hydrogen sulfate salt form A. The crystalline form of the hydrate of the hydrogen sulfate salt of the compound of formula (I) may be, for example, crystalline hydrogen sulfate salt form B. The crystalline form of the hemisulfate salt of the compound of formula (I) may be, for example, crystalline sulfate salt form A.

[0077] As described in the Examples, crystalline form B was found to be crystalline with block-like crystals (see FIG. 1). This form has a melting range of 243° C. (onset) to 248° C. (peak) by DSC (see FIG. 3), and DVS analysis showed it to be slightly hygroscopic when subjected to a 25° C. / 0-90% RH change (FIG. 4). XRPD analysis of samples collected after DVS showed that the crystalline form did not change.

[0078] Form C was crystalline with a needle / plate-like morphology (Figures 5A and 5B). Form C appeared to lose approximately 5.6% of its mass when heated to 200°C by TG (Figure 7). Form C melted at approximately 245°C (onset) to 247°C (peak) by DSC (Figure 7). The material was slightly hygroscopic when subjected to a 25°C / 0-90% RH change (Figure 8), but the XRPD pattern changed after DVS compared to the starting material and was consistent with Form J, the free base of the compound of formula (I) (Figure 9).

[0079] Form F was found to be crystalline with a cube-like morphology (see FIG. 10). This form exhibited a weight loss of 4.2% when heated to 200° C. by TG (see FIG. 12). The first endotherm in DSC corresponds to dehydration and melting was observed at about 245° C. (onset) to about 248° C. (peak) (FIG. 12). The material was non-hygroscopic by DVS (FIG. 13) and no morphological changes were observed after heating / drying (FIG. 15) or exposure to 0-90% RH by XRPD analysis.

[0080] Crystalline form M was found to be crystalline with an endotherm in DSC corresponding to melting at about 252° C. (onset) to 253° C. (peak) (by XRPD, FIG. 64) (FIG. 65).

[0081] The crystalline hydrogen sulfate salt form A was found to be crystalline with a tetragonal-like morphology (Figure 20). The form had a weight loss of 0.097% when heated to 100°C by TG and melted at approximately 183°C (onset) followed by decomposition (Figure 22). The material was slightly hygroscopic with a water uptake of 1.42% when subjected to a RH change from 0 to 90% by DVS (Figure 23). No morphological change was observed by XRPD analysis after subjecting this form to 0 to 90% RH (Figure 24).

[0082] The crystalline hydrogen sulfate salt form B was found to be crystalline with a needle / plate-like morphology (Figures 25A and 25B). This form had a weight loss of 10.5% when heated from 16°C to 188°C by TG (Figure 27). This form appeared to lose water when heated to approximately 92°C (onset) (Figure 27). The material was hygroscopic, having a water uptake of 15.75% when subjected to a RH change from 0 to 90% by DVS (Figure 28).

[0083] The crystalline sulfate salt form A was found to be crystalline with elongated particles (Figure 58). This form had a weight loss of 2.2% when heated from 50°C to 160°C and a weight loss of 3.9% when heated from 160°C to 210°C by TG (Figure 60, top). A first endotherm in DSC was observed at about 166°C (onset) to about 179°C (peak) (Figure 60, bottom). A second endotherm in DSC was observed at about 215°C (onset) to about 239°C (peak) (Figure 60, bottom).

[0084] The present invention also provides the hydrogen sulfate salt of the compound of formula (I) or a hydrate thereof. The present invention further provides the hemisulfate salt of the compound of formula (I). The present invention further provides the sulfate salt of the compound of formula (I). Advantageously, the salts described herein (e.g., hydrogen sulfate salts) may have superior physicochemical properties for the purpose of pharmaceutical development.

[0085] How to use Methods for treating a disease or condition having a symptom of cellular hyperproliferation (e.g., cancer) and methods for ATR kinase are described in WO 2020 / 087170, the disclosure of which is incorporated herein by reference in its entirety.

[0086] A method of inhibiting ATR kinase in a cell expressing ATR kinase (e.g., a cell in a subject) can include contacting the cell with an effective amount of a crystalline form or a pharmaceutical composition containing a crystalline form disclosed herein.

[0087] A method of treating a subject in need of treatment (e.g., a subject suffering from and in need of treatment for a disease or condition having a symptom of cellular hyperproliferation (e.g., cancer (e.g., carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma) and / or a pre-malignant condition) can include administering to the subject an effective amount of a crystalline form or a pharmaceutical composition containing the crystalline form disclosed herein.

[0088] Non-limiting examples of cancer include medullary thyroid cancer, familial medullary thyroid cancer, lobular cell carcinoma, acinic cell carcinoma, adenocell carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid cell carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolocarcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, and compact carcinoma. durum, embryonal carcinoma, encephalo-like carcinoma, epidermoid carcinoma, tonsillar carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, glassy carcinoma, adrenal-like carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in situ, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullare, medullary carcinoma, melanoma, carcinoma molle, mucinous carcinoma, mucin-secreting carcinoma muciparum, mucous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, globular cell carcinoma, spindle cell carcinoma, porotic carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, telangiectasia carcinoma, telangiectasia-like carcinoma, transitional cell carcinoma, nodular carcinomatuberosum), nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

[0089] In some embodiments, the crystalline form used in the methods described herein is crystalline form B. In some embodiments, the crystalline form used in the methods described herein is crystalline form C. In some embodiments, the crystalline form used in the methods described herein is crystalline form F. In some embodiments, the crystalline form used in the methods described herein is crystalline form M. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is crystalline sulfate form A.

[0090] Non-limiting examples of leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblast ... These include lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia. In some embodiments, the crystalline form used in the methods described herein is crystalline form B. In some embodiments, the crystalline form used in the methods described herein is crystalline form C. In some embodiments, the crystalline form used in the methods described herein is crystalline form F. In some embodiments, the crystalline form used in the methods described herein is crystalline form M. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is crystalline sulfate form A.

[0091] Non-limiting examples of melanoma include acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma. In some embodiments, the crystalline form used in the methods described herein is crystalline form B. In some embodiments, the crystalline form used in the methods described herein is crystalline form C. In some embodiments, the crystalline form used in the methods described herein is crystalline form F. In some embodiments, the crystalline form used in the methods described herein is crystalline form M. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is crystalline sulfate form A.

[0092] Non-limiting examples of cancer include prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the crystalline form used in the methods described herein is crystalline form B. In some embodiments, the crystalline form used in the methods described herein is crystalline form C. In some embodiments, the crystalline form used in the methods described herein is crystalline form F. In some embodiments, the crystalline form used in the methods described herein is crystalline form M. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is crystalline sulfate form A.

[0093] Other non-limiting examples of cancer include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesion, testicular cancer, lymphoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, or papillary thyroid cancer. In some embodiments, the crystalline form used in the methods described herein is crystalline form B. In some embodiments, the crystalline form used in the methods described herein is crystalline form C. In some embodiments, the crystalline form used in the methods described herein is crystalline form F. In some embodiments, the crystalline form used in the methods described herein is crystalline form M. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is crystalline hydrogen sulfate salt form B. In some embodiments, the crystalline form used in the methods described herein is crystalline sulfate salt form A.

[0094] Pharmaceutical Compositions The crystalline forms described herein (e.g., crystalline forms of the compound of formula (I)) can be formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. The pharmaceutical composition typically includes an active agent described herein and a physiologically acceptable excipient (e.g., a pharma- ceutically acceptable excipient). The formulation principles of the compound of formula (I) are described in WO 2020 / 087170, the disclosure of which is incorporated herein by reference in its entirety. The crystalline forms described herein are particularly useful for solid pharmaceutical compositions, such as solid dosage forms (e.g., tablets, powders, lozenges, sachets, cachets, and soft and hard gelatin capsules).

[0095] The compound of formula (I) can be administered, for example, by oral, parenteral, buccal, sublingual, nasal or rectal administration, and the pharmaceutical composition can be formulated accordingly.Preferably, the crystalline form of the compound of formula (I) is administered orally.

[0096] Suitable pharmaceutical carriers and pharmaceutical requirements for use in pharmaceutical formulations are described in Remington: The Science and Practice of Pharmacy, 21 st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and in the USP / NF (United States Pharmacopeia and the National Formulary). EXAMPLES

[0097] The following examples are intended to illustrate the invention but are not intended to limit it in any way.

[0098] [Table 1]

[0099] Methods. During the preparations described in the Examples, the experimental set-up and the products obtained were monitored using the methods described herein below. X-ray powder diffraction (XRPD) Bruker D2 Phaser 2nd Gen Equipment: Bruker D2 Phaser 2nd Gen Parameters: X-ray tube Cu(Kα) of 1.54184[Å]; Tube voltage: 30 kV, tube current: 10 mA Scanning range: 2~4°2θ(degrees) Step size: 0.01° Scanning speed: 1 or 2° / min Malvern Panalytical Equipment: Panalytical X'Pert3 Powder Parameters: X-ray tube Cu (Kα), tube voltage 45 kV, tube current 40 mA Scanning range: 2~4°2θ(degrees) Step size: 0.01° Scanning speed: 6° / min Peak lists were generated using HighScore Plus: Parameter: Minimum significance: 2.00 Minimum tip width deviation angle (Gonio): 0.01 Maximum tip width deflection angle: 1.00 Peak base width deviation angle: 2.00 Method: Least second derivative Peaks were visually assessed and manually removed / added. Profile fitting with default settings was used.

[0100] nuclear magnetic resonance (NMR) Equipment: Bruker 400 Ultrashield Solvent: DMSO Thermogravimetric analysis (TG) Instrument: TA Instruments Discovery TGA Parameters: 10°C / min ramp, 25-300°C, 50mL / min N2 sweep Dynamic Vapor Sorption Analysis (DVS) Equipment: DVS specific, surface measurement system Parameters: 25℃, 0~90~0%RH for 2 cycles Polarized Optical Microscopy (PLM) Equipment: Nikon Eclipse Ci POL Camera: Nikon DS-Fi3 Software: Nikon NIS Elements Differential Scanning Calorimetry (DSC) Instrument: TA Instruments Discovery DSC Parameters: Temperature rise 5 / 10 / 20℃ / min, max 300℃ Example 1. Preparation of crystalline forms of the compound of formula (I) The preparation of compounds of formula (I) is described in WO 2020 / 087170, the disclosure of which is incorporated herein by reference in its entirety.

[0101] Preparation of the compound of formula (I) as crystalline form B. The crystalline form B of the compound of formula (I) was obtained by suspending the compound of formula (I) (50 mg, crystalline form A) in EtOAc and then adding methanol to dissolve it. The solvent was evaporated to obtain crystals of crystalline form B. Table 1 summarizes the physical and chemical characteristics for crystalline form B.

[0102] [Table 2]

[0103] Preparation of the compound of formula (I) in crystalline form C. The compound of formula (I) (form A) was suspended in acetone-water, evaporated, and then dried under vacuum at room temperature overnight to obtain form C. Form C was also isolated from aqueous ethanol. The physical and chemical properties of form C are summarized in Table 2.

[0104] [Table 3]

[0105] Preparation of the compound of formula (I) in crystalline form F. The compound of formula (I) (form A) was suspended in aqueous ethanol at room temperature, which gave large, long rod / prism crystals of form C, which later transformed into cubic-like crystals of form F shown in FIG. 10 and confirmed by comparison to simulated XRPD from SCXRD. Bulk crystals of form F were oven-dried and analyzed by XRPD, DSC, TG and DVS. Table 3 summarizes the physical and chemical characteristics of form F.

[0106] [Table 4]

[0107] Further, to better understand the behavior of form F upon heating, samples were generated by heating form F to 170°C, 190°C and 195°C using a TG instrument and analyzed by XRPD. Prior to selecting these temperature points, open pan DSC was performed (Figure 14). The results of the XRPD analysis are shown in Figure 15 along with the pattern collected earlier for the sample heated to 235°C. It showed that 1) the dehydrated / partially dehydrated phase (after heating to 170°C) showed the same pattern as form F, 2) crystallization of the neat form (form B) from the melt of the dehydrated phase was observed as early as 190°C by XRPD analysis, but the onset of the exotherm (crystallization) was at 203°C, and 3) the endotherm (onset) at about 245°C was the melting of the neat form (form B). The XRPD analysis of these samples showed reduced crystallinity. The PLM of the sample heated to 195°C appeared to contain some amorphous particles (Figure 16). To confirm the presence of amorphous particles, the sample was analyzed by modulated DSC. A glass transition at 157°C (midpoint) was observed (Figure 17).

[0108] Preparation of other crystalline forms of the compound of formula (I). Table 4 summarizes the crystalline free base forms. Figure 56 shows an overlay of the respective XRPD patterns for each solid state.

[0109] [Table 5]

[0110] Table 5 summarizes other solvents in which the various crystalline forms were isolated.

[0111] [Table 6]

[0112] Crystalline form K was obtained after suspending 50 mg of the compound of formula (I) (form A) in DCM for 3 days. The sample was oven dried overnight and XRPD was collected on the solid. The material was a DCM solvate of the free base compound before oven drying, which was confirmed by SCXRD. The XRPD changed after oven drying at 48° C. (FIG. 32).

[0113] After suspending 50 mg of the compound of formula (I) (form A) in THF for 3 days, crystalline form D was obtained. The sample was dried overnight and an XRPD was collected on the solid (Figure 33). The material was a mono-THF solvate of the free base compound.

[0114] Crystalline form E was obtained after suspending 50 mg of the compound of formula (I) (crystal form A) in 2-MeTHF for 3 days. The sample was dried overnight and the XRPD was collected on the solid (Figure 34). The material is a 2-MeTHF solvate of the free base compound, which was produced by stirring the compound of formula (I) in 2-MeTHF overnight (bottom trace in Figure 35) followed by stirring at room temperature for 2 days (second-to-bottom trace in Figure 35). The XRPD changed after oven drying at 48°C overnight (top trace in Figure 35).

[0115] After heating crystalline form H (isolated from isopropyl acetate) to 248° C., crystalline form M was obtained. Example 2. Preparation of the crystalline hydrogen sulfate salt form of the compound of formula (I) Preparation of crystalline hydrogen sulfate salt form A. Crystalline hydrogen sulfate salt form A (neat) was prepared using crystalline form H (82 mg) in EtOH. Sulfuric acid was added to the suspension in a molar ratio of 1:1.5 (compound of formula (I) : H2SO4) and precipitation was observed. After stirring for 18 hours, the solid was isolated and dried in an oven vacuum at room temperature. Table 6 summarizes the physical and chemical properties of crystalline hydrogen sulfate salt form A.

[0116] [Table 7]

[0117] The material was slightly hygroscopic with a water uptake of 1.42% when subjected to a RH change from 0 to 90% by DVS (Figure 23). No morphological changes were observed by XRPD after subjecting the crystalline form to DVS (Figure 24).

[0118] Preparation of crystalline hydrogen sulfate salt form B. Approximately 1.0 g of compound of formula (I) (97.3% pure by quantitative NMR, 99.9% pure by HPLC (A), 0.9% water (w / w, as determined by Karl Fischer titration), 1.9% residual EtOAc (w / w)) was added to a 20 mL vial, followed by 2 mL of THF:water (9:1 v / v). A white slurry was formed and stirred at 45 °C for 1 h. A solution of concentrated sulfuric acid (95-98%) was then prepared at a concentration of 98.0 mg / mL in THF:water (9:1 v / v). A total of 3.1 equivalents of sulfuric acid (8.0 mL total volume from the prepared solution) was then added dropwise in 8 equal portions to the slurry of compound of formula (I) over a period of 2 h. After each addition, the sample was stirred for 5 min, and then the pH of the slurry was measured. The pH value exceeded the saturation level of the pH probe after the first addition. After the sixth addition, the sample was seeded with crystalline hydrogen sulfate salt Form B (spatula tip). All the required amount of sulfuric acid was added and the sample was stirred at 45° C. for 1 hour and then at room temperature overnight. Observations from the scale-up experiment are included in Table 15. After stirring overnight, the sample was filtered for 3 minutes and washed with 2×1 volume of THF:water (9:1 v / v). An aliquot was collected from the wet cake and XRPD analysis confirmed the solid state to be crystalline hydrogen sulfate salt Form B. The filtered solid was then transferred to a vacuum oven and dried at 50° C. under positive vacuum (approximately 29.5 inHg (99898.2 Pa)) for 5 hours. The sample was then transferred to an oven at room temperature and dried under positive vacuum for 5 hours and then under static vacuum for 3 days. XRPD analysis confirmed that the crystalline hydrogen sulfate salt Form B was stable after drying. The yield after drying was 79.6% w / w (with respect to the monosulfate monohydrate salt). The sulfate content determined for the sample was 19.5 wt%, which is slightly higher than the 18.6 wt% value expected from the monosulfate monohydrate salt. The stoichiometry of crystalline hydrogen sulfate Form B, determined from the sulfate content, was 1:1.05 API:monosulfate monohydrate. Table 7 summarizes the physical and chemical characteristics for crystalline hydrogen sulfate Form B.

[0119] [Table 8]

[0120] The material is hygroscopic, with a water absorption of 15.75% when subjected to a RH change from 0 to 90% according to DVS (Figure 28). Preparation of crystalline sulfate salt form A. Crystalline sulfate salt form A was prepared from compound of formula (I) stirred with 0.55, 0.75, 1.0, and 1.5 equivalents of sulfuric acid in ethanol (see FIG. 59 for XRPD patterns). Scaling up at 0.55 equivalents proceeded as follows: Approximately 1.0 g of (97.3% pure by quantitative NMR, 99.9% pure by HPLC (A), 0.9% water (w / w, as determined by Karl Fischer titration), 1.9% residual EtOAc (w / w)) was added to a 20 mL vial, followed by 15 mL of EtOH. A low viscosity white slurry was formed and stirred at 45° C. for 1.5 hours. A solution of concentrated sulfuric acid (95-98%) was then prepared in EtOH at a concentration of 46.0 mg / mL. A total of 0.55 equivalents of sulfuric acid (3.0 mL total from the prepared solution) was then added dropwise in 8 equal portions to the slurry over 2 hours. After the 4th addition, the sample was seeded with crystalline sulfate salt form A (spatula tip). Aliquots were collected, filtered, and analyzed by XRPD after the 4th (0.28 equivalents) and 5th (0.34 equivalents) additions. With all the required amount of sulfuric acid added, the sample was stirred at 45° C. for 2 hours, then at room temperature for 45 minutes. An aliquot was collected at that point, and crystalline sulfate salt form A was confirmed by XRPD analysis. The sample was then filtered for 3 minutes and washed with 2×1 volume of EtOH. The filtered solid was then transferred to a vacuum oven and dried under static vacuum (approximately 29.5 inHg (99898.2 Pa)) at 50° C. overnight (approximately 16 hours), then under positive vacuum for 4 hours. XRPD analysis confirmed that the crystalline sulfate salt Form A was stable after drying. The sulfate content of the sample (determined by ELTRA) was 10.74 wt%, consistent with the expected value of 9.64 wt% for the hemisulfate salt. The stoichiometry of the crystalline sulfate salt Form A, determined from the sulfate content, was 1:0.56 API:sulfate.

[0121] Crystalline sulfate form A showed slightly reduced crystallinity after drying under positive vacuum (-29.5 inHg (99898.2 Pa)) at 50°C for 3 hours. The TG thermogram of crystalline sulfate form A showed two mass losses of 2.2 wt% between 50-160°C and 3.9 wt% between 160-210°C (Figure 60, top). The DSC thermogram of crystalline sulfate form A showed two endothermic peaks with onsets at 165.7°C and 215.4°C (Figure 60, bottom). The TG thermogram of crystalline sulfate form A from scale-up showed two mass losses of 0.32 wt% between 40-140°C and 7.35 wt% between 140-200°C (Figure 61A, top). Two overlapping endotherms were observed from the DSC thermogram with onset temperatures of 171.3° C. and 182.3° C. (FIG. 61A (bottom) and FIG. 61B). Microscopic images of the crystalline sulfate salt form A showed elongated particles (FIG. 58). 1 The H NMR spectrum is shown in Figure 62.

[0122] [Table 9]

[0123] Example 3. Analysis of crystalline forms of the compound of formula (I) X-ray powder diffraction The XRPD peak list for crystalline form B is provided in Table 8, the XRPD peak list for crystalline form C is provided in Table 9, the XRPD peak list for crystalline form F is provided in Table 10, the XRPD peak list for crystalline form M is provided in Table 10A, the XRPD peak list for crystalline hydrogen sulfate form A is provided in Table 11, the XRPD peak list for crystalline hydrogen sulfate form B is provided in Table 12, and the XRPD peak list for crystalline sulfate form A is provided in Table 12A. The XRPD diffractogram for crystalline form B is provided in Figure 2, the XRPD diffractogram for crystalline form C is provided in Figure 6, the XRPD diffractogram for crystalline form F is provided in Figure 11, and the XRPD diffractogram for crystalline form M is provided in Figure 64. An XRPD diffractogram of crystalline hydrogensulfate salt form A is provided in FIG. 21, an XRPD diffractogram of crystalline hydrogensulfate salt form B is provided in FIG. 26, and an XRPD diffractogram of crystalline sulfate salt form A is provided in FIG.

[0124] [Table 10-1]

[0125] [Table 10-2]

[0126] [Table 10-3]

[0127] [Table 11-1]

[0128] [Table 11-2]

[0129] [Table 12-1]

[0130]

Table 12-2

[0131]

Table 12-3

[0132]

Table 13

[0133]

Table 14-1

[0134]

Table 14-2

[0135]

Table 15-1

[0136]

Table 15-2

[0137]

Table 16

[0138] Polarized optical micromirror method (PLM) A PLM image of crystalline form B isolated from ethyl acetate is shown in FIG. 1, which shows material with a block-like morphology under plane polarized light. PLM images of crystalline form C isolated from acetone / water are shown in FIGS. 5A and 5B, which show material with a needle / plate-like morphology under plane polarized light. A PLM image of crystalline form F isolated from aqueous ethanol is shown in FIG. 10, which shows material with a cubic-like morphology under plane polarized light. A PLM image of crystalline hydrogen sulfate salt form A is shown in FIG. 20, which shows material with a tetragonal-like morphology under plane polarized light. PLM images of crystalline hydrogen sulfate salt form B are shown in FIGS. 25A and 25B, which show material with a needle / plate-like morphology under plane polarized light. A PLM image of crystalline sulfate salt form A is shown in FIG. 58.

[0139] Example 4. Free Form Solid State Water Solubility at Room Temperature Appropriate amounts of crystalline form B and crystalline form F were weighed into 4 mL vials each, and water was added to the solids in 0.1 mL increments until 0.7 mL was added to each vial. Samples were shaken at 25° C. and 200 rpm. XRPD (taken after mixing the crystalline forms with water and after suspending them in water one day later) and PLM (after 5 days) were recorded. Crystal form B changed to crystalline form C in water, as confirmed by PLM (FIGS. 19A and 19B) and XRPD (FIG. 18). The aqueous solubility of crystalline form C was about 0.05 mg / mL. Crystal form F remained unchanged in water, with a solubility of about 0.046 mg / mL. Table 13 summarizes the aqueous solubility of crystalline forms C and F.

[0140] [Table 17]

[0141] Example 5. Stability of the metastable hydrogen sulfate form During the preparation of crystalline hydrogen sulfate salt Form A in EtOH, the suspension was monitored by PLM (Figures 29A, 29B, 30A, and 30B). A metastable form was discovered. The crystalline particles had a fine needle-like morphology and had a different XRPD pattern compared to crystalline hydrogen sulfate salt Form A (Figure 31). However, after 18 hours of stirring, the particles transformed into tetragonal-like crystals. The XRPD recorded on the solid was compared with the pattern simulated by SCXRD, confirming that crystalline hydrogen sulfate salt Form A was obtained (Figure 31). No further characterization was performed to identify this metastable form. The conversion of this form to crystalline hydrogen sulfate salt Form A was accelerated with excess acid.

[0142] Example 6. Morphological stability of crystalline form F in 0.5% methylcellulose (v / v) (400 cps (400 mPa·s)) / 0.02% sodium lauryl sulfate (v / v) Crystalline form F (56 mg) was weighed into a 20 mL vial and 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) (14 mL) was added to the solid and stirred (500 rpm) at room temperature. Another vial was prepared under the same experimental conditions but with ground crystal form F instead. Samples were evaluated at the indicated time points and PLM images were recorded for up to 7 days. No morphological changes were obtained after 7 days, as also confirmed by XRPD (Figure 36). Crystalline form F had very low aqueous solubility, while other crystal forms had better aqueous solubility and changed to crystal form F in the formulations tested.

[0143] Example 7. Morphological stability of crystalline hydrogen sulfate salt forms A and B in buffered 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) Crystalline hydrogen sulfate salt form A was used for morphological stability studies in 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) with citrate buffer (pH 4.5) at concentrations of 0.1 mg / mL, 0.2 mg / mL, 0.5 mg / mL and 1 mg / mL, with and without stirring. HPLC purity was obtained for the solutions on days 3 and 7. The purity of the solutions remained in the range of 99.8-99.9% (Table 14).

[0144] An additional sample of crystalline hydrogen sulfate form A in the same buffered formulation was prepared at a concentration of 1 mg / ml and stirred at 500 rpm at room temperature. The sample was monitored hourly for morphology assessment. The solution was nearly clear for the first 3 hours. Precipitation of the free form, crystalline form C, was observed after 3 hours. XRPD analysis of the precipitate confirmed that crystalline form C had formed (Figure 37).

[0145] [Table 18]

[0146] Crystalline hydrogen sulfate salt form B (10 mg) was suspended in 10 mL of 0.5% methylcellulose (v / v) (400 cps (400 mPa s)) / 0.02% sodium lauryl sulfate (v / v) with and without sodium citrate buffer (pH 4.5) and stirred at 500 rpm at room temperature overnight. The resulting solid was determined to be the free form, crystalline form C, as confirmed by XRPD (Figure 38).

[0147] Example 8. Storage stability of crystalline forms Crystalline Form F and Crystalline Hydrogen Sulfate Form A. 7-day, 14-day and 4-week stability evaluations of crystalline Form F and crystalline hydrogen sulfate Form A were performed as follows: Samples of each form were weighed (approximately 40 mg) into separate vials and placed under 25°C / 60% RH and 40°C / 75% RH. Closed and open vials were used to evaluate the forms. XRPD of samples after 1, 2 and 4 weeks of exposure were consistent with the starting material (t=0) pattern (Figures 39-43). Both crystalline hydrogen sulfate Form A and crystalline Form F showed similar thermal behavior under DSC compared to t=0 (Figures 44-49). TG (Figures 50-55) and HPLC data are summarized in Table 15 (Summary of Crystalline Form F) and Table 16 (Crystalline Hydrogen Sulfate Form A).

[0148] [Table 19]

[0149] [Table 20]

[0150] Crystalline hydrogen sulfate salt form B. The solid state stability of crystalline hydrogen sulfate salt form B was tested after exposure to 75% RH at 40° C. for one week. Approximately 30 mg of crystalline hydrogen sulfate salt form B was weighed into a 4 mL vial and covered with KIMWIPE®. The vial was placed into a 20 mL scintillation vial containing saturated sodium chloride (NaCl) solution to generate 75% RH at 40° C. The vial was sealed with PARAFILM® and placed on a hot plate and allowed to sit for one week. After one week, no significant changes were observed (confirmed by XRPD analysis) and the sample remained a free-flowing white powder.

[0151] Crystalline Sulfate Form A. The solid state stability of crystalline sulfate Form A was tested after exposure to 75% RH at 40° C. for 1 week. Approximately 30 mg of crystalline sulfate Form A was weighed into a 4 mL vial and covered with KIMWIPE®. The vial was placed in a 20 mL scintillation vial containing saturated sodium chloride (NaCl) solution to generate 75% RH at 40° C. The vial was sealed with PARAFILM®, placed on a hot plate, and allowed to sit for 1 week. After 1 week, no significant changes were observed and the sample remained a free-flowing white powder. XRPD analysis showed that crystalline sulfate Form A changed to a mixture of crystalline sulfate Form A + another crystalline form of the sulfate salt of compound of formula (I) after 1 week at 75% RH (FIG. 63).

[0152] Example 9. Free Base Solid State Screening Solid state screening of compound of formula (I) was performed by slurry crystallization. The solubility of crystalline form A in 25 single solvents was measured at room temperature (Table 17). Approximately 20 mg of starting material was weighed into a 2 mL vial and 0.2 mL of solvent was added. Crystalline form A had low solubility in the tested solvents, except for DMF, DMSO, NMP and DMAc (>100 mg / mL). XRPD data was collected on the solid obtained after 7 days.

[0153] [Table 21]

[0154] Example 10. Salt Screening Salt screening of the compound of formula (I) was carried out using multiple solvents (Table 18). The compound of formula (I) (about 41 mg in each experiment) was mixed with the corresponding amount of each acid to give a 1:1 molar ratio. The samples were stirred at room temperature overnight and XRPD was recorded on the solid obtained after oven drying.

[0155] [Table 22]

[0156] pw: powder * No further identification was made -: Not executed Form B, Form F, and Form L refer to crystalline forms B, F, and L, respectively.

[0157] Thirteen salt hits of the compound of formula (I) obtained in the salt screening were scaled up using 82 mg of starting material (crystalline form A) in the appropriate solvent. Eight salts were repeated in comparison with the previous data. HCl-2, SA-4, BSA-3, MSA-1 and MSA-2 were not reproduced. Screening conditions with H2SO4 were repeated, and four salt hits were obtained. Five salts (bold in Table 19) were selected based on crystallinity, reproducibility, physical stability (drying, heat (by DSC and TG), ambient moisture absorption), excluding MSA and BSA (see Table 19). An overlay of the XRPD diffractograms of the selected salts is shown in Figure 57.

[0158] [Table 23]

[0159] Other embodiments Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the present invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the present invention.

[0160] Other embodiments are within the scope of the claims.

Claims

1. A crystal of a hydrogen sulfate salt of a compound of formula (I), 【Chemical 1】 wherein the crystal is characterized by a powder X-ray diffraction pattern having peaks at 13.0° 2θ ± 0.2° 2θ, 19.7° 2θ ± 0.2° 2θ, and 25.6° 2θ ± 0.2° 2θ.

2. The crystal according to claim 1, further characterized by a powder X-ray diffraction pattern having peaks at 14.8° 2θ ± 0.2° 2θ and 16.5° 2θ ± 0.2° 2θ.

3. The crystal according to claim 1, further characterized by a powder X-ray diffraction pattern having peaks at 20.1° 2θ ± 0.2° 2θ and 24.5° 2θ ± 0.2° 2θ.

4. The crystal according to claim 1, further characterized by a powder X-ray diffraction pattern having peaks at 14.3° 2θ ± 0.2° 2θ, 17.9° 2θ ± 0.2° 2θ, and 18.2° 2θ ± 0.2° 2θ.

5. The crystal according to claim 1, further characterized by a powder X-ray diffraction pattern having peaks at 19.3° 2θ ± 0.2° 2θ and 21.4° 2θ ± 0.2° 2θ.

6. The crystal according to claim 1, further characterized by a powder X-ray diffraction pattern having peaks at 24.6° 2θ ± 0.2° 2θ and 25.6° 2θ ± 0.2° 2θ.

7. The crystal according to claim 1, further characterized by a differential scanning calorimetry thermogram having an endothermic event start at 183°C to 218°C.

8. A hydrogen sulfate salt of a compound of formula (I), 【Chemical 2】 or a hydrate thereof.

9. A hemisulfate salt of a compound of formula (I). 【Chemical Formula 3】

10. A sulfate salt of a compound of formula (I). 【Chemical Formula 4】

11. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 7 or the salt according to any one of claims 8 to 10.

12. A pharmaceutical composition for use in a method of inhibiting ATR kinase in cells expressing ATR kinase, said method comprising contacting said cells with an effective amount of the pharmaceutical composition according to claim 11.

13. The pharmaceutical composition according to claim 12, wherein said cells are in a subject.

14. A pharmaceutical composition for use in a method of treating a subject in need of treatment, said method comprising administering to said subject an effective amount of the pharmaceutical composition according to claim 11.

15. The pharmaceutical composition according to claim 14, wherein the subject is suffering from a disease or condition having symptoms of cell over-proliferation and requires treatment thereof.

16. The pharmaceutical composition according to claim 15, wherein the disease or condition is cancer.

17. The cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia or melanoma, (i) the carcinoma is selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, lobular cell carcinoma, alveolar cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid cell carcinoma, basal spinous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, encephaloid carcinoma, cholangiocarcinoma, chorionic cell carcinoma, colloid carcinoma, comedocarcinoma, solid carcinoma, cribriform carcinoma, scirrhous carcinoma, cutaneous carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, desmoplastic carcinoma, fetal carcinoma, encephaloid carcinoma, epidermoid carcinoma, pharyngeal tonsil epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatinous carcinoma, colloid adenocarcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, glassy carcinoma, adrenoid carcinoma, neonatal fetal carcinoma, intraepithelial carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitsky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanotic carcinoma, soft carcinoma, mucinous carcinoma, mucin-secreting carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucinous carcinoma, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spinous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, storage cell carcinoma, sarcomatoid carcinoma, Schnyder carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, soranoid carcinoma, globular cell carcinoma, spindle cell carcinoma, porous carcinoma, squamous cell carcinoma, squamous epithelial cell carcinoma, string carcinoma, telangiectatic carcinoma, telangiectatic-like carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, verrucous carcinoma, and villous carcinoma; (ii) the sarcoma is selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanocarcinoma, myxosarcoma, osteosarcoma, urban sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblast sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen sarcoma, Kaposi sarcoma, astrocytic sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticuloerythroblastic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma; (iii) the leukemia is selected from the group consisting of non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemocytoblastic leukemia, hemoblastocytic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphangitic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacytic leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, leader cell leukemia, Ring leukemia, stem cell leukemia, subaleukemic leukemia, and undifferentiated cell leukemia; (iv) the melanoma is selected from the group consisting of acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigo melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma, the pharmaceutical composition according to claim 16.

18. The pharmaceutical composition according to claim 16, wherein the cancer is prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, bulbar cancer, colorectal cancer, pancreatic cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, essential thrombocythemia, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, pre-malignant skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, papillary thyroid cancer, or hepatocellular carcinoma.

19. The pharmaceutical composition according to claim 16, wherein the subject is suffering from a pre-malignant condition and in need of treatment thereof.

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