Crystalline and Salt Forms of Kinase Inhibitors

Abstract

The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The present invention also relates to crystalline salts of Compound 1. The present invention also relates to pharmaceutical compositions comprising solid polymorphs of the free base and salts of Compound 1. The present invention further relates to methods of treating diseases, disorders, or syndromes mediated, at least in part, by modulating the in vivo activity of protein kinases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 63 / 292,748, filed December 22, 2021. The entire contents of the aforementioned application are incorporated herein by reference.

[0002] The present invention relates to crystalline free base of the tyrosine kinase inhibitor, Compound 1. The present invention also relates to crystalline salts of Compound 1. The present invention also relates to solid state polymorphs of the free base and pharmaceutical compositions comprising salts of Compound 1. The present invention further relates to methods of treating a disease, disorder, or syndrome mediated, at least in part, by modulating the in vivo activity of a protein kinase. [Background technology]

[0003] Human Axl belongs to the Tyro3, ​​Axl, and Mer (TAM) subfamily of Mer-containing receptor tyrosine kinases. TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Axl is overexpressed in many tumor cell types and was originally cloned from a patient with chronic myeloid leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is thought to cause tumor growth through activation of proliferative and antiapoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, glioma, melanoma, thyroid cancer, renal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. Overexpression of Axl results in poor prognosis for patients with the indicated cancers.

[0004] Activation of Mer, like Axl, signals downstream signaling pathways that lead to tumor proliferation and activation. Mer binds to ligands such as the soluble protein Gas-6. Binding of Gas-6 to Mer induces autophosphorylation of Mer at its intracellular domain, resulting in downstream signal activation. Overexpression of Mer in cancer cells leads to increased metastasis, most likely due to the generation of soluble Mer ectodomain protein as a decoy receptor. Tumor cells secrete a soluble form of the extracellular Mer receptor that reduces the ability of the soluble Gas-6 ligand to activate Mer on endothelial cells, leading to cancer progression.

[0005] Therefore, compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mer, are needed for the treatment of selected cancers. Summary of the Invention

[0006] The present invention provides crystalline forms of the free base and selected salts of the compound 1,N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide, which has the structure: [ka]

[0007] Compound 1 is disclosed in WO2019 / 148044, the entire contents of which are incorporated herein by reference.

[0008] Certain crystalline forms of active pharmaceutical ingredients (APIs), such as Compound 1, may have several advantages over other crystalline or amorphous forms, such as increased stability during storage or processing, more favorable solubility, and increased bioavailability. Various crystalline solids and crystalline salts of Compound 1 are disclosed in WO2020123800 and WO2020247019, the entire contents of each of which are incorporated herein by reference. Reported herein are additional new crystalline solids of Compound 1 and crystalline salts of Compound 1.

[0009] In one aspect, the present invention provides a crystalline solid of Compound 1, or a hydrate or solvate thereof, wherein the crystalline solid is selected from the group consisting of Compound 1 form R, Compound 1 form S, Compound 1 form T, Compound 1 form U, Compound 1 form V, Compound 1 form W, Compound 1 form X, and Compound 1 form Y.

[0010] In one aspect, the invention comprises a crystalline salt of Compound 1, the crystalline salt being selected from the group consisting of hemifumarate Form C of Compound 1, hemifumarate Form D of Compound 1, hemifumarate Form E of Compound 1, hemifumarate Form F of Compound 1, hemi-edisylate Form A, heminapadisylate Form A, napsylate Form A, napsylate Form B, and napsylate Form C.

[0011] In one aspect, the invention includes a pharmaceutical composition comprising a crystalline solid or a salt described herein and a pharma- ceutically acceptable excipient.

[0012] In another aspect, the invention includes a method of treating a disease, disorder, or syndrome mediated at least in part by modulating the in vivo activity of a protein kinase, comprising administering to a subject in need thereof a crystalline solid, crystalline salt, or pharmaceutical composition described herein.

[0013] In one embodiment of this aspect, said disease, disorder, or syndrome mediated at least in part by modulating the in vivo activity of a protein kinase is cancer.

[0014] In another aspect, the invention includes a method for inhibiting a protein kinase comprising contacting the protein kinase with a crystalline solid, crystalline salt, or pharmaceutical composition described herein.

[0015] In one embodiment of this aspect, the protein kinase is Axl, Mer, c-Met, KDR, or a combination thereof. [Brief description of the drawings]

[0016] [Figure 1] 1 is an XRPD pattern of Form R of Compound 1.

[0017] [Diagram 2] 1 is a TGA thermogram of Compound 1, Form R.

[0018] [Diagram 3] 1 is a DSC thermogram of Compound 1, Form R.

[0019] [Figure 4] 1 is an XRPD pattern of Form S of Compound 1.

[0020] [Diagram 5] 1 is an XRPD pattern of Form T of Compound 1.

[0021] [Figure 6] 1 is an XRPD pattern of form U of compound 1.

[0022] [Figure 7] 1 is a DSC thermogram of Form U of Compound 1.

[0023] [Figure 8] 1 is a 1H NMR spectrum of form U of compound 1.

[0024] [Figure 9]1 is an XRPD pattern of Form V of Compound 1.

[0025] [Figure 10] 1 is an XRPD pattern of Form W of Compound 1.

[0026] [Figure 11] 1 is an XRPD pattern of Form X of Compound 1.

[0027] [Figure 12] 1 is an XRPD pattern of form Y of compound 1.

[0028] [Figure 13] FIG. 1 is an XRPD pattern of amorphous Compound 1 by DCM rotary evaporation.

[0029] [Figure 14] 1 is a TGA thermogram of amorphous Compound 1 by DCM rotary evaporation.

[0030] [Figure 15] 1 is a DSC thermogram of amorphous Compound 1 by DCM rotary evaporation.

[0031] [Figure 16] 1 is a cycling DSC thermogram of amorphous Compound 1 by THF rotary evaporation.

[0032] [Figure 17] 1 is an XRPD pattern of the hemi-edisylate salt Form A of Compound 1.

[0033] [Figure 18] 1 is a TGA thermogram of the hemi-edisylate salt Form A of Compound 1.

[0034] [Figure 19] 1 is a DSC thermogram of the hemi-edisylate salt Form A of Compound 1.

[0035] [Figure 20] 1 is an XRPD pattern of hemina padisylate Form A of Compound 1.

[0036] [Figure 21] 1 is a TGA thermogram of hemina padisylate Form A of Compound 1.

[0037] [Figure 22] 1 is a DSC thermogram of hemina padisylate Form A of Compound 1.

[0038] [Diagram 23] 1 is an XRPD pattern of napsylate salt Form A of Compound 1.

[0039] [Figure 24] 1 is a TGA thermogram of Compound 1 napsylate salt Form A (as a mixture with a small amount of napsylate salt Form B).

[0040] [Diagram 25] 1 is a DSC thermogram of napsylate salt Form A of Compound 1.

[0041] [Figure 26] 1 is a 1H NMR spectrum of napsylate salt form A of compound 1.

[0042] [Figure 27] 1 is an XRPD pattern of napsylate Form A, Form B, and Form C of Compound 1.

[0043] [Figure 28] 1 is a TGA thermogram of napsylate salt forms B+C of Compound 1.

[0044] [Figure 29] 1 is a DSC thermogram of napsylate salt forms B+C of Compound 1.

[0045] [Diagram 30] 1 is an XRPD pattern of the hemifumarate salt Form C of Compound 1.

[0046] [Diagram 31] 1 is a 1H NMR spectrum of the hemifumarate salt form C of compound 1.

[0047] [Diagram 32] 1 is an XRPD pattern of hemifumarate salt Form D of Compound 1.

[0048] [Diagram 33] 1 is an XRPD pattern of hemifumarate salt Form E of Compound 1.

[0049] [Diagram 34] 1 is a TGA and DSC thermogram of hemifumarate salt Form F of Compound 1.

[0050] [Diagram 35] 1 is an XRPD pattern of the hemifumarate salt form F of Compound 1.

[0051] [Diagram 36] 1 is an SEM image of hemifumarate salt Form E of Compound 1.

[0052] [Figure 37] 1A-C are TGA and DSC thermograms of hemifumarate salt Form E of Compound 1 (top and bottom traces taken from left, respectively).

[0053] [Figure 38] Figure 12 is a 13C cross-polarization total sideband suppression (CPTOSS) solid-state NMR spectrum (-11 to 211 ppm region) of the hemifumarate salt form E of compound 1 acquired at 5 kHz MAS speed.

[0054] [Figure 39]12 hour 19F solid state NMR spectrum of hemifumarate salt form E of compound 1 acquired using a 1H / 19F cross polarization (CP) experiment and 15 kHz MAS speed.

[0055] [Diagram 40] FIG. 1 is a 9F HPDEC solid-state NMR spectrum (full) of the hemifumarate salt form E of compound 1 acquired at 15 kHz MAS speed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] Definitions, Abbreviations and Acronyms [Table 18]

[0057] [Table 19]

[0058] [Table 20]

[0059] [Table 21]

[0060] As used herein, the following definitions shall apply unless otherwise stated.

[0061] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry" 2000, pp. 111-115, 1997. ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and March's Advanced Organic Chemistry, 7th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are incorporated herein by reference.

[0062] As used herein, the term "low / limited / significant hygroscopicity" refers to forms that exhibit <0.5 / <2.0 / ≧2.0 wt. % water uptake over the specified RH range.

[0063] As used herein, the term "stoichiometric hydrate" refers to a crystalline form having a defined water content over an extended RH range. Common stoichiometric hydrates are hemihydrates, monohydrates, sesquihydrates, dihydrates, etc.

[0064] As used herein, the term "variable hydrate" refers to a crystalline form that has variable water content over an extended RH range but does not undergo a phase change.

[0065] As used herein, the chemical term designated as "Form" refers to a crystalline compound or a salt thereof that exhibits a unique SRPD pattern.

[0066] As used herein, the terms "low / limited / medium / good / high solubility" refer to materials that have a solubility of <1 / 1-20 / 20-100 / 100-200 / >200 mg / mL.

[0067] As used herein, the term "disordered crystalline" refers to a material that produces an XRPD pattern with broad peaks (relative to the instrumental peak width) and / or strong diffuse scattering. Disordered materials can be: 1) Microcrystals, 2) Crystals with a high defect density, 3) a mixture of crystalline and X-ray amorphous phases, or 4) A combination of the above.

[0068] As used herein, the term "insufficient signal" means that spectral analysis of a sample produced a spectrum or pattern (output) that had insufficient signal above the expected background noise.

[0069] As used herein, the term "slurry" refers to a suspension prepared by adding sufficient solids to a given solvent at ambient conditions such that undissolved solids are present. Typically, the solids are recovered after a given time using the methods described herein.

[0070] As used herein, the term "amorphous" refers to a material that has diffuse scattering in its XRPD pattern but no evidence of Bragg peaks.

[0071] As used herein, the term "crystal" refers to a solid compound having a periodic and repeating three-dimensional internal arrangement of atoms, ions, or molecules characteristic of a crystal, e.g., arranged in a fixed geometric pattern or lattice having strict long-range order. The term crystalline does not necessarily mean that the compound exists as a crystal, but rather that it has such a crystal-like internal structural arrangement.

[0072] As used herein, the term "substantially crystalline" refers to a solid material that is preferentially arranged in a fixed geometric pattern or lattice and has strict long-range order. For example, a substantially crystalline material has a crystallinity of greater than about 85% (e.g., greater than about 90% crystallinity, greater than about 95% crystallinity, or greater than about 99% crystallinity). It is also noted that the term "substantially crystalline" includes the descriptor "crystalline" as defined in the previous paragraph.

[0073] A "patient" for the purposes of the present invention includes humans and any other animals, particularly mammals, and other organisms. Thus, the method is applicable to both human therapy and veterinary use. In a preferred embodiment, the patient is a mammal, and in a most preferred embodiment, the patient is a human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, and primates.

[0074] "Kinase-dependent disease or condition" refers to a pathological condition that depends on the activity of one or more kinases. Kinases directly or indirectly participate in the signal transduction pathways of various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include pathological angiogenesis that supports tumor growth, solid tumor growth, and is associated with other diseases involving excessive local angiogenesis, such as ocular diseases (e.g., diabetic retinopathy, age-related macular degeneration) and inflammation (e.g., psoriasis, rheumatoid arthritis).

[0075] A "therapeutically effective amount" is an amount of a crystalline form or crystalline salt of the invention that ameliorates a symptom of a disease when administered to a patient. The amount of a crystalline form or crystalline salt of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the patient being treated, etc. The therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0076] As used herein, the phrase "pharmacologically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, within the scope of sound medical judgment and commensurate with a reasonable benefit-risk ratio.

[0077] As used herein, the phrase "pharmaceutically acceptable excipient" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients that are acceptable for veterinary and human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of ’ See Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0078] "Cancer" means: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Head and neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral and pharyngeal carcinoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, non-small cell lung carcinoma), alveolar (bronchiolar) carcinoma, bronchial sarcoma, alveolar soft part sarcoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Colon: colorectal cancer, adenocarcinoma, tumor of the gastrointestinal stroma, Lymphoma, carcinoid, Turcot's syndrome;Gastrointestinal: gastric cancer, adenocarcinoma of the gastroesophageal junction, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma , tubular adenocarcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; genitourinary system: kidney (adenocarcinoma, Wilms' tumor [nephroblastomatosis], lymphoma, leukemia, renal cell carcinoma, metastatic renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castration-resistant prostate cancer, bone metastases, bone metastases associated with castration-resistant prostate cancer), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), clear cell carcinoma, papillary carcinoma; penis Cancer, squamous cell carcinoma of the penis; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chondroma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hürthle cell carcinoma, and anaplastic thyroid carcinoma;Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans); meninges (meningioma, meningeal sarcoma, gliomatosis); brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors); spinal cord neurofibroma, meningioma, glioma, sarcoma); NF1, neurofibromatosis, plexiform neurofibroma; gynecology: uterus (endometrial cancer), cervix (cervical cancer) , preneoplastic cervical dysplasia), ovary (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia ... The term "cancerous cell" refers to cell proliferative disease conditions including, but not limited to, myeloproliferative leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), myelofibrosis, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. Thus, the term "cancerous cell" as provided herein includes cells suffering from any one of the above-identified conditions. In some embodiments, the compounds or combinations disclosed herein may be used to treat diseases including HIV, sickle cell disease, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, and sickle cell anemia.;

[0079] In general, the nomenclature used in this application is based on the naming conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). The chemical structures shown herein were generated using CHEMDRAW®. Any open valency found on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[0080] Embodiment In one aspect, the present invention provides a crystalline solid of Compound 1: [ka] or a salt, solvate, or hydrate thereof. Compound 1 is known as 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide or N'-(4-fluorophenyl)-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide.

[0081] In some embodiments of this aspect, the salt is an inorganic salt, an organic salt, or a pharma- ceutically acceptable salt.

[0082] In one aspect, the present invention provides a crystalline solid of Compound 1. [ka] or a hydrate or solvate thereof.

[0083] In one embodiment of this aspect, the crystalline solid of Compound 1 is a crystalline solid of the free base characterized as Form R, Form S, Form T, Form U, Form V, Form W, Form X, or Form Y.

[0084] In one embodiment, the crystalline solid is characterized as Form R of Compound 1.

[0085] In still further embodiments, Form R of Compound 1 is characterized by one or more of the following peaks (±0.20) in an XRPD pattern on the 2-theta scale, wherein the one or more peaks are: 4.65, 5.33, 6.55, 7.56, 9.31, 10.69, 11.38, 14.63, 15.17, 15.74, 16.09, 16.41, 16. 51, 17.05, 17.39, 17.93, 18.24, 18.78, 19.24, 19.93, 20.15, 20.71, 21.44, 22.22, 22.66, 22.99, 23.39, 24.06, 24.38, 24.70, 25.75, 26.15, 26.48, 27.05, 27.24, 27.54, 27.88, and 28.71.

[0086] In another embodiment, Form R of Compound 1 is characterized by three or more of the following peaks (±0.20) in an XRPD pattern on the 2-theta scale, the peaks being: 4.65, 5.33, 6.55, 7.56, 9.31, 10.69, 11.38, 14.63, 15.17, 15.74, 16.09, 16.41, 16.51, 17. 05, 17.39, 17.93, 18.24, 18.78, 19.24, 19.93, 20.15, 20.71, 21.44, 22.22, 22.66, 22.99, 23.39, 24.06, 24.38, 24.70, 25.75, 26.15, 26.48, 27.05, 27.24, 27.54, 27.88, and 28.71.

[0087] In another embodiment, Form R of Compound 1 is characterized by five or more peaks (±0.20) in an XRPD pattern on the 2-theta scale, the peaks being: 4.65, 5.33, 6.55, 7.56, 9.31, 10.69, 11.38, 14.63, 15.17, 15.74, 16.09, 16.41, 16.51, 17.05, 17.39, 17.93, 18.24, 18.78, 19.24, 19.93, 20.15, 20.71, 21.44, 22.22, 22.66, 22.99, 23.39, 24.06, 24.38, 24.70, 25.75, 26.15, 26.48, 27.05, 27.24, 27.54, 27.88, and 28.71.

[0088] In another embodiment, Form R of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.20), the one or more peaks being selected from 10.69, 16.09, 16.41, 16.51, 17.39, 18.78, 19.24, 19.93, 21.44, 22.66, 22.99, and 26.48.

[0089] In another embodiment, Form R of Compound 1 is characterized by three or more peaks (±0.20) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.69, 16.09, 16.41, 16.51, 17.39, 18.78, 19.24, 19.93, 21.44, 22.66, 22.99, and 26.48.

[0090] In another embodiment, Form R of Compound 1 is characterized by five or more peaks (±0.20) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.69, 16.09, 16.41, 16.51, 17.39, 18.78, 19.24, 19.93, 21.44, 22.66, 22.99, and 26.48.

[0091] In another embodiment, Form R of Compound 1 is characterized by all of the following peaks (±0.20) in an XRPD pattern on the 2-theta scale: 10.69, 16.09, 16.41, 16.51, 17.39, 18.78, 19.24, 19.93, 21.44, 22.66, 22.99, and 26.48.

[0092] In another embodiment, Form R of Compound 1 is characterized by all of the following peaks (±0.20) in an XRPD pattern on the 2-theta scale, the peaks being 4.65, 5.33, 6.55, 7.56, 9.31, 10.69, 11.38, 14.63, 15.17, 15.74, 16.09, 16.41, 16.51, 17. 05, 17.39, 17.93, 18.24, 18.78, 19.24, 19.93, 20.15, 20.71, 21.44, 22.22, 22.66, 22.99, 23.39, 24.06, 24.38, 24.70, 25.75, 26.15, 26.48, 27.05, 27.24, 27.54, 27.88, and 28.71.

[0093] In another embodiment, Form R of Compound 1 is characterized by an endotherm with a first onset temperature of about 110° C. and a second onset temperature of about 226° C. in a DSC thermogram.

[0094] In another embodiment, Form R of Compound 1 is characterized by a weight loss of about 27.5% by weight in a TGA thermogram at temperatures between 46° C. and 177° C.

[0095] In yet a further embodiment, Form R of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0096] In another embodiment, the crystalline solid is characterized as Form S of Compound 1.

[0097] In one embodiment, Form S of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 5.56, 8.37, 11.22, 12.49, 12.83, 13.69, 16.85, 17.60, 17.98, 18.69, 19.62, 20.11, 20.70, 21.03, 21.65, 21.89, 22.90, 23.79, 24.58, 25.12, 25.89, 26.20, 26.94, 27.43, 28.15, 29.73, and 30.22.

[0098] In another embodiment, Form S of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale selected from 5.56, 8.37, 11.22, 12.49, 12.83, 13.69, 16.85, 17.60, 17.98, 18.69, 19.62, 20.11, 20.70, 21.03, 21.65, 21.89, 22.90, 23.79, 24.58, 25.12, 25.89, 26.20, 26.94, 27.43, 28.15, 29.73, and 30.22.

[0099] In another embodiment, Form S of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 5.56, 8.37, 11.22, 12.49, 12.83, 13.69, 16.85, 17.60, 17.98, 18.69, 19.62, 20.11, 20.70, 21.03, 21.65, 21.89, 22.90, 23.79, 24.58, 25.12, 25.89, 26.20, 26.94, 27.43, 28.15, 29.73, and 30.22.

[0100] In another embodiment, Form S of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 8.37, 12.49, 12.83, 13.69, 16.85, 18.69, 19.62, 20.11, 20.70, 21.65, 23.79, 24.58, 25.12, and 25.89.

[0101] In another embodiment, Form S of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 8.37, 12.49, 12.83, 13.69, 16.85, 18.69, 19.62, 20.11, 20.70, 21.65, 23.79, 24.58, 25.12, and 25.89.

[0102] In another embodiment, Form S of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 8.37, 12.49, 12.83, 13.69, 16.85, 18.69, 19.62, 20.11, 20.70, 21.65, 23.79, 24.58, 25.12, and 25.89.

[0103] In another embodiment, Form S of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 8.37, 12.49, 12.83, 13.69, 16.85, 18.69, 19.62, 20.11, 20.70, 21.65, 23.79, 24.58, 25.12, and 25.89.

[0104] In another embodiment, Form S of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 5.56, 8.37, 11.22, 12.49, 12.83, 13.69, 16.85, 17.60, 17.98, 18.69, 19.62, 20.11, 20.70, 21.03, 21.65, 21.89, 22.90, 23.79, 24.58, 25.12, 25.89, 26.20, 26.94, 27.43, 28.15, 29.73, and 30.22.

[0105] In yet a further embodiment, Form S of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0106] In another embodiment, the crystalline solid is characterized as Form T of Compound 1.

[0107] Form T of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 7.15, 8.92, 9.59, 10.56, 11.20, 12.29, 13.44, 13.87, 14.31, 15.72, 16.85, 17.48, 17.95, 18.27, 18.48, 19.36, 21.16, 21.58, 22.02, 22.52, 23.34, 24.74, 25.97, 26.41, 27.01, 27.47, 28.66, 29.07, 29.43, and 30.25.

[0108] In another embodiment, Form T of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale selected from 7.15, 8.92, 9.59, 10.56, 11.20, 12.29, 13.44, 13.87, 14.31, 15.72, 16.85, 17.48, 17.95, 18.27, 18.48, 19.36, 21.16, 21.58, 22.02, 22.52, 23.34, 24.74, 25.97, 26.41, 27.01, 27.47, 28.66, 29.07, 29.43, and 30.25.

[0109] In another embodiment, Form T of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 7.15, 8.92, 9.59, 10.56, 11.20, 12.29, 13.44, 13.87, 14.31, 15.72, 16.85, 17.48, 17.95, 18.27, 18.48, 19.36, 21.16, 21.58, 22.02, 22.52, 23.34, 24.74, 25.97, 26.41, 27.01, 27.47, 28.66, 29.07, 29.43, and 30.25.

[0110] In another embodiment, Form T of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 10.56, 12.29, 14.31, 18.27, 19.36, 21.16, 21.58, 22.52, 24.74, 27.47, and 28.66.

[0111] In another embodiment, Form T of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.56, 12.29, 14.31, 18.27, 19.36, 21.16, 21.58, 22.52, 24.74, 27.47, and 28.66.

[0112] In another embodiment, Form T of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.56, 12.29, 14.31, 18.27, 19.36, 21.16, 21.58, 22.52, 24.74, 27.47, and 28.66.

[0113] In another embodiment, Form T of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 10.56, 12.29, 14.31, 18.27, 19.36, 21.16, 21.58, 22.52, 24.74, 27.47, and 28.66.

[0114] In another embodiment, Form T of Compound 1 is characterized by all of the following peaks in an XRPD pattern on the 2-theta scale (±0.2): 7.15, 8.92, 9.59, 10.56, 11.20, 12.29, 13.44, 13.87, 14.31, 15.72, 16.85, 17.48, 17.95, 18.27, 18.48, 19.36, 21.16, 21.58, 22.02, 22.52, 23.34, 24.74, 25.97, 26.41, 27.01, 27.47, 28.66, 29.07, 29.43, and 30.25.

[0115] In yet a further embodiment, Form T of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0116] In another embodiment, the crystalline solid is characterized as Form U of Compound 1.

[0117] In one embodiment, Form U of Compound 1 is characterized by one or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the one or more peaks being 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18.9 6, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24.

[0118] In one embodiment, Form U of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18.96, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24.

[0119] In one embodiment, Form U of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18.96, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24.

[0120] In another embodiment, Form U of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0121] In another embodiment, Form U of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0122] In another embodiment, Form U of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0123] In another embodiment, Form U of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0124] In another embodiment, Form U of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18. 96, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24.

[0125] In another embodiment, Form U of Compound 1 is characterized by an endotherm with an onset temperature of about 199° C. in a DSC thermogram.

[0126] In another embodiment, Form U of Compound 1 is characterized by a first endotherm at a temperature of about 145° C., a second endotherm at about 203° C., and a third endotherm at about 221° C. in a DSC thermogram.

[0127] In yet a further embodiment, Form U of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0128] In another embodiment, the present disclosure provides compound 1 [ka] or a crystalline solid form of a hydrate or solvate thereof characterized by at least one of the following: (1) One or more peaks (±0.2) in an XRPD pattern on the 2 theta scale that are 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18.96, 19.43, 19.57, 20.08, 21.06, 22.08, 23.09, 24.09, 25.09, 26.09, 27.09, 28.09, 29.09, 30.09, 31.09, 32.09, 33.09, 34.09, 35.09, 36.09, 37.09, 38.09, 39.09, 40.09, 41.09, 42.09, 43.09, 44.09, 45.09, 46.09, 47.09, 48.09, 49.09, 50.09, 51.09, 52.09, 53.09, 54.09, 55.09, 56.09, 57.09, 58.09, 59.09, 60.09, 61.09, 62.09, 63.09, 64.09, 65.09, 66.09, 67.09, 68.09, 69.09, 70 one or more peaks selected from 0.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24; (2) an endotherm with an onset temperature of approximately 199°C in the DSC thermogram; (3) a first endotherm at a temperature of about 145° C., a second endotherm at about 203° C., and a third endotherm at about 221° C. in a DSC thermogram; (4) an XRPD pattern substantially identical to FIG. 6; and (5) Substantially the same as FIG. 1 H NMR spectrum.

[0129] In one embodiment, the crystalline solid of Compound 1 is characterized as Form U of Compound 1.

[0130] In another embodiment, Form U of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0131] In another embodiment, Form U of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89.

[0132] In another embodiment, Form U of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18. 96, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24.

[0133] In another embodiment, Form U of Compound 1 is characterized by at least two of (1), (2), (3), (4), and (5).

[0134] In another embodiment, Form U of Compound 1 is characterized by at least three of (1), (2), (3), (4), and (5).

[0135] In another embodiment, form U of compound 1 is characterized by at least all of (1), (2), (3), (4), and (5).

[0136] In another embodiment, the crystalline solid is characterized as Form V of Compound 1.

[0137] In another embodiment, Form V of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being 6.05, 9.21, 9.66, 10.45, 11.45, 11.58, 12.14, 12.29, 12.86, 13.62, 14.32, 16.08, 16.86, 17.40, 17.66, 18.26, 18.45, 18.79, 19.31, 19.41, 20.28, 20.98, 21.36, 21.54, 21.85, 22.23, 22.45, 22.78, 23.00, 23.34, 23.96, 24.90, 25.69, 25.90, 26.38, 27.18, 28.02, 28.25, 28.54, 29.24, and 29.89.

[0138] In another embodiment, Form V of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 6.05, 9.21, 9.66, 10.45, 11.45, 11.58, 12.14, 12.29, 12.86, 13.62, 14.32, 16.08, 16.86, 17.40, 17.66, 18.08, 19.08, 20.08, 21.08, 22.08, 23.08, 24.08, 25.08, 26.08, 27.08, 28.08, 29.08, 30.08, 31.08, 32.08, 33.08, 34.08, 35.08, 36.08, 37.08, 38.08, 39.08, 40.08, 41.08, 42.08, 43.08, 44.08, 45.08, 46.08, 47.08, 48.08, 49.08, 50.08, 51.08, 52.08, 53.08, 54.08, 55.08, 56.08, 57.08, 58.08, 59.08, 60.08, 61.08, 62.08, 63.08, 64.08, 65.08, 66.08, 67.08, 68.08, 69.08, .26, 18.45, 18.79, 19.31, 19.41, 20.28, 20.98, 21.36, 21.54, 21.85, 22.23, 22.45, 22.78, 23.00, 23.34, 23.96, 24.90, 25.69, 25.90, 26.38, 27.18, 28.02, 28.25, 28.54, 29.24, and 29.89.

[0139] In another embodiment, Form V of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 6.05, 9.21, 9.66, 10.45, 11.45, 11.58, 12.14, 12.29, 12.86, 13.62, 14.32, 16.08, 16.86, 17.40, 17.66, 18.02, 19.06, 20.04, 21.08, 22.06, 23.08, 24.06, 25.08, 26.06, 27.06, 28.06, 29.06, 30.06, 31.06, 32.06, 33.06, 34.06, 35.06, 36.06, 37.06, 38.06, 39.06, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06, 63.06, 64.06, 65.06, 66.06, 67.06, 68.06, 69.06, .26, 18.45, 18.79, 19.31, 19.41, 20.28, 20.98, 21.36, 21.54, 21.85, 22.23, 22.45, 22.78, 23.00, 23.34, 23.96, 24.90, 25.69, 25.90, 26.38, 27.18, 28.02, 28.25, 28.54, 29.24, and 29.89.

[0140] In another embodiment, Form V of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 9.21, 10.45, 14.32, 16.86, 19.31, 19.41, 20.28, 21.36, 21.54, 23.34, 23.96, 24.90, and 28.25.

[0141] In another embodiment, Form V of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 9.21, 10.45, 14.32, 16.86, 19.31, 19.41, 20.28, 21.36, 21.54, 23.34, 23.96, 24.90, and 28.25.

[0142] In another embodiment, Form V of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 9.21, 10.45, 14.32, 16.86, 19.31, 19.41, 20.28, 21.36, 21.54, 23.34, 23.96, 24.90, and 28.25.

[0143] In another embodiment, Form V of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 9.21, 10.45, 14.32, 16.86, 19.31, 19.41, 20.28, 21.36, 21.54, 23.34, 23.96, 24.90, and 28.25.

[0144] In another embodiment, Form V of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 6.05, 9.21, 9.66, 10.45, 11.45, 11.58, 12.14, 12.29, 12.86, 13.62, 14.32, 16.08, 16.86, 17.40, 17.66 , 18.26, 18.45, 18.79, 19.31, 19.41, 20.28, 20.98, 21.36, 21.54, 21.85, 22.23, 22.45, 22.78, 23.00, 23.34, 23.96, 24.90, 25.69, 25.90, 26.38, 27.18, 28.02, 28.25, 28.54, 29.24, and 29.89.

[0145] In yet a further embodiment, Form V of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0146] In another embodiment, the crystalline solid is characterized as Form W of Compound 1.

[0147] In another embodiment, Form W of Compound 1 is characterized by one or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the one or more peaks being 8.82, 9.58, 10.50, 10.85, 11.21, 11.44, 11.57, 13.16, 13.22, 14.22, 14.40, 14.91, 15.81, 16.74, 17.10, 17.55, 17.95, 18.13, 18.35, 18.73, 19.26, 19.28, 19.29, 19.33, 19.41, 19.46, 19.48, 19.49, 19.50, 19.60, 19.70, 19.72, 19.76, 19.78, 19.77, 19.77, 19.76, 19.78, 19.79, 19.82, 19.83, 19.86, 19.87, 19.89, 19.96, 19.97, 19.99, 19.98, 19.99, 19.96, 19.9 ... .16, 19.37, 19.56, 19.91, 20.65, 21.02, 21.30, 21.54, 21.84, 22.34, 22.62, 22.98, 23.27, 23.53, 24.10, 24.66, 25.08, 25.36, 25.62, 25.90, 26.41, 26.85, 27.07, 27.24, 27.70, 28.27, 28.73, 28.94, 29.25, 29.54, 30.11, and 30.53.

[0148] In another embodiment, Form W of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 8.82, 9.58, 10.50, 10.85, 11.21, 11.44, 11.57, 13.16, 13.22, 14.22, 14.40, 14.91, 15.81, 16.74, 17.10, 17.55, 17.95, 18.13, 18.35, 18.73, 19.16 , 19.37, 19.56, 19.91, 20.65, 21.02, 21.30, 21.54, 21.84, 22.34, 22.62, 22.98, 23.27, 23.53, 24.10, 24.66, 25.08, 25.36, 25.62, 25.90, 26.41, 26.85, 27.07, 27.24, 27.70, 28.27, 28.73, 28.94, 29.25, 29.54, 30.11, and 30.53.

[0149] In another embodiment, Form W of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 8.82, 9.58, 10.50, 10.85, 11.21, 11.44, 11.57, 13.16, 13.22, 14.22, 14.40, 14.91, 15.81, 16.74, 17.10, 17.55, 17.95, 18.13, 18.35, 18.73, 19.16 , 19.37, 19.56, 19.91, 20.65, 21.02, 21.30, 21.54, 21.84, 22.34, 22.62, 22.98, 23.27, 23.53, 24.10, 24.66, 25.08, 25.36, 25.62, 25.90, 26.41, 26.85, 27.07, 27.24, 27.70, 28.27, 28.73, 28.94, 29.25, 29.54, 30.11, and 30.53.

[0150] In another embodiment, Form W of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 8.82, 11.21, 11.44, 11.57, 13.16, 13.22, 14.40, 16.74, 17.95, 18.13, 19.16, 19.37, 19.56, 19.91, 21.84, 22.98, and 24.10.

[0151] In another embodiment, Form W of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 8.82, 11.21, 11.44, 11.57, 13.16, 13.22, 14.40, 16.74, 17.95, 18.13, 19.16, 19.37, 19.56, 19.91, 21.84, 22.98, and 24.10.

[0152] In another embodiment, Form W of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 8.82, 11.21, 11.44, 11.57, 13.16, 13.22, 14.40, 16.74, 17.95, 18.13, 19.16, 19.37, 19.56, 19.91, 21.84, 22.98, and 24.10.

[0153] In another embodiment, Form W of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 8.82, 11.21, 11.44, 11.57, 13.16, 13.22, 14.40, 16.74, 17.95, 18.13, 19.16, 19.37, 19.56, 19.91, 21.84, 22.98, and 24.10.

[0154] In another embodiment, Form W of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 8.82, 9.58, 10.50, 10.85, 11.21, 11.44, 11.57, 13.16, 13.22, 14.22, 14.40, 14.91, 15.81, 16.74, 17.10, 17.55, 17.95, 18.13, 18.35, 18.73, 19.06, 19.29, 19.46, 19.63, 19.89, 19.96, 19.87, 19.77, 19.76, 19.78, 19.79, 19.86, 19.95, 19.94, 19.99, 19.04, 19.06, 19.08, 19.09, 19.10, 19.26, 19.28, 19.30, 19.36, 19.37, 19.39, 19.46, 19.45, 19.50, 19.66, 19.74, 19.78, 19.89, 19.96, 19.99, 19.06, 19.08, 19.09, 19.13, 19.26, 19.28, 19.30, 19.44, 19.46, 19.50, 19.66, 19.74, .16, 19.37, 19.56, 19.91, 20.65, 21.02, 21.30, 21.54, 21.84, 22.34, 22.62, 22.98, 23.27, 23.53, 24.10, 24.66, 25.08, 25.36, 25.62, 25.90, 26.41, 26.85, 27.07, 27.24, 27.70, 28.27, 28.73, 28.94, 29.25, 29.54, 30.11, and 30.53.

[0155] In yet a further embodiment, Form W of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0156] In another embodiment, the crystalline solid is characterized as Form X of Compound 1.

[0157] In one embodiment, Form X of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 5.34, 5.88, 9.45, 10.71, 11.84, 13.36, 15.06, 16.55, 17.99, 18.80, 21.69, 22.60, 23.59, 25.54, and 26.98.

[0158] In one embodiment, Form X of Compound 1 is characterized by three or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the peaks being selected from 5.34, 5.88, 9.45, 10.71, 11.84, 13.36, 15.06, 16.55, 17.99, 18.80, 21.69, 22.60, 23.59, 25.54, and 26.98.

[0159] In one embodiment, Form X of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 5.34, 5.88, 9.45, 10.71, 11.84, 13.36, 15.06, 16.55, 17.99, 18.80, 21.69, 22.60, 23.59, 25.54, and 26.98.

[0160] In another embodiment, Form X of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 5.34, 5.88, 9.45, and 10.71.

[0161] In another embodiment, Form X of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, where the peaks are 5.34, 5.88, 9.45, and 10.71.

[0162] In one embodiment, Form X of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 5.34, 5.88, 9.45, 10.71, 11.84, 13.36, 15.06, 16.55, 17.99, 18.80, 21.69, 22.60, 23.59, 25.54, and 26.98.

[0163] In yet a further embodiment, Form X of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0164] In another embodiment, the crystalline solid is characterized as Form Y of Compound 1.

[0165] In another embodiment, Form Y of Compound 1 is characterized by one or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the one or more peaks being 9.77, 10.22, 11.09, 11.60, 12.83, 13.20, 13.71, 14.57, 14.99, 16.06, 16.55, 17.43, 18.12, 18.45, 18.98, 19.17, 19.62, 19.85, 20.5 6, 20.78, 20.89, 21.13, 21.41, 21.59, 22.02, 22.28, 22.72, 22.93, 23.47, 24.06, 24.22, 24.54, 24.73, 25.34, 25.68, 26.01, 26.41, 27.04, 27.47, 27.78, 28.12, 28.32, 28.77, 29.41, 30.31, 31.01, 31.24, 31.54 and 32.18.

[0166] In another embodiment, Form Y of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 9.77, 10.22, 11.09, 11.60, 12.83, 13.20, 13.71, 14.57, 14.99, 16.06, 16.55, 17.43, 18.12, 18.45, 18.98, 19.17, 19.62, 19.85, 20.56, 21.04, 22.02, 23.06, 24.09, 25.06, 26.09, 27.06, 28.09, 29.08, 30.06, 31.04, 32.06, 33.08, 34.09, 35.06, 36.09, 37.06, 38.09, 39.12, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06, 63.06, 64.06, 65.06, 66.06, 67.06, 68.06, 0.78, 20.89, 21.13, 21.41, 21.59, 22.02, 22.28, 22.72, 22.93, 23.47, 24.06, 24.22, 24.54, 24.73, 25.34, 25.68, 26.01, 26.41, 27.04, 27.47, 27.78, 28.12, 28.32, 28.77, 29.41, 30.31, 31.01, 31.24, 31.54, and 32.18.

[0167] In another embodiment, Form Y of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 9.77, 10.22, 11.09, 11.60, 12.83, 13.20, 13.71, 14.57, 14.99, 16.06, 16.55, 17.43, 18.12, 18.45, 18.98, 19.17, 19.62, 19.85, 20.56, 21.04, 22.02, 23.06, 24.09, 25.06, 26.09, 27.06, 28.09, 29.08, 30.06, 31.04, 32.06, 33.08, 34.09, 35.06, 36.09, 37.06, 38.09, 39.12, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06, 63.06, 64.06, 65.06, 66.06, 67.06, 68.06 0.78, 20.89, 21.13, 21.41, 21.59, 22.02, 22.28, 22.72, 22.93, 23.47, 24.06, 24.22, 24.54, 24.73, 25.34, 25.68, 26.01, 26.41, 27.04, 27.47, 27.78, 28.12, 28.32, 28.77, 29.41, 30.31, 31.01, 31.24, 31.54, and 32.18.

[0168] In another embodiment, Form Y of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 10.22, 11.09, 11.60, 13.71, 14.57, 18.12, 19.17, 19.85, 21.41, 21.59, 23.47, 24.54, 24.73, 25.34, 28.32, and 28.77.

[0169] In another embodiment, form Y of compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.22, 11.09, 11.60, 13.71, 14.57, 18.12, 19.17, 19.85, 21.41, 21.59, 23.47, 24.54, 24.73, 25.34, 28.32, and 28.77.

[0170] In another embodiment, Form Y of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 10.22, 11.09, 11.60, 13.71, 14.57, 18.12, 19.17, 19.85, 21.41, 21.59, 23.47, 24.54, 24.73, 25.34, 28.32, and 28.77.

[0171] In another embodiment, form Y of compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 10.22, 11.09, 11.60, 13.71, 14.57, 18.12, 19.17, 19.85, 21.41, 21.59, 23.47, 24.54, 24.73, 25.34, 28.32, and 28.77.

[0172] In another embodiment, Form Y of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 9.77, 10.22, 11.09, 11.60, 12.83, 13.20, 13.71, 14.57, 14.99, 16.06, 16.55, 17.43, 18.12, 18.45, 18.98, 19.17, 19.62, 19.85, 20.5 6, 20.78, 20.89, 21.13, 21.41, 21.59, 22.02, 22.28, 22.72, 22.93, 23.47, 24.06, 24.22, 24.54, 24.73, 25.34, 25.68, 26.01, 26.41, 27.04, 27.47, 27.78, 28.12, 28.32, 28.77, 29.41, 30.31, 31.01, 31.24, 31.54, and 32.18.

[0173] In yet a further embodiment, form Y of compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0174] In another aspect, the present invention relates to a crystalline salt of Compound 1 having the structure: [ka] wherein the crystalline salt of Compound 1 is selected from hemi-edisylate Form A of Compound 1, heminapadisylate Form A of Compound 1, napsylate Form A of Compound 1, napsylate Form B of Compound 1, napsylate Form C of Compound 1, and mixtures thereof.

[0175] In one embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 4.99, 5.99, 10.05, 10.37, 12.11, 13.49, 15.30, 16.20, 17.62, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, 25.23, 27.28, 27.96, and 28.70.

[0176] In one embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.99, 5.99, 10.05, 10.37, 12.11, 13.49, 15.30, 16.20, 17.62, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, 25.23, 27.28, 27.96, and 28.70.

[0177] In one embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.99, 5.99, 10.05, 10.37, 12.11, 13.49, 15.30, 16.20, 17.62, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, 25.23, 27.28, 27.96, and 28.70.

[0178] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 4.99, 5.99, 12.11, 13.49, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, and 27.28.

[0179] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.99, 5.99, 12.11, 13.49, 18.64, 20.09, 21.00, 22.30, 24.53, and 27.28.

[0180] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.99, 5.99, 12.11, 13.49, 18.64, 20.09, 21.00, 22.30, 24.53, and 27.28.

[0181] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 4.99, 5.99, 12.11, 13.49, 18.64, 20.09, 21.00, 22.30, 24.53, and 27.28.

[0182] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 4.99, 5.99, 10.05, 10.37, 12.11, 13.49, 15.30, 16.20, 17.62, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, 25.23, 27.28, 27.96, and 28.70.

[0183] In still a further embodiment, Form A of the hemi-edisylate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0184] In another embodiment, Form A of the hemi-edisylate salt of Compound 1 is characterized by an endotherm with an onset temperature of about 259° C. in a DSC thermogram.

[0185] In another embodiment, the hemi-edisylate salt Form A of Compound 1 is characterized by a weight loss of about 0.6% by weight up to a temperature of 135° C. in a TGA thermogram.

[0186] In another embodiment, the crystalline salt is characterized as hemina padisylate Form A of Compound 1.

[0187] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 4.74, 8.03, 10.50, 12.27, 12.72, 14.37, 15.38, 15.92, 16.33, 16.96, 18.16, 18.72, 19.13, 20.01, 21.11, 22.96, 23.83, 24.89, 25.68, 26.69, 27.53, and 28.24.

[0188] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.03, 10.50, 12.27, 12.72, 14.37, 15.38, 15.92, 16.33, 16.96, 18.16, 18.72, 19.13, 20.01, 21.11, 22.96, 23.83, 24.89, 25.68, 26.69, 27.53, and 28.24.

[0189] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.03, 10.50, 12.27, 12.72, 14.37, 15.38, 15.92, 16.33, 16.96, 18.16, 18.72, 19.13, 20.01, 21.11, 22.96, 23.83, 24.89, 25.68, 26.69, 27.53, and 28.24.

[0190] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 4.74, 8.03, 10.50, 12.27, 16.33, 16.96, 18.72, 19.13, 21.11, 22.96, 23.83, 24.89, and 25.68.

[0191] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.03, 10.50, 12.27, 16.33, 16.96, 18.72, 19.13, 21.11, 22.96, 23.83, 24.89, and 25.68.

[0192] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.03, 10.50, 12.27, 16.33, 16.96, 18.72, 19.13, 21.11, 22.96, 23.83, 24.89, and 25.68.

[0193] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 4.74, 8.03, 10.50, 12.27, 16.33, 16.96, 18.72, 19.13, 21.11, 22.96, 23.83, 24.89, and 25.68.

[0194] In another embodiment, the hemina padisylate Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 4.74, 8.03, 10.50, 12.27, 12.72, 14.37, 15.38, 15.92, 16.33, 16.96, 18.16, 18.72, 19.13, 20.01, 21.11, 22.96, 23.83, 24.89, 25.68, 26.69, 27.53, and 28.24.

[0195] In still a further embodiment, Form A of the hemina padisylate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0196] In another embodiment, Form A of the hemina padisylate salt of Compound 1 is characterized by an endotherm with an onset temperature of about 240° C. in a DSC thermogram.

[0197] In another embodiment, hemina padisylate Form A of Compound 1 is characterized by a weight loss of about 1.5% by weight up to a temperature of 144° C. in a TGA thermogram.

[0198] In another embodiment, the crystalline salt form is characterized as napsylate Form A of Compound 1.

[0199] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by one or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the one or more peaks being 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17.2 9, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05.

[0200] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17.29, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05.

[0201] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17.29, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05.

[0202] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being selected from 4.74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99, and 28.95.

[0203] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99, and 28.95.

[0204] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 4.74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99, and 28.95.

[0205] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 4.74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99, and 28.95.

[0206] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17. 29, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05.

[0207] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by an endotherm at about 123° C. and another endotherm at about 214° C. in a DSC thermogram.

[0208] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by a weight loss of about 5.2 wt % up to a temperature of 165° C. in a TGA thermogram.

[0209] In still a further embodiment, Form A of the napsylate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0210] In another embodiment, the crystalline salt form is characterized as napsylate Form B of Compound 1.

[0211] In another embodiment, the crystalline salt form is characterized as napsylate Form C of Compound 1.

[0212] In still further embodiments, napsylate Form B and Form C of Compound 1 are characterized by XRPD patterns as in FIG.

[0213] In another embodiment, the present disclosure relates to a crystalline salt of Compound 1, [ka] The napsylate salt form A of Compound 1 is characterized by at least one of the following: (1) one or more peaks (±0.2) in an XRPD pattern on the 2 theta scale, the one or more peaks being 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17.29, 17.68, 18.40, selected from 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05; (2) an endotherm at about 123°C and another endotherm at about 214°C in a DSC thermogram; (3) a weight loss of about 5.2 wt % at temperatures up to 165° C. in the TGA thermogram; (4) an XRPD pattern substantially identical to FIG. 23; and (5) Substantially the same as FIG. 1 H NMR spectrum.

[0214] In another embodiment, the napsylate salt Form A is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99.

[0215] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99.

[0216] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17. 29, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05.

[0217] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by at least two of (1), (2), (3), (4), and (5).

[0218] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by at least three of (1), (2), (3), (4), and (5).

[0219] In another embodiment, the napsylate salt Form A of Compound 1 is characterized by at least all of (1), (2), (3), (4), and (5).

[0220] In another aspect, the present invention provides a crystalline fumarate salt of Compound 1. [ka] wherein the crystalline fumarate salt of Compound 1 is selected from hemifumarate Form C of Compound 1, hemifumarate Form D of Compound 1, hemifumarate Form E of Compound 1, hemifumarate Form F of Compound 1, and mixtures thereof.

[0221] In one embodiment, the crystalline fumarate salt is characterized as hemifumarate Form C of Compound 1.

[0222] In still a further embodiment, Form C of the hemifumarate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0223] In one embodiment, the crystalline fumarate salt is characterized as hemifumarate Form D of Compound 1.

[0224] In still a further embodiment, Form D of the hemifumarate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0225] In one embodiment, the crystalline fumarate salt is characterized as hemifumarate Form E of Compound 1.

[0226] In another embodiment, the hemifumarate form E of Compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), the one or more peaks being 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.30, 16.40, 16.50, 16.52, 16.60, 16.70, 16.80, 16.90, 17.00, 17.02, 17.06, 17.08, 17.13, 17.27, 17.36, 17.40, 17.57, 17.06, 17.08, 17.09, 17.16, 17.27, 17.30, 17.40, 17.52, 17.06, 17.08, 17.09, 17.17, 17.26, 17.30, 17.40, 17.52, 17.09, 17.52, 17.09, 17.13, 17.27 ... 47, 17.89, 18.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84.

[0227] In another embodiment, the hemifumarate form E of Compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.47 , 17.89, 18.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84.

[0228] In another embodiment, the hemifumarate Form E of Compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being: 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.47 , 17.89, 18.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84.

[0229] In another embodiment, the hemifumarate form E of compound 1 is characterized by one or more peaks in an XRPD pattern on the 2-theta scale (±0.2), wherein the one or more peaks are selected from 7.07, 9.64, 11.44, 15.41, 16.20, 16.47, 19.54, 20.51, 22.18, 22.72, 23.81, 26.14, and 27.18.

[0230] In another embodiment, the hemifumarate form E of compound 1 is characterized by three or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 7.07, 9.64, 11.44, 15.41, 16.20, 16.47, 19.54, 20.51, 22.18, 22.72, 23.81, 26.14, and 27.18.

[0231] In another embodiment, the hemifumarate form E of compound 1 is characterized by five or more peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being selected from 7.07, 9.64, 11.44, 15.41, 16.20, 16.47, 19.54, 20.51, 22.18, 22.72, 23.81, 26.14, and 27.18.

[0232] In another embodiment, the hemifumarate form E of compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale: 7.07, 9.64, 11.44, 15.41, 16.20, 16.47, 19.54, 20.51, 22.18, 22.72, 23.81, 26.14, and 27.18.

[0233] In another embodiment, the hemifumarate form E of Compound 1 is characterized by all of the following peaks (±0.2) in an XRPD pattern on the 2-theta scale, the peaks being 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.41, 16.42, 16.43, 16.46, 16.47, 16.49, 17.66, 17.74, 17.76, 17.78, 17.79, 18.27, 18.29, 18.33, 18.46, 18.29, 18.47, 18.51, 18.27, 18.31, 18.32, 18.31, 18.33, 18.32, 18.3 ... .47, 17.89, 18.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84.

[0234] In still a further embodiment, Form E of the hemifumarate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0235] In another embodiment, the hemifumarate form E of Compound 1 has a solid state solubility with peaks at 171.3, 170.6, 167.1, 167.0, 165.5, 164.2, 164.0, 160.9, 160.0, 157.8, 149.9, 147.0, 138.2, 136.1, 129.5, 128.1, 125.3, 123.5, 121.2, 120.3, 120.0, 114.9, 114.0, 102.3, 64.2, 62.7, 61.4, 56.0, 55.5, 26.6, and 21.6±0.2 ppm relative to the 170.6 ppm chemical shift. 13 Characterized by C NMR spectroscopy.

[0236] In another embodiment, the hemifumarate form E of Compound 1 is a solid form substantially identical to that shown in FIG. 13 Characterized by C NMR spectroscopy.

[0237] In another embodiment, the hemifumarate form E of compound 1 has the following relative chemical shifts from a cross polarization experiment: 85.7, 84.8, 79.1, 44.9, 41.8, 5.0, 2.0, 1.3, -35.0, -38.0, -38.7, -43.0, -70.7, -72.6, -74.8, -77.6, - Solids with peaks at 77.9, -78.5, -82.9, -114.8, -115.9, -117.8, -118.5, -122.9, -154.6, -155.8, -157.7, -158.4, -162.8, -194.5, -195.8, -197.6, -198.3, and -202.7 ± 0.2 ppm 19 Characterized by F NMR spectrum.

[0238] In another embodiment, the hemifumarate form E of Compound 1 is a solid form substantially identical to that shown in FIG. 19 Characterized by F NMR spectrum.

[0239] In another embodiment, the hemifumarate salt form E of compound 1 is a solid having peaks at 45.1, 5.0, 2.1, -34.9, -38.1, -38.7, -74.3, -74.8, -77.7, -114.7, -115.9, -117.9, -118.8, -122.8, -154.6, -155.9, -157.8, -158.4, -162.8, -194.5, -197.7, and -198.5 ± 0.2 ppm relative to the -118.8 ppm chemical shift from the HPDEC experiment. 19 Characterized by F NMR spectrum.

[0240] In another embodiment, the hemifumarate form E of Compound 1 is a solid form substantially identical to that shown in FIG. 19 Characterized by F NMR spectrum.

[0241] In some embodiments, Form E of Compound 1 is characterized in a DSC thermogram by an endotherm with an onset temperature of about 109° C. In some embodiments, Form E of Compound 1 is further characterized in a DSC thermogram by an endotherm with a peak temperature of about 131° C.

[0242] In some embodiments, Form E of Compound 1 is characterized by a weight loss of 8-17% by weight (e.g., about 10-15% by weight, or about 9.9% by weight) at temperatures between 30° C. and 155° C. in a TGA thermogram.

[0243] In another embodiment, the hemifumarate salt form E of Compound 1 is characterized by at least one of the following: (1) One or more, three or more, or five or more peaks (±0.2) in an XRPD pattern on the 2 theta scale, the peaks being 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.47, 17.89, 1 selected from 8.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84; (2) an XRPD pattern substantially identical to Figure 33; (3) A solid having peaks at 171.3, 170.6, 167.1, 167.0, 165.5, 164.2, 164.0, 160.9, 160.0, 157.8, 149.9, 147.0, 138.2, 136.1, 129.5, 128.1, 125.3, 123.5, 121.2, 120.3, 120.0, 114.9, 114.0, 102.3, 64.2, 62.7, 61.4, 56.0, 55.5, 26.6, and 21.6 ± 0.2 ppm relative to the 170.6 ppm chemical shift. 13 C NMR spectrum; (4) A solid body substantially identical to that shown in FIG. 13 C NMR spectrum; (5) A solid having peaks at 85.7, 84.8, 79.1, 44.9, 41.8, 5.0, 2.0, 1.3, -35.0, -38.0, -38.7, -43.0, -70.7, -72.6, -74.8, -77.6, -77.9, -78.5, -82.9, -114.8, -115.9, -117.8, -118.5, -122.9, -154.6, -155.8, -157.7, -158.4, -162.8, -194.5, -195.8, -197.6, -198.3, and -202.7 ± 0.2 ppm relative to the -118.5 ppm chemical shift from a cross polarization experiment. 19 F NMR spectrum; (6) A solid body substantially identical to that shown in FIG. 19F NMR spectrum; (7) A solid with peaks at 45.1, 5.0, 2.1, -34.9, -38.1, -38.7, -74.3, -74.8, -77.7, -114.7, -115.9, -117.9, -118.8, -122.8, -154.6, -155.9, -157.8, -158.4, -162.8, -194.5, -197.7, and -198.5 ± 0.2 ppm relative to the -118.8 ppm chemical shift from the HPDEC experiment. 19 F NMR spectrum; (8) A solid body substantially identical to that shown in FIG. 19 F NMR spectrum; (9) an endotherm with an onset temperature of about 109° C. and / or a peak temperature of about 131° C. in a DSC thermogram; (10) a weight loss of 8 to 17 wt % (e.g., about 10 to 15 wt %, or about 9.9 wt %) between temperatures of 30° C. and 155° C. in a TGA thermogram;

[0244] In another embodiment, the hemifumarate form E of compound 1 is characterized by at least two of (1)-(10).

[0245] In another embodiment, the hemifumarate form E of compound 1 is characterized by at least three of (1)-(10).

[0246] In another embodiment, the hemifumarate form E of compound 1 is characterized by at least five of (1)-(10).

[0247] In another embodiment, the hemifumarate salt form E of compound 1 is characterized by all of (1)-(10).

[0248] In one embodiment, the crystalline fumarate salt is characterized as hemifumarate Form F of Compound 1.

[0249] In yet a further embodiment, the hemifumarate salt Form F of Compound 1 is characterized by TGA and DSC thermograms substantially identical to FIG.

[0250] In still a further embodiment, Form F of the hemifumarate salt of Compound 1 is characterized by an XRPD pattern substantially identical to FIG.

[0251] In another aspect, the invention relates to a pharmaceutical composition comprising a crystalline form or a crystalline salt form described herein and a pharma- ceutically acceptable excipient.

[0252] In yet another aspect, the invention relates to a method of treating a disease, disorder, or syndrome mediated at least in part by modulating the in vivo activity of a protein kinase, comprising administering to a subject in need thereof a crystalline form or crystalline salt form, or pharmaceutical composition described herein.

[0253] In one embodiment of this aspect, said disease, disorder, or syndrome mediated at least in part by modulating the in vivo activity of a protein kinase is cancer.

[0254] In one aspect, the invention relates to a method for inhibiting a protein kinase comprising contacting the protein kinase with a crystalline form or crystalline salt form described herein.

[0255] In one embodiment of this aspect, the protein kinase is Axl, Mer, c-Met, KDR, or a combination thereof.

[0256] Crystalline Forms of the Invention

[0257] Form R of compound 1

[0258] Form R of compound 1 is a dioxane solvate likely observed from experiments with p-dioxane, likely 2 moles of dioxane per mole of compound 1. Form R desolvates and converts to form K or a mixture of forms K and X when exposed to elevated temperatures near and above 105°C.

[0259] Characterization of Form R of Compound 1 is provided herein by XRPD, DSC, and TGA.

[0260] The XRPD pattern of Form R of Compound 1 is provided in FIG. 1, and a list of the peaks in this pattern is provided in Table 1 below.

[0261] [Table 1-1] [Table 1-2]

[0262] Thermograms of form R of compound 1 are shown in Figures 2 and 3. The TGA weight loss of 27.5% (maximum at 177 °C) is consistent with an apparent volatilization endotherm between 50 and 150 °C by DSC. Assuming the weight loss is due to volatilization of dioxane, the loss is consistent with 2 mol / mol. DSC analysis showed a weak endotherm with a peak maximum near 80 °C, followed by a strong endotherm starting at 110 °C, followed by an exotherm trend up to 145 °C. A final endotherm with an onset at 226 °C is observed. At this condition, desolvation to form K or a mixture of forms K and X is likely. The final endotherm near 226 °C is likely melting and / or decomposition of the desolvated material(s).

[0263] [Table 22]

[0264] [Table 23]

[0265] Form S of Compound 1

[0266] Form S of compound 1 is likely an NMP solvate that was only obtained as a mixture with form A. This solvate is likely metastable and readily converts to form A, providing the observed mixture.

[0267] The XRPD pattern of Form S of Compound 1 is provided in FIG. 4, and a list of the peaks in this pattern is provided in Table 2 below.

[0268] [Table 2]

[0269] Form T of Compound 1

[0270] Form T is anhydrous and is obtained by desolvation under vacuum of either Form O at 170° C. or Form U at above 60° C. Based on the thermal properties of Forms O and U, melting (and possibly accompanying decomposition) of Form T is suspected near 203° C. Weak exotherms and endotherms are observed at 106° C. and 162° C., respectively, before the final accompanying melting / decomposition endotherm with an onset at 199° C.

[0271] The XRPD pattern of Form T of Compound 1 is shown in FIG. 5, and a list of the peaks in this pattern is provided in Table 3 below.

[0272] [Table 3]

[0273] Form U of compound 1

[0274] Form U of compound 1 is a methylene chloride solvate that is isostructural to solvate forms O, Q, and potentially Form V. Form U desolvates to form T at or above 60° C. under vacuum or to a mixture of forms T and A upon exposure to more extreme temperatures such as 170° C. An attempt at desolvation of form U is shown below: [Table 24]

[0275] The XRPD pattern of form U was successfully indexed as a single unit cell, providing strong evidence that the pattern represents a single crystalline phase (Figure 6). This form has a triclinic unit cell that likely contains two compound molecules. Thus, the calculated lattice width of 736 Å from the indexing results. 3 The formula unit volume of would be consistent with a solvate that could theoretically accommodate up to 1 mol / mol of methylene chloride. The unit cell parameters and space groups are similar to those obtained for forms Q and O, suggesting that forms O, Q, and U are isostructural.

[0276] [Table 25]

[0277] The XRPD pattern of Form U of Compound 1 is shown in FIG. 6, and a list of the peaks in this pattern is provided in Table 4 below.

[0278] [Table 4-1] [Table 4-2]

[0279] The XRPD pattern was successfully indexed. The unit cell data for Form U of compound 1 is shown below: [Table 26]

[0280] The DSC thermogram of Form U is shown in Figure 7. A broad endotherm is seen at 145°C (peak maximum). A sharp endotherm shows a peak maximum at 203°C followed by a third endotherm at a peak maximum temperature of 221°C. The events between 80-180°C are likely associated with volatilization of methylene chloride and conversion to a mixture of two or more anhydrous forms. Based on the physical stability evaluation discussed above, the endotherms near 203°C and 221°C are likely associated with melting and / or decomposition of Form T and another anhydrous form such as Form K or Form A, respectively.

[0281] The proton NMR spectrum of form U of compound 1 (Figure 8) is consistent with the chemical structure of compound 1, with the peak due to methylene chloride integrated at 0.5 mol / mol.

[0282] Form V of Compound 1

[0283] Form V of compound 1 is likely a DMF solvate obtained only in admixture with form T due to the disproportion of the hemifumarate cocrystal. Due to the visual similarity of the XRPD peaks attributed to form V with forms O, U, and Q, form V is likely isostructural with its solvate family.

[0284] The XRPD pattern of Form V of Compound 1 is shown in FIG. 9, and a list of the peaks in this pattern is provided in Table 5 below.

[0285] [Table 5-1] [Table 5-2]

[0286] The proton NMR spectrum is consistent with the chemical structure of compound 1. Peaks due to DMF and IPA integrate at 0.6 and <0.1 mol / mol, respectively.

[0287] Form W of Compound 1

[0288] Form W of Compound 1 was obtained by co-crystal disequilibrium of the hemifumarate salt. The XRPD pattern of Form W of Compound 1 is shown in Figure 10, and a list of the peaks in the pattern is provided in Table 6 below.

[0289] [Table 6-1] [Table 6-2]

[0290] The proton NMR spectrum of Form W of Compound 1 is consistent with the chemical structure of Compound 1. Peaks due to CPME integrate to negligible amounts. No peaks attributable to HFIPA were evident.

[0291] Form X of Compound 1

[0292] Form X of Compound 1 was only obtained as a mixture with either Form K or Form R. The mixture of Forms X and K was either crystallized from amorphous Compound 1 upon contact with diethyl ether or produced by desolvation of Form R upon exposure to elevated temperatures around 110° C.

[0293] The XRPD pattern of Form X of Compound 1 is shown in FIG. 11, and a list of the peaks in this pattern is provided in Table 7 below.

[0294] [Table 7]

[0295] Form Y of Compound 1

[0296] Form Y of compound 1 is an acetone solvate and a DMSO solvate that is isostructural to form J. Form Y was obtained by heterogenization of a hemifumarate co-crystal.

[0297] The XRPD pattern of Form Y was successfully indexed as a single unit cell, and the pattern shows strong evidence of a single crystalline phase. This form has an initially monoclinic unit cell that likely contains one molecule of four compounds. Thus, the calculated 731 Å from the indexing results. 3 The formula unit volume of would be consistent with a solvate that could theoretically accommodate up to 1 mol / mol of dimethylsulfoxide. The unit cell parameters and space group are similar to those obtained for form J, suggesting that forms Y and J are isostructural. The XRPD pattern of form Y of compound 1 is provided in Figure 12, and a list of peaks from this pattern is provided in Table 8 below.

[0298] [Table 8-1] [Table 8-2]

[0299] The proton NMR spectrum of Form Y is consistent with the chemical structure of Compound 1. Peaks due to DMSO and 1-BuOH integrate at 1 and <0.05 mol / mol, respectively.

[0300] The XRPD pattern was successfully indexed. The unit cell data for Form Y of compound 1 is shown below: [Table 27]

[0301] Amorphous Compound 1

[0302] Amorphous compound 1 was successfully produced by rotary evaporation from DCM, THF, or chloroform. However, the resulting form carried a significant electrostatic charge and was difficult to handle. Characterization is summarized below: [Table 28]

[0303] No visual improvement in aqueous solubility was observed for amorphous Compound 1 compared to Form A. Amorphous Compound 1 is not physically stable, crystallizing into a mixture of Forms X and K upon contact with diethyl ether and into material K upon exposure to elevated temperatures.

[0304] Diffuse scattering from XRPD exhibited by material produced by rotary evaporation from DCM is presented in Figure 13. TGA and DSC thermograms of material from the same preparation are presented in Figures 14-16. The TGA weight loss of 1.6% (maximum 176 °C) coincides with a volatilization endotherm with peak maxima near 72 °C and 111 °C by DSC.

[0305] Amorphous compound 1 produced by rotary evaporation from THF was used in cycling DSC experiments to help identify the glass transition temperature (Figure 16). The observation of a glass transition may be characteristic of an amorphous material. The first heating cycle is used to remove residual moisture and / or solvent. The final heating cycle reveals an apparent glass transition near 67°C (measured as the inflection midpoint), a crystallization exotherm near 148°C, and simultaneous melting / decomposition of the crystallized form beginning near 223°C. Based on an evaluation of the physical stability of the material at elevated temperatures, crystallization to form K is likely to occur at these conditions.

[0306] Salt Screening

[0307] In this salt screening study, ethanol, aqueous ethanol, and THF were primarily used. 21 counterions and neutral coformers were selected for screening. 40 crystallization experiments were performed. Counterions were selected based on known pKa values ​​to be likely to form salts with the free base. These experiments generally involved adding approximately 1 molar equivalent of counterion or coformer directly to the free base in solution or suspension. Other stoichiometries were explored where applicable. If a sufficient amount of precipitation occurred, the solid material was either recovered or additional steps, such as (but not limited to) cooling, addition of anti-solvent, evaporation, and / or slurrying, were performed to induce crystallization or increase yield.

[0308] Most experiments failed to provide anything other than the free base form A of compound 1. Evaporation of the filtrate from attempts to utilize (+)-camphoric, malonic, orotic, and salicylic acids showed XRPD patterns composed primarily of the acids used along with additional diffraction peaks that could not be identified. However, these materials also showed XRPD patterns composed primarily of the acids used along with additional protons that could not be assigned. 1 H NMR spectrum is shown, suggesting that decomposition also occurred. Three salts were successfully isolated, including hemi-edisylate, hemina padisylate, and napsylate. Three desired polymorphs of the napsylate salt and one crystalline form each of the hemi-edisylate and hemina padisylate salts were observed.

[0309] Hemi-edisylate Form A of Compound 1

[0310] The unique crystalline hemi-edisylate salt was isolated from an ethanol slurry using either 1 or 5 molar equivalents of ethane-1,2-disulfonic acid. The hemi-edisylate salt Form A used for characterization was produced by the following method.

[0311] The XRPD pattern of the hemi-edisylate salt Form A of Compound 1 is shown in FIG. 17, and a list of the peaks in this pattern is provided in Table 9 below.

[0312] [Table 9]

[0313] The proton NMR spectrum of the hemi-edisylate salt form A of compound 1 is consistent with the chemical structure of compound 1 and contains peaks assigned to ethane-1,2-disulfonic acid with an integration of 0.5 mol / mol of acid. No residual organic solvent is observed.

[0314] Thermograms are shown in Figures 18 and 19. The TGA weight loss of 0.6% (maximum at 135°C) is consistent with a broad volatilization endotherm near 77°C by DSC. No residual organic solvent was evident by NMR above. Therefore, this loss is likely due to volatilization of residual moisture. The slight exotherm observed near 173°C is likely an instrumental artifact. The final endotherm beginning near 259°C likely accompanies simultaneous melting and decomposition.

[0315] [Table 29]

[0316] Hemina padisylate form A of compound 1

[0317] Unique crystalline hemina padisylate was isolated from an ethanol slurry using either 1 or 5 molar equivalents of naphthalene-1,5-disulfonic acid. Attempts to utilize 5 molar equivalents of naphthalene-1,5-disulfonic acid provided a physical mixture of hemina padisylate Form A and excess naphthalene-1,5-disulfonic acid as dihydrate Form 1B.

[0318] The XRPD pattern of compound 1 hemina padisylate Form A is shown in FIG. 20 and a list of the peaks in this pattern is provided in Table 10 below.

[0319] [Table 10]

[0320] The proton NMR spectrum of Compound 1 hemina padisylate Form A is consistent with the chemical structure of Compound 1 and contains peaks assigned to naphthalene-1,5-disulfonic acid with an integration of 0.5 mol / mol of acid. No residual organic solvent is observed.

[0321] Thermograms are presented in Figures 21 and 22. The TGA weight loss of 1.5% (maximum 144°C) is consistent with a broad volatilization endotherm near 63°C by DSC. No residual organic solvent was evident by NMR above. Thus, the loss is likely due to volatilization of residual moisture. The final endotherm with an onset near 239°C is followed by decomposition.

[0322] [Table 30]

[0323] Napsylate Form A, Napsylate Form B, and Napsylate Form C of Compound 1

[0324] The native crystalline napsylate salt was isolated as a THF solvate from a THF slurry using 2 molar equivalents of naphthalene-2-sulfonic acid.

[0325] FIG. 23 shows an XRPD pattern representing napsylate salt form A. Form A was successfully indexed as a single unit cell. The indexing results provide a robust description of the crystalline form through tentative crystallographic unit cell parameters and clearly identify peaks representative of the crystalline phase. This form has a triclinic unit cell that likely contains two compound 1 molecules and two naphthalene-2-sulfonic acid molecules. Thus, the formula unit volume of 1013 Å3 calculated from the indexing results would be consistent with a solvate that could theoretically accommodate up to 1 mol / mol THF.

[0326] A list of peaks from the XRPD pattern of napsylate salt Form A is provided in Table 11 below.

[0327] [Table 11-1] [Table 11-2]

[0328] The XRPD pattern was successfully indexed. The unit cell data for the naphthalene salt form A of compound 1 is shown below: [Table 31]

[0329] The proton NMR spectrum of the mixture is consistent with the chemical structure of compound 1 and contains peaks assigned to naphthalene-2-sulfonic acid and THF, integrated at 1 mol / mol of acid and 0.5 mol / mol of solvent, respectively.

[0330] Thermograms are presented in Figures 24 and 25. The TGA weight loss of 5.2% (maximum 165°C) is consistent with broad volatilization endotherms near 63°C and 123°C by DSC. Assuming the weight loss is due to volatilization of THF, the loss is consistent with 0.5 mol / mol THF. The final endotherm with an onset near 205°C is likely the concomitant melting and decomposition of the desolvated napsylate salt, tentatively identified as either napsylate salt form B or form C.

[0331] The physical stability of napsylate salt Form A was investigated under various drying conditions. The XRPD peaks assigned to napsylate salt Form B increased in intensity compared to those of Form A upon exposure to 48° C. under vacuum for about 3 days. A mixture of napsylate salt Forms B and C was shown upon exposure to 120° C. for 30 minutes (FIG. 27).

[0332] Thermograms of mixtures of napsylate Form B and Form C are presented in Figures 28 and 29. As expected for desolvated material, the negligible TGA weight loss of 0.2% (up to 240°C) is consistent with a very weak volatilization endotherm by DSC near 61°C. Endotherms with onset near 206°C and 222°C are likely the concomitant melting and decomposition of napsylate Form B and / or Form C.

[0333] [Table 32]

[0334] Hemi-fumarate form C of compound 1

[0335] The hemifumarate salt Form C of Compound 1 was formed from acetic acid, water, and ACN. By NMR, the isolated material was consistent with the chemical structure of Compound 1 and contained 0.5 moles of fumaric acid, 0.4 moles of ACN, and 0.2 moles of acetic acid.

[0336] The material was dried under vacuum at 80° C. for 1 day, and the dried sample appeared to be a mixture of hemifumarate Form B, trace amounts of free base Form A of Compound 1, and several additional peaks. Based on these results, prior to drying, the material was likely a mixture with hemifumaric acid solvate as the major phase. This solvated hemifumarate phase was designated hemifumarate Form C of Compound 1.

[0337] The XRPD pattern of hemifumarate salt Form C of Compound 1 is provided in FIG.

[0338] Hemi-fumarate form D of compound 1

[0339] Hemi-fumarate Form D of Compound 1 was generated from a polymorphism experiment using EGEE. It was observed as a mixture with the free base Form A.

[0340] The XRPD pattern of hemifumarate salt Form D of Compound 1 is shown in FIG.

[0341] The NMR spectrum of this material is consistent with the chemical structure of Compound 1, which contains approximately 0.5 moles of fumaric acid and 1.1 moles of EGEE.

[0342] The material was dried under vacuum at 80° C. for 1 day, and the dried solid appears to be a mixture of free base Form A of Compound 1 and hemifumarate Form B of Compound 1. Based on these results, the material before drying contained a solvated fumaric acid phase along with free base Form A. The solvated fumaric acid phase was designated fumarate Form D of Compound 1.

[0343] Hemifumarate Form E and Hemifumarate Form F of Compound 1

[0344] From polymorphic experiments involving TFE and nitromethane, a unique crystalline material was observed, designated as hemifumarate Form E of Compound 1. The XRPD pattern of hemifumarate Form E was successfully indexed. Based on the indexing solution, the unit cell volume is consistent with a solvated form of the hemifumarate salt of Compound 1 that can accommodate one mole of either TFE or nitromethane. The unit cell data for hemifumarate Form E of Compound 1 is shown below. [Table 33]

[0345] The XRPD pattern of the hemifumarate salt Form E of Compound 1 is shown in Figure 33, and a list of the peaks in this pattern is provided in Table 12 below.

[0346] [Table 12-1] [Table 12-2]

[0347] Hemi-fumarate form E 1The H NMR spectrum is consistent with the hemifumarate salt of Compound 1 containing 0.4 moles of nitromethane and 0.4 moles of TFE. Thus, the hemifumarate salt form E may be solvated with nitromethane and / or TFE.

[0348] An SEM image of hemifumarate form E of Compound 1 is shown in Figure 36, which indicates the presence of large aggregates and very small particles aggregated on the surface of larger particles. The DSC and TGA of hemifumarate form E are shown in Figure 37. A broad endotherm at 100.9°C is observed by DSC, reflecting the presence of solvent in the material. A peak temperature of approximately 131°C is observed in the SDC thermogram. A weight loss of approximately 9.86% is observed by TGA between temperatures of 30°C and 155°C.

[0349] FIG. 38 shows a 12 hour analysis of the hemifumarate form E of Compound 1 acquired at 5 kHz MAS speed. 13 The C cross-polarization total sideband suppression (CPTOSS) spectrum (-11 to 211 ppm region) is shown. The chemical shifts of each peak are labeled and summarized in Table 14 below.

[0350] Table 13 shows the relaxivity values ​​for the hemifumarate salt form E of Compound 1. Table 14 shows the relaxivity values ​​for the hemifumarate salt form E of Compound 1. 13 C chemical shifts and normalized signal intensities are shown. Reported signal intensities from the Topspin® software package were exported to Microsoft® Excel® and normalized to the 170.6 ppm peak by normalizing the intensities of all peaks to an intensity of 100 at 170.6 ppm. [Table 13] Approximately 55.6kHz 1 Determined from the H spin locking field and the maximum spin locking time of 64 ms. 1 HT 1rho Measurements. [Table 14]

[0351] Figure 39 shows 1 H / 19 FCP experiment and 15 kHz MAS speed were used to obtain a 12 hour analysis of the hemifumarate form E of compound 1. 19 The F spectrum (full) is shown. Asterisks indicate spinning sidebands. The chemical shifts of each peak are labeled and summarized in Table 15.

[0352] Table 15 shows 19F From the H / F CP spectrum 19 Table 16 shows the F chemical shifts and Table 17 shows the relaxation values ​​for the hemifumarate salt form E of Compound 1. Signal intensities were normalized to the predominant isotropic chemical shift of the -118.5 ppm peak by exporting the reported intensities from the Topspin® software package into Microsoft® Excel® and normalizing the intensities of all peaks to a -118.5 ppm intensity of 100. [Table 15-1] [Table 15-2] [Table 16]

[0353] FIG. 40 shows the hemifumarate form E of Compound 1 acquired at 15 kHz MAS speed. 19 F HPDEC spectrum (full). Asterisks indicate spinning sidebands. Chemical shifts of each peak are labeled and summarized in Table 17. [Table 17]

[0354] Hemi-fumarate Form E was dried under vacuum at 72° C. for 1 day, and the dried solid exhibited a unique disordered crystalline pattern. This change in morphology may be due to desolvation. In an attempt to further desolvate the material, the dried sample was further dried under vacuum at 88° C. for 1 day, and the dried solid maintained the same morphology. Indexing of the XRPD pattern was not successful, which may be due to obstructions. This dried form was designated hemifumarate Form F of Compound 1.

[0355] Hemi-fumarate form F 1 The H NMR spectrum is consistent with the hemifumarate salt of compound 1. No presence of nitromethane or TFE was observed from the spectrum, indicating that this sample was completely desolvated. Therefore, hemifumarate form F is likely the unsolvated hemifumarate salt of compound 1.

[0356] By TGA (Figure 34, top thermogram), hemifumarate form F exhibits a slight weight loss of 0.1% between 50 and 130°C, which is consistent with an anhydrous / nonsolvated material. Apparent decomposition begins at approximately 208°C.

[0357] By DSC (Figure 34, lower thermogram), hemifumarate Form F exhibits multiple thermal events including a broad end at 135°C, which is partially attributed to melting based on the HSM images. Recrystallization was observed during HSM at about 151.5°C. Melting and discoloration of the recrystallized material was observed at about 201.4°C, consistent with the apparent decomposition observed from the TGA thermogram.

[0358] The XRPD pattern of hemifumarate Form F of Compound 1 is shown in FIG. General Dosage

[0359] Administration of the crystalline or crystalline salt forms of the present invention, either in pure form or as a suitable pharmaceutical composition, can be carried out by any of the approved modes of administration or agents serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisternally, or rectally in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, and the like, preferably in unit dosage forms suitable for convenient administration of precise dosage amounts.

[0360] The composition contains as an active agent a conventional pharmaceutical excipient and the crystalline form or crystalline salt form of the present invention, but may also contain other drugs, pharmaceutical agents, excipients, adjuvants, etc. The composition of the present invention may be used in combination with anticancer drugs or other drugs that are generally administered to patients undergoing cancer treatment. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatic agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin.

[0361] The pharmaceutical compositions of the present invention, if desired, may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.

[0362] Compositions suitable for parenteral injection may include physiologically acceptable aqueous or non-aqueous sterile solutions, dispersions, suspensions or emulsions, and sterile powders that are reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (olive oil, etc.), and injectable organic esters such as ethyl oleate. For example, proper fluidity can be maintained by using a coating agent such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0363] One of the preferred routes of administration is oral, using a convenient monthly dosing regimen that can be adjusted according to the severity of the condition being treated.

[0364] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert commonly used excipient, such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, such as glycerol, (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginates, and alginates. (e) solution retarders such as paraffin, (f) absorption promoters such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, glycerol monostearate, magnesium stearate, and the like, (h) adsorbents such as kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0365] The above solid dosage forms may be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain pacifying agents and may be of such composition that they release the active compound(s) in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used may be polymeric substances and waxes. The active compound may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0366] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the crystalline form or crystalline salt form of Compound I and, optionally, pharmaceutical adjuvants in excipients, such as water, saline, aqueous dextrose, glycerol, ethanol, etc.; solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, and dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; or mixtures of these substances, to form a solution or suspension.

[0367] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.

[0368] For example, compositions for rectal administration are suppositories which can be prepared, for example, by mixing a crystalline form or a crystalline salt of a compound of formula I with a suitable non-irritating excipient, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ordinary temperature but liquid at body temperature and thus will melt in a suitable body cavity and release the active ingredient therein.

[0369] The dosage form for topical administration of the compound of the present invention includes ointments, powders, sprays and inhalants.The active ingredient is mixed under sterile conditions with physiologically acceptable excipients and, if necessary, any preservatives, buffers or propellants.Ophthalmic compositions, eye ointments, powders and solutions are also contemplated within the scope of this disclosure.

[0370] In general, depending on the intended mode of administration, a pharma- ceutically acceptable composition will contain from about 1% to about 99% by weight of a crystalline form or crystalline salt of Compound I, and 99% to 1% by weight of suitable pharmaceutical excipients. In one example, the composition is from about 5% to about 75% by weight of a crystalline form or crystalline salt of Compound 1, with the remainder being suitable pharmaceutical excipients.

[0371] Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art: see, for example, Remington's Pharmaceutical Sciences, 21st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). The composition to be administered will, in each case, contain a therapeutically effective amount of a crystalline form or crystalline salt of Compound I or a pharma- ceutically acceptable salt thereof to treat a condition according to the teachings of the present disclosure.

[0372] The crystalline form or crystalline salt of Compound 1 is administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of Compound 1, the metabolic stability and length of action of Compound 1, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of the particular medical condition, and the host being treated. The crystalline form or crystalline salt form of Compound 1 can be administered to a patient at dosage levels ranging from about 0.1 to about 1,000 mg per day. For a healthy human adult having a body weight of about 70 kilograms, dosages ranging from about 0.01 to about 100 mg per kilogram of body weight per day are exemplary. However, the particular dosage used may vary. For example, the dosage may depend on many factors, including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. Determining the optimal dosage for a particular patient is well within the skill of one of ordinary skill in the art.

[0373] Combination therapy

[0374] The crystalline forms or crystalline salts of Compound 1 disclosed herein may be administered as monotherapy or in combination with one or more additional therapies ("co-administration") for the treatment of a disease or disorder, for example, a disease or disorder associated with hyperproliferation, such as cancer. Therapies that may be used in combination with the compounds disclosed herein include (i) surgery, (ii) radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T cell therapy; and (v) other chemotherapeutic agents.

[0375] The term "co-administered" ("co-administering") refers to either simultaneous administration or any method of separate sequential administration of a crystalline form or crystalline salt of Compound 1 disclosed herein with additional active pharmaceutical ingredient(s), including cytotoxic agents and radiation therapy. When administration is not simultaneous, the compounds are administered in a time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, for example, one compound may be administered topically and another compound may be administered orally.

[0376] Generally, any drug that is active against the disease or condition being treated may be co-administered. Examples of such drugs for cancer treatment can be found, for example, in https: / / www.cancer.gov / about-cancer / treatment / drugs (last accessed January 22, 2019) and in Cancer Principles and Practice of Oncology by VTDevita and S. Hellman (editors), 11 th edition (2018), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of drugs would be useful based on the particular characteristics of the drugs and the disease involved.

[0377] In one embodiment, the method of treatment includes co-administration of a crystalline form or crystalline salt of Compound 1 as disclosed herein with at least one immunotherapy. Immunotherapy (also called biological response modifier therapy, biological therapy, biotherapy, immunotherapy, or biologic therapy) is a treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize cancer cells or enhance the response to cancer cells. Immunotherapy includes active and passive immunotherapy. Active immunotherapy stimulates the body's own immune system, while passive immunotherapy generally uses immune system components created outside the body.

[0378] Examples of active immunotherapy include, but are not limited to, vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or vaccines including tumor infiltrating lymphocyte (TIL) vaccines with interleukin-2 (IL-2), or lymphokine-activated killer (LAK) cell therapy.

[0379] Examples of passive immunotherapy include, but are not limited to, targeted therapy that contains monoclonal antibodies and toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not have drugs or radioactive substances attached to them, whereas conjugated monoclonal antibodies are attached to, for example, chemicals (chemical labels), radioactive particles (radiolabels), or toxins (immunotoxins). Examples of these naked monoclonal antibody drugs include, but are not limited to, rituximab (Rituxan), an antibody against the CD20 antigen used, e.g., to treat B-cell non-Hodgkin's lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein used, e.g., to treat advanced breast cancer; aleimutuzumab (Campath), an antibody against the CD52 antigen used, e.g., to treat B-cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein used, e.g., in combination with irinotecan to treat advanced colorectal and head and neck cancer; and bevacizumab (Avastin), an anti-angiogenic therapy that acts on the VEGF protein and is used, e.g., in combination with chemotherapy to treat metastatic colorectal cancer. Examples of conjugated monoclonal antibodies include, but are not limited to, ibritumomab tiuxetan (Zevalin), a radiolabeled antibody that delivers radioactivity directly to cancerous B lymphocytes and is used, for example, to treat B cell non-Hodgkin's lymphoma, tositumomab (Bexar), a radiolabeled antibody that is used, for example, to treat certain types of non-Hodgkin's lymphoma; and gemtuzumab ozogamicin (Mylotarg), an immunotoxin that contains calicheamicin and is used, for example, to treat acute myeloid leukemia (AML). BL22 is a conjugated monoclonal antibody, for example, to treat hairy cell leukemia, an immunotoxin for example, to treat leukemia, lymphoma, and brain tumors, and radiolabeled antibodies such as OncoScint, for example, for colorectal and ovarian cancer, and ProstaScint, for example, for prostate cancer.

[0380] Further examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN™ (Trastuzumab), a humanized anti-HER2 monoclonal antibody for the treatment of metastatic breast cancer patients (Genentech, Calif.), and REOPRO, an anti-glycoprotein IIb / IIIa receptor on platelets to prevent blood clot formation.RTM (abciximab) (Centocor); ZENAPAX™ (daclizumab), an immunosuppressive humanized anti-CD25 monoclonal antibody for preventing acute renal allograft rejection (Roche Pharmaceuticals, Switzerland); PANOREX™, a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome / Centocor); BEC2, a murine anti-idiotypic (GD3epitope) IgG antibody (ImClone System); IMC-C225, a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™, a humanized anti-αVβ3 integrin antibody (Applied Molecular Evolution / MedImmune); Campath1H / LDP-03, a humanized anti-CD52 IgG1 antibody (Leukosite); SmartM195, a humanized anti-CD33 IgG antibody (Protein Design Lab / Kanebo); RITUXAN™, a chimeric anti-CD20 IgG1 antibody (IDEC Pharm / Genentech, Roche / Zettyaku); LYMPHOCIDE™, a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99m labeled, radioimaging, Immunomedics); Nuvion (against CD3, Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatized anti-CD80 antibody (IDEC Pharm / Mitsubishi; ZEVALIN™ ZEVALIN™ ZEVALIN™ is a radiolabeled murine anti-CD20 antibody (IDEC / ScheringAG); IDEC-131 is a humanized anti-CD40L antibody (IDEC / Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC / Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized anti-TNF-α antibody (CAT / BASF); CDP870 is a humanized anti-TNF-alpha Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgG1 antibody (IDEC Pharm / SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex / Eisai / Genmab); CD20-streptavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha 4 beta 7 antibody (LeukoSite / Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a humanized anti-CD40L IgG antibody (Biogen); ANCEGREN™ is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-beta. 2 Antibodies (Cambridge Ab Tech). Others are listed in the following paragraphs.

[0381] Immunotherapies that can be used in combination with the crystalline forms or crystalline salt forms of Compound 1 disclosed herein include adjuvant immunotherapy. Examples include cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1-α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-α), and interferons (including IFN-α, IFN-β, and IFN-gamma); aluminum hydroxide (alum); bacillus Calmette-Guerin (BCG); keyhole limpet hemocyanin (KLH); incomplete Freund's adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl phosphate (DNP), as well as combinations thereof, such as combinations of interleukins, such as IL-2, with other cytokines such as IFN-α.

[0382] In various embodiments, the crystalline or crystalline salt forms of Compound 1 can be combined with immunotherapy and / or immunotherapeutic agents. In various embodiments, the immunotherapy and / or immunotherapeutic agents can include one or more of the following: adoptive cell transfer, angiogenesis inhibitors, Bacillus Calmette-Guerin therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, immunoconjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy. The immunotherapy or immunotherapeutic agents are collectively referred to herein as "immunotherapeutic agents."

[0383] The present disclosure provides a method for preventing, treating, alleviating, inhibiting or controlling a neoplasm, tumor or cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a crystalline form or crystalline salt form of Compound 1 in combination with an immunotherapeutic agent. In one non-limiting embodiment, the method comprises administering a therapeutically effective amount of a combination comprising a crystalline form or crystalline salt form of Compound 1 in combination with an immunotherapeutic agent. In various embodiments, the combination provides a synergistic, additive or synergistic effect in reducing the number of cancer cells when treated with the combination compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination comprising a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent results in a synergistic anti-tumor activity and / or anti-tumor activity that is greater than the additive effect of administering a crystalline form or crystalline salt form of Compound 1 or an immunotherapeutic agent alone.

[0384] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, composed of T and B lymphocytes, has potent anticancer potential, with broad capacity and sophisticated specificity to respond to diverse tumor antigens. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully exploiting all these attributes of the adaptive immune system makes immunotherapy unique among all cancer treatment modalities.

[0385] The present disclosure provides a combination of a crystalline form or crystalline salt form of Compound 1 with an immunotherapeutic agent. These exemplary combinations can be used to treat a subject with cancer. In various embodiments, the immunotherapeutic agent that finds utility in the compositions, formulations, and methods of the present invention can include one or more of the following agents or treatments: adoptive cell transfer, angiogenesis inhibitors, Bacillus Calmette-Guerin therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, such as immune checkpoint inhibitors, immunoconjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

[0386] In certain embodiments of the disclosure, the therapeutically effective combination comprises a crystalline form or a crystalline salt form of Compound 1 and an immunotherapeutic agent. In various related embodiments, the crystalline form or a crystalline salt form of Compound 1 enhances the activity of the immunotherapeutic agent.

[0387] In certain embodiments of each of the foregoing aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of a crystalline form or a crystalline salt form of Compound 1 of the invention.

[0388] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere herein, the crystalline or crystalline salt form of Compound 1 and the immunotherapeutic agent act synergistically. In various embodiments described herein, an exemplary immunotherapeutic agent is an immune cell (e.g., T cell, dendritic cell, natural killer cell, etc.) modulator selected from an agonist or activator of a costimulatory molecule, which is a monoclonal antibody, a bispecific antibody, a trispecific antibody, or an immune cell-binding multivalent antibody / fusion protein / construct that includes one or more immune checkpoint antigen-binding moieties, as known in the art. In some embodiments, the immunotherapeutic agent can be an antibody that modulates a costimulatory molecule, an antibody that binds to an antigen on the surface of an immune cell or a cancer cell. In each of these different embodiments, the antibody modulator may be a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a trispecific or multispecific format antibody, a fusion protein, or a fragment thereof, such as a diabody, a single chain (sc)-diabody (scFv)2, a miniantibody, a minibody, a barnase-burster, a scFv-Fc, a sc(Fab)2, a trimeric antibody construct, a triabody antibody construct, a trimeric body antibody construct, a tribody antibody construct, a collaborating antibody construct, (scFv-TNFa)3, or a F(ab)3 / DNL antibody construct.

[0389] In certain embodiments of each of the foregoing aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulates the immune response, e.g., a checkpoint inhibitor or a checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances an anti-tumor immune response. In some embodiments, the immunotherapeutic agent is an agent that enhances cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that increases T cell activity. In some embodiments, the immunotherapeutic agent is an agent that increases cytolytic T cell (CTL) activity.

[0390] In some embodiments, the therapeutic methods of the invention may include administering a crystalline form or a crystalline salt form of Compound 1 in combination with a molecule, e.g., a binding agent, e.g., an antibody or functional fragment thereof, that modulates (activates or inhibits) a checkpoint protein. A checkpoint inhibitor can be any molecule, agent, treatment, and / or method that inhibits an immune checkpoint and / or promotes, e.g., an endogenous immune checkpoint inhibitor, e.g., by promoting an inhibitor of an immune checkpoint; by inhibiting a transcription factor involved in the expression of an immune checkpoint, and / or by acting in concert with any additional exogenous factor. For example, a checkpoint inhibitor can include a treatment that inhibits a transcription factor involved in the expression of an immune checkpoint gene or promotes the expression of a transcription factor of a tumor suppressor gene, e.g., BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983).Additionally, checkpoint inhibitors may inhibit the transcription of immune checkpoint genes; modification and / or processing of immune checkpoint mRNA; translation of immune checkpoint proteins; and / or molecules involved in immune or immune checkpoint pathways, such as PD-1 transcription factors, e.g., HIF-1, STAT3, NF-κB, and AP-1, or activation of common oncogenic pathways, e.g., JAK / STAT, RAS / ERK, or PI3K / AKT / mTOR (Zerdes et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations, Oncogene volume 37, pages 4639-4661 (2018), the disclosure of which is incorporated herein by reference in its entirety).

[0391] Checkpoint inhibitors may include therapies, molecules, agents, and / or methods that regulate immune checkpoints at the transcriptional level, for example, using co-suppression of RNA interference pathways and / or post-transcriptional gene silencing (PTGS) (e.g., microRNA, miRNA; silencing-RNA, small interfering-RNA, or short interfering-RNA (siRNA)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTR of checkpoint mRNAs CD80, CD274 (PD-L1), and CD40 (Leibowitz et al., Post-transcriptional regulation of immune checkpoint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating the expression of PD-1 in lung adenocarcinoma (see Boldini et al., Role of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017;17:105, the disclosure of which is incorporated herein by reference in its entirety).

[0392] T cell-specific aptamer-siRNA chimeras have been proposed as a highly specific method to inhibit molecules in the immune checkpoint pathway (Hossain et al., The aptamer-siRNA conjugates: reprogramming T cells for cancer therapy, Ther. Deliv. 2015, Jan;6(1):1-4, the disclosure of which is incorporated herein by reference in its entirety).

[0393] Alternatively, members of immune checkpoint pathways can be inhibited using treatments that affect related pathways, e.g., metabolism. For example, oversupply of the glycolytic intermediate pyruvate in CAD macrophage-derived mitochondria promoted PD-L1 expression via induction of the bone morphogenetic protein 4 / phosphorylated SMAD1 / 5 / IFN regulatory factor 1 (BMP4 / p-SMAD1 / 5 / IRF1) signaling pathway. Thus, implementing treatments that modulate metabolic pathways can result in subsequent modulation of the immunosuppressive PD-1 / PD-L1 checkpoint pathway (Watanabe et al.,Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity,J Clin Invest.2017 Jun 30;127(7):2725-2738).

[0394] Checkpoint immunity can be modulated through oncolytic viruses that selectively replicate in tumor cells and induce acute immune responses in the tumor microenvironment, i.e., by acting as gene vectors to deliver specific agents (e.g., antibodies, miRNA, siRNA, etc.) to cancer cells, achieving tumor lysis and secretion of cytokines and chemokines to synergize with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci. 2018 May;19(5):1389). Currently, clinical trials are underway utilizing the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenovirus, poxvirus, herpes simplex virus (HSV), coxsackievirus, reovirus, Newcastle disease virus (NDV), T-VEC (a herpesvirus encoded by GM-CSF (granulocyte macrophage colony stimulating factor)), and H101 (Shi et al., supra).

[0395] Checkpoint inhibitors may function at the translational level of checkpoint immunity. Because translation of mRNA into protein represents a key event in the regulation of gene expression, inhibition of immune checkpoint translation is a way in which immune checkpoint pathways can be inhibited.

[0396] Inhibition of immune checkpoint pathways can occur at any stage of the immune checkpoint translation process. For example, drugs, molecules, agents, treatments, and / or methods can inhibit the initiation process (whereby the 40S ribosomal subunit is recruited to the 5' end of the mRNA and scans the 5'UTR of the mRNA toward its 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl transfer RNA (tRNA) (Met-tRNAi), base pairing with the start codon, or recruitment of the 60S subunit to initiate the elongation and sequential addition of amino acids in the translation of immune checkpoint-specific genes. Alternatively, checkpoint inhibitors can inhibit checkpoints at the translation level by preventing the formation of the ternary complex (TC), i.e., eukaryotic initiation factor (eIF) 2 (or one or more of its α, β, and γ subunits); GTP; and Met-tRNAi.

[0397] Checkpoint inhibition can occur through destabilization of eIF2α by eliminating its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by eliminating TC binding to the 40S ribosome and / or other initiation factors, thus preventing the preinitiation complex (PIC) from forming; by inhibiting the eIF4F complex and / or its cap-binding protein eIF4E, scaffolding protein eIF4G, or eIF4A helicase. Methods for considering translational control in cancer are discussed in Truitt et al., New frontiers in translational control of the cancer genome, Nat Rev Cancer. 2016 Apr 26;16(5):288-304, the disclosure of which is incorporated herein by reference in its entirety.

[0398] Checkpoint inhibitors can also include treatments, molecules, agents, and / or methods that modulate immune checkpoints at the cellular and / or protein level, for example, by inhibiting immune checkpoint receptors. Inhibition of checkpoints can occur through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and / or other drugs, agents, treatments, and / or methods.

[0399] Immune checkpoints refer to inhibitory pathways of the immune system involved in maintaining self-tolerance and regulating the degree of immune system response to minimize peripheral tissue damage. However, tumor cells can also activate immune system checkpoints to reduce the effectiveness of the immune response against tumor tissues ("block" the immune response). In contrast to the majority of anticancer drugs, checkpoint inhibitors do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance the intrinsic antitumor activity of the immune system. (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0400] In some embodiments, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, a modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some embodiments, the immune checkpoint modulator is, i.e., an inhibitor or antagonist, or an activator or agonist, such as a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD40 modulator, a GITR modulator, a TGF-β modulator, a TIM-3 modulator, a SIRP-α modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, an ICOS modulator, a B7H3 modulator, a B7H4 modulator, a FAS modulator, and / or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody that may be in the form of a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or a multivalent antibody / fusion protein / construct that binds to immune cells as known in the art).

[0401] In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of PD-1. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of PD-L1 and / or PD-L2. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of CTLA-4. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of CD80 and / or CD86. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of TIGIT. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of KIR. In some embodiments, the immunotherapeutic agent is an agent that enhances or stimulates the activity of activating immune checkpoint receptors.

[0402] PD-1 (also known as programmed death 1, CD279, PDCD1) is a cell surface receptor that regulates the balance between stimulatory and inhibitory signals in the immune system and plays an important role in maintaining peripheral tolerance (Ishida, Y et al. 1992 EMBO J. 11 3887; Kier, Mary E et al. 2008 Annual Rev Immunol 26 677-704; Okazaki, Taku et al. 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin superfamily that is homologous to CD28. The structure of PD-1 is a monomeric type 1 transmembrane protein consisting of one immunoglobulin variable-like extracellular domain and a cytoplasmic domain that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). PD-1 expression is inducible on T cells, B cells, natural killer (NK) cells, and monocytes upon lymphocyte activation, for example, via T cell receptor (TCR) or B cell receptor (BCR) signaling (Kier,Mary E.et al.2008 Annu Rev Immunol 26 677-704;Agata,Y et al 1996 Int Immunol 8 765-72). PD-1 is the receptor for the ligands CD80, CD86, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), which are cell surface expressed members of the B7 family (Freeman,Gordon et al.2000 J Exp Med 192 1027;Latchman,Y et al.2001 Nat Immunol 2:261). Upon ligand engagement, PD-1 recruits phosphatases, such as SHP-1 and SHP-2, to its intracellular tyrosine motifs, which subsequently dephosphorylate effector molecules activated by TCR or BCR signaling (Chemnitz, J. et al. 2004, J. Immunol. 173:945-954; Riley, James L 2009 Immunological Reviews 229:114-125).Thus, PD-1 transmits inhibitory signals to T cells and B cells only when it simultaneously engages the TCR or BCR.

[0403] PD-1 has been demonstrated to downregulate effector T cell responses through both cell-intrinsic and cell-extrinsic functional mechanisms. Inhibitory signaling through PD-1 induces an unresponsive state in T cells, which cannot clone and proliferate or produce optimal levels of effector cytokines. PD-1 can induce T cell apoptosis through its ability to inhibit costimulatory survival signals, which leads to reduced expression of key antiapoptotic molecules such as Bcl-XL (Kier,Mary E et al.2008 Annu Rev Immunol 26:677-704). In addition to these direct effects, recent publications have implicated PD-1 in suppressing effector cells by promoting the induction and maintenance of regulatory T cells (TREG). For example, it has been shown that PD-L1 expressed on dendritic cells acts synergistically with TGF-β to promote the induction of CD4+FoxP3+TREGs with enhanced suppressor function (Francisco, Loise M. et al. 2009, J. Exp. Med. 206:3015-3029).

[0404] TIM-3 (also known as T cell immunoglobulin and mucin domain-containing 3, TIM-3, hepatitis A virus cellular receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3, and CD366) is a type I membrane protein of approximately 33.4 kDa that is involved in immune responses (Sanchez-Fueyo et al., Tim-3 inhibits Thelper type 1-mediated auto-andalloimmuneresss and promotes immunological translation, Nat. Immunol. 4:1093-1101 (2003)).

[0405] TIM-3 is selectively expressed in Th1 cells and phagocytes (e.g., macrophages, dendritic cells). The use of siRNA or blocking antibodies to reduce the expression of human TIM-3 enhances the secretion of interferon gamma (IFN-γ) from CD4 positive T cells, implicating an inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases did not show expression of TIM-3 in CD4 positive cells. In particular, T cell clones derived from the cerebrospinal fluid of multiple sclerosis patients expressed lower levels of TIM-3 and secreted higher IFN-γ than clones derived from normal healthy subjects (Koguchi K. et al., J. Exp Med. 203: 1413-8. (2006)).

[0406] TIM-3 is a member of the galectin family that is ubiquitously expressed in a variety of cell types and binds β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al., T cell / transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells, J Immunol. 2010 Feb 15;184(4):1918-30); high mobility group protein 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1, and high mobility group box 1) (Chiba et al., Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol. 2012 Sep;13(9):832-42); and is a receptor for the ligand galectin-9, which binds to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also known as BGP, BGP1, BGPI, carcinoembryonic antigen-related cell adhesion molecule 1) (Huang et al.,CEACAM1 regulates TIM-3-mediated tolerance and exhaustion,Nature.2015 Jan 15;517(7534):386-90).

[0407] BTLA (also known as B and T lymphocyte attenuator, BTLA1, CD272, and B and T lymphocyte-associated) is a single-pass type I membrane protein of approximately 27.3 kDa involved in lymphocyte inhibition during immune responses. BTLA is constitutively expressed in both B and T cells. BTLA interacts with HVEM (herpes virus entry mediator), a member of the tumor necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102:1116-21). The interaction of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, with HVEM, a costimulatory tumor necrosis factor (TNF) receptor (TNFR), is unique in that it defines a crosstalk between these two receptor families. BTLA contains a membrane-proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and a membrane-distal immunoreceptor tyrosine-based switch motif (ITSM). Disruption of either the ITIM or ITSM abolishes the ability of BTLA to recruit either SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in a manner distinct from PD-1 and that both tyrosine motifs are required to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine-containing motif in the cytoplasmic domain that is similar in sequence to the Grb-2 recruitment site (YXN). Phosphorylated peptides containing this BTLA N-terminal tyrosine motif can also interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain to be elucidated in vivo (Gavrieli et al., Biochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is the receptor for the ligands PTPN6 / SHP-1; PTPN11 / SHP-2; TNFRSF14 / HVEM and B7H4.

[0408] VISTA (also known as V-domain Ig suppressor of T cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DD1 alpha, VISTA, C10orf54, chromosome 10 open reading frame 54, PD-1H, and V-set immunoregulatory receptor) is a ~33.9 kDa single-pass type I membrane protein involved in T cell inhibitory responses, embryonic stem cell differentiation via inhibition of BMP4 signaling, and MMP14-mediated activation of MMP2 (Yoon et al.,Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53,Science.2015 Jul 31;349(6247):1261669). VISTA interacts with the ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell function, Immunology, 2019, Jan;156(1):74-85).

[0409] LAG-3 (also known as lymphocyte activation gene 3, LAG3, CD223, and lymphocyte activation 3) is a single-pass type I membrane protein of approximately 57.4 kDa involved in lymphocyte activation that also binds to HLA class II antigens. LAG-3 is a member of the immunoglobulin supergene family and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39:213), NK cells (Triebel et al., 1990, J. Exp. Med. 171:1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21:503-513; Camisaschi et al., 2010, J Immunol. 184:6545-6551; Gagliani et al., 2013, Nat Med 19:739-746), and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182:1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12 and is structurally and genetically related to CD4. Like CD4, LAG-3 can interact with MHC class II molecules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176:327-337; Huard et al., 1996, Eur. J. Immunol. 26:1180-1186). Direct binding of LAG-3 to MHC class II has been suggested to play a role in downregulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24:3216-3221), and LAG-3 blockade has also been shown to reactivate CD8+ lymphocytes in both tumor or self-antigen (Gross et al., 2007, J Clin Invest. 117:3383-3392) and viral models (Blackburn et al., 2009, Nat. Immunol. 10:29-37).Furthermore, the cytoplasmic region of LAG-3 can interact with LAP (LAG-3 associated protein), a signaling molecule involved in downregulation of the CD3 / TCR activation pathway (Iouzalen et al., 2001, Eur. J. Immunol. 31:2885-2891). Furthermore, CD4+CD25+ regulatory T cells (Treg) have been shown to express LAG-3 upon activation, which contributes to the suppressor activity of Treg cells (Huang, C. et al., 2004, Immunity, 21:503-513). LAG-3 can also negatively regulate T cell homeostasis by Treg cells through both T cell-dependent and -independent mechanisms (Workman, CJ. and Vignali, DA, 2005, J. Immunol. 174:688-695).

[0410] LAG-3 has been shown to interact with MHC class II molecules (Huard et al., CD4 / major histocompatibility complex class II interaction analyzed with CD4-and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins, Eur. J. Immunol. 1995 Sep;25(9):2718-21).

[0411] Additionally, several kinases are known to be checkpoint inhibitors, for example, CHEK-1, CHEK-2, and A2aR.

[0412] CHEK-1 (also known as CHK1 kinase, CHK1, and checkpoint kinase 1) is an approximately 54.4 kDa serine / threonine-protein kinase involved in checkpoint-mediated cell cycle arrest and activation of DNA repair in response to DNA damage and / or unreplicated DNA.

[0413] CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is a serine / threonine protein kinase of approximately 60.9 kDa that is involved in checkpoint-mediated cell cycle arrest, activation of DNA repair, and double-strand break-mediated apoptosis.

[0414] The A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is an approximately 44.7 kDa multispan membrane receptor for adenosine and other ligands.

[0415] In some embodiments, exemplary immunotherapeutic agents may include one or more antibody modulators targeting PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and / or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGFbeta, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, and / or BTNL2, among others known in the art. In some embodiments, the immunotherapeutic agent is an agent that increases the activity of natural killer (NK) cells. In some embodiments, the immunotherapeutic agent is an agent that inhibits the suppression of an immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppressor cells or the activity of suppressor cells. In some embodiments, the immunotherapeutic agent is an agent or treatment that inhibits Treg activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of an inhibitory immune checkpoint receptor.

[0416] In some embodiments, the disclosed combination comprises a crystalline or crystalline salt form of Compound 1 and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T cell modulator selected from an agonist or activator of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from GITR, OX40, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKp80, CD160, B7-H3, or an agonist of a CD83 ligand (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion). In other embodiments, the effector cell combination comprises a bispecific T cell engager (e.g., a bispecific antibody molecule that binds to CD3 and a tumor antigen (e.g., EGFR, PSCA, PSMA, EpCAM, HER2, among others).

[0417] In some embodiments, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, a modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 a modulator of IL-1 activity, a modulator of IDO1 activity, a modulator of SIRP-alpha activity, a modulator of TIGIT activity, a modulator of VSIG8 activity, a modulator of BTLA activity, a modulator of SIGLEC7 activity, a modulator of SIGLEC9 activity, a modulator of ICOS activity, a modulator of B7H3 activity, a modulator of B7H4 activity, a modulator of FAS activity, a modulator of BTNL2 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide.

[0418] In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor, e.g., an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an anti-CD40 antibody molecule), (xi) an OX40 agonist (e.g., an anti-OX40 antibody molecule), or (xii) a CD27 agonist (e.g., an anti-CD27 antibody molecule). In one embodiment, the immunotherapeutic agent is selected from the following: PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG In one embodiment, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, -3, and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGF beta, galectin 9, CD69, galectin-1, CD113, GPR56, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4. In one embodiment, the inhibitor of an immune checkpoint molecule inhibits PD-1, PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1, 3, and / or -5), CTLA-4, or any combination thereof.

[0419] In one embodiment, the immunotherapeutic agent is an agonist of proteins that stimulate T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0420] In some embodiments, the immunotherapeutic agent used in the combinations disclosed herein (e.g., in combination with a crystalline or crystalline salt form of Compound 1 of the invention) is an activator or agonist of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from CD2, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or a CD83 ligand agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion).

[0421] Inhibition of inhibitory molecules can be carried out at the DNA, RNA, or protein level. In embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA, or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of an inhibitory signal is a polypeptide, e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4Ig), or an antibody or antigen-binding fragment thereof, e.g., a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding moieties, a trispecific antibody, or an immune cell-binding multivalent antibody / fusion protein / construct known in the art that binds to said inhibitory molecule; e.g., an antibody or fragment thereof (also referred to herein as an "antibody molecule") that binds to PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and / or -5), VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGF beta, Galectin 9, CD69, Galectin-1, CD113, GPR56, CD48, GARP, PD1H, LAIR1, TIM-1, TIM-4, or a combination thereof.

[0422] In some embodiments, when the combination comprises a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent, the immunotherapeutic agent is a monoclonal antibody or a bispecific antibody. For example, the monoclonal or bispecific antibody may specifically bind to a member of the c-Met pathway and / or an immune checkpoint modulator (e.g., a bispecific antibody binds to both the hepatocyte growth factor receptor (HGFR) and an immune checkpoint modulator described herein, e.g., an antibody that binds to PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, or CD27). In certain embodiments, the bispecific antibody specifically binds to the human HGFR protein and one of PD-1, PD-L1, and CTLA-4.

[0423] In some embodiments of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a PD-L2 antagonist, a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a KIR antagonist, a Tim-3 antagonist, a LAG3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, or an IDO1 antagonist.

[0424] In some embodiments, the PD-1 antagonist is an antibody that specifically binds to PD-1. In some embodiments, the antibody that binds to PD-1 is pembrolizumab (KEYTRUDA®, MK-3475; Merck), pidilizumab (CT-011, Curetech Ltd.), nivolumab (OPDIVO®, BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca / MedImmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some embodiments, the antibody that binds PD-1 is described in PCT Publication No. WO2014 / 179664, e.g., the antibodies identified as APE2058, APE1922, APE1923, APE1924, APE1950, or APE1963 (Anaptysbio), or an antibody comprising the CDR regions of any of these antibodies. In other embodiments, the PD-1 antagonist is a fusion protein comprising the extracellular domain of PD-L1 or PD-L2, e.g., AMP-224 (AstraZeneca / MedImmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, e.g., AUNP-12 (Aurigene).

[0425] In some embodiments, the PD-L1 antagonist is an antibody that specifically binds to PD-L1. In some embodiments, the antibody that binds to PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca / MedImmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KD033 (Kadmon), an antibody portion of KD033, or STI-A1014 (Sorrento Therapeutics). In some embodiments, the antibody that binds PD-L1 is described in PCT Publication WO2014 / 055897, such as Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, or Ab-55, or an antibody containing the CDR regions of any of these antibodies, the disclosure of which is incorporated herein by reference in its entirety.

[0426] In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to anti-CTLA-4. In some embodiments, the antibody that binds to CTLA-4 is ipilimumab (YERVOY®; Bristol Myer Squibb) or tremelimumab (CP-675,206; Pfizer). In some embodiments, the CTLA-4 antagonist is a CTLA-4 fusion protein or a soluble CTLA-4 receptor, e.g., KARR-102 (Kahr Medical Ltd.).

[0427] In some embodiments, the LAG3 antagonist is an antibody that specifically binds to LAG3. In some embodiments, the antibody that binds to LAG3 is IMP701 (Prima BioMed), IMP731 (Prima BioMed / GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist comprises a soluble LAG3 receptor, e.g., IMP321 (Prima BioMed).

[0428] In some embodiments, the KIR antagonist is an antibody that specifically binds to KIR. In some embodiments, the antibody that binds to KIR is lirilumab (Bristol Myer Squibb / Innate Pharma).

[0429] In some embodiments, the immunotherapeutic agent is a cytokine, such as a chemokine, interferon, interleukin, lymphokine, or member of the tumor necrosis factor family, hi some embodiments, the cytokine is IL-2, IL15, or interferon-gamma.

[0430] In some embodiments of any of the above aspects, or aspects described anywhere herein, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung carcinoma (NSCLC)), kidney cancer (e.g., renal urothelial carcinoma), bladder cancer (e.g., bladder urothelial (transitional cell) carcinoma), breast cancer, colorectal cancer (e.g., colon adenocarcinoma), ovarian cancer, pancreatic cancer, gastric cancer, esophageal cancer, mesothelioma, melanoma (e.g., cutaneous melanoma), head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), thyroid cancer, sarcoma (e.g., soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteogenic sarcoma, osteosarcoma, chondrosarcoma, hematopoietic sarcoma, and / or hematopoietic sarcoma). sarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, leiomyosarcoma, or rhabdomyosarcoma), prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia (e.g., acute lymphocytic leukemia (ALL)), acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), chronic eosinophilic leukemia, or chronic lymphocytic leukemia (CLL)), lymphoma (e.g., Hodgkin's lymphoma, or non-Hodgkin's lymphoma (NHL), myeloma (multiple myeloma (MM), mycosis fungoides, Merkel cell carcinoma, hematological malignancies, cancers of blood tissue, B-cell carcinoma, bronchial Cancer, stomach cancer, cancer of the brain or central nervous system, cancer of the peripheral nervous system, cancer of the uterus or endometrium, cancer of the oral cavity or pharynx, liver cancer, testicular cancer, biliary tract cancer, small intestine or appendix cancer, salivary gland cancer, adrenal gland cancer, adrenal cortical carcinoma, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), polycythemia vera, chordoma, synovium, Ewing's tumor, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, fetal The cancer cell is selected from the group consisting of: neoplastic cell carcinoma, Wilms' tumor, bladder carcinoma, epithelial carcinoma, glioma, anaplastic astrocytoma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid carcinoma, small cell carcinoma, essential thrombocythemia, myelodysplasia of unknown cause, hypereosinophilic syndrome, systemic mastocytosis, familial eosinophilia, neuroendocrine carcinoma, or carcinoid tumor.

[0431] In some embodiments of any of the aspects described above or elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist), or the subject's cancer or tumor has progressed after an initial response to immune checkpoint inhibition (e.g., any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or a PD-L1 antagonist).

[0432] In various embodiments, the immunotherapeutic agent may comprise an antibody or an antigen-binding fragment thereof. Within this definition, immune checkpoint inhibitors include bispecific antibodies known in the art and multivalent antibodies / fusion proteins / constructs that bind to immune cells. In some embodiments, the immunotherapeutic agent may comprise a bispecific antibody that is bivalent and binds to either the same epitope of an immune checkpoint molecule, two different epitopes of the same immune checkpoint molecule, or different epitopes of two different immune checkpoints.

[0433] One of skill in the art may implement a number of bispecific antibody formats known in the art to target one or more of CTLA4, PD1, PD-L1 TIM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK1 and CHK2 kinases, BTLA, A2aR, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, SIRP-alpha, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2, and others for use in the combinations described herein.

[0434] In various embodiments, the immunotherapeutic agent may comprise a multivalent antibody / fusion protein / construct that binds to immune cells.

[0435] In one embodiment of the disclosure, checkpoint inhibitors, in combination with a crystalline form or crystalline salt form of Compound 1, are used to reduce or inhibit metastasis of a primary tumor or cancer to other sites, or the formation or establishment of a metastatic tumor or cancer at other sites distal to the primary tumor or cancer, thereby inhibiting or reducing tumor or cancer recurrence or tumor or cancer progression.

[0436] In a further embodiment of the disclosure, provided herein is a combination therapy for treating cancer comprising a crystalline form or a crystalline salt form of Compound 1 and a checkpoint inhibitor capable of eliciting a robust and durable immune response with improved therapeutic efficacy and further manageable toxicity.

[0437] In a further embodiment of the disclosure, provided herein is a combination therapy for treating cancer, comprising a crystalline form or a crystalline salt form of Compound 1 and an immune checkpoint inhibitor. In one embodiment of the disclosure, provided herein is a method of treating cancer and / or preventing the establishment of metastasis by employing a crystalline form or a crystalline salt form of Compound 1 of the present invention, which acts synergistically with a checkpoint inhibitor.

[0438] In further embodiments, the present disclosure provides a method for one or more of the following: 1) reducing or inhibiting the growth, proliferation, migration or invasiveness of tumor cells or cancer cells that are or will develop metastases; 2) reducing or inhibiting the formation or establishment of metastases originating from a primary tumor or cancer to one or more other sites, locations or regions different from the primary tumor or cancer; 3) reducing or inhibiting the growth or proliferation of metastases at one or more other sites, locations or regions different from the primary tumor or cancer after the metastases have formed or established; 4) reducing or inhibiting the formation or establishment of additional metastases after the metastases have formed or established; 5) prolonging overall survival; 6) prolonging progression-free survival; or 7) stabilizing disease. The method includes administering to a subject in need thereof a crystalline form or crystalline salt form of compound 1 of the present invention in combination with a checkpoint inhibitor as described herein.

[0439] In one embodiment of the disclosure, administration of a crystalline form or crystalline salt form of Compound 1 in combination with an immunotherapeutic agent provides a detectable or measurable improvement in a given subject's condition, e.g., alleviating or ameliorating one or more adverse (physical) symptoms associated with a cell proliferative or hyperproliferative disorder, a neoplasm, tumor or cancer, or the presence of metastases, i.e., a therapeutic benefit or beneficial effect.

[0440] Therapeutic benefit or beneficial effect refers to an objective or subjective, temporary, episodic, or long-term improvement of a condition or pathology, or a reduction in the onset, severity, duration, or frequency of adverse symptoms associated with or caused by a cell proliferation or cell hyperproliferative disorder, e.g., a neoplasm, tumor, or cancer, or metastasis. This may lead to improved survival rates. A satisfactory clinical endpoint of a therapeutic method according to the present disclosure is achieved, for example, when there is a gradual or partial reduction in the severity, duration, or frequency of one or more associated pathologies, adverse symptoms, or complications, or the inhibition or reversal of one or more of the physiological, biochemical, or cellular symptoms or characteristics of a cell proliferation or cell hyperproliferative disorder, such as a neoplasm, tumor, or cancer, or metastasis. Thus, a therapeutic benefit or improvement may be, but is not limited to, the destruction of a target proliferating cell (e.g., a neoplasm, tumor, or cancer, or metastasis), or the disappearance of one or more, most, or all of the lesions, adverse symptoms, or complications associated with or caused by a cell proliferation or cell hyperproliferative disorder, e.g., a neoplasm, tumor, or cancer, or metastasis. However, a therapeutic benefit or improvement need not be a cure or complete destruction of all target proliferative cells (e.g., neoplasm, tumor or cancer, or metastasis), or the elimination of all pathologies, adverse symptoms, or complications associated with or caused by a cell proliferation or hyperproliferative disorder, e.g., neoplasm, tumor or cancer, or metastasis. For example, partial destruction of a tumor or cancer cell mass, or stabilization of tumor or cancer mass, size, or cell number, by inhibiting tumor or cancer progression or worsening, can reduce mortality and extend lifespan, even if some or most of the tumor or cancer mass, size, or cells remain, even if only for a few days, weeks, or months.

[0441] Specific non-limiting examples of therapeutic benefit include a reduction in neoplasm, tumor or cancer, or metastasis volume (size or cell mass) or cell number; inhibiting or preventing an increase in neoplasm, tumor or cancer volume (e.g., stabilization); slowing or inhibiting the progression, progression, or metastasis of a neoplasm, tumor or cancer; or inhibiting the proliferation, growth, or metastasis of a neoplasm, tumor, or cancer.

[0442] In one embodiment of the present disclosure, administration of the immunotherapeutic agent, in combination with a crystalline form or crystalline salt form of Compound 1, results in a detectable or measurable improvement or overall response according to irRC (derived from time point response assessments and based on tumor burden), including one or more of the following: (i) irCR--complete disappearance of all lesions beyond measurable or not, and no new lesions (confirmed by repeat assessments within 4 weeks from the date of first documentation); (ii) iPR--a 50% or greater reduction in tumor burden compared to baseline (confirmed by serial assessments at least 4 weeks after initial documentation).

[0443] Optionally, the methods described herein may not have an immediate effect, for example, treatment may be followed by an increase in the number or mass of neoplastic, tumor or cancer cells, but may be followed by an eventual stabilization or reduction in tumor cell mass, size or cell number in a given subject over time.

[0444] Additional adverse symptoms and complications associated with neoplasms, tumors, cancers and metastases that can be inhibited, alleviated, reduced, delayed or prevented include, for example, nausea, lack of appetite, lethargy, pain and discomfort. Thus, partial or complete reduction or reduction in the severity, duration or frequency of adverse symptoms or complications associated with or caused by a cell hyperproliferative disorder, improvement in the subject's quality of life and / or health, for example, increased energy, appetite, mental well-being, are all specific, non-limiting examples of therapeutic benefits.

[0445] Thus, the therapeutic benefit or improvement can also include a subjective improvement in the quality of life of the treated subject. In additional embodiments, the method extends or prolongs the lifespan (survival) of the subject. In further embodiments, the method improves the quality of life of the subject.

[0446] In one embodiment, administration of an immunotherapeutic agent in combination therapy with a crystalline form or crystalline salt form of Compound 1 results in a clinically relevant improvement in one or more markers of disease state and progression selected from one or more of the following: (i) overall survival, (ii) progression-free survival, (iii) overall response rate, (iv) reduction in metastatic disease, (v) circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA19.9) and other tumor-dependent antigens such as carcinoembryonic antigen (CEA), (vii) nutritional status (weight, appetite, serum albumin), (viii) pain control or use of analgesics, and (ix) CRP / albumin ratio.

[0447] Treatment with the crystalline form or crystalline salt form of Compound 1 in combination with an immunotherapeutic agent results in more complex immunity involving not only the development of innate and type 1 immunity, but also immune modulation to more efficiently restore proper immune function.

[0448] In various exemplary methods, the checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecific, or multivalent antibody / fusion protein / construct that binds to immune cells) directed to the checkpoint molecule of interest (e.g., PD-1) may be sequenced, and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment may be maintained in a vector in a host cell, which may then be propagated and frozen for future use. The production of recombinant monoclonal antibodies in cell culture may be carried out through cloning of antibody genes from B cells by means known in the art. See, for example, Tiller et al., 2008, J. Immunol. Methods 329:112; US Pat. No. 7,314,622.

[0449] Pharmaceutical compositions containing the crystalline or crystalline salt forms of Compound 1 according to the present disclosure will generally contain an effective amount of the crystalline or crystalline salt form of Compound 1, an immunotherapeutic agent, and / or both dispersed in a pharma- ceutically acceptable excipient. The phrase "pharmaceutical or pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other undesirable reactions when administered to an animal, such as a human, as appropriate. Preparation of pharmaceutical compositions containing the crystalline or crystalline salt forms of Compound 1 is described in Remington's Pharmaceutical Sciences, 21 st In light of the present disclosure, as exemplified in Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006), it is known to those skilled in the art. Furthermore, for animal (e.g., human) administration, preparations should be understood to meet sterility, pyrogenicity, general safety and purity standards. A specific example of a pharmacologically acceptable excipient for combination composition containing crystalline form or crystalline salt form of Compound 1 mixed with immunotherapeutic agent described herein is borate buffer or sterile saline (0.9% NaCl).

[0450] Formulation of immunotherapeutic agents, e.g., immune checkpoint modulator antibodies, used in accordance with the present disclosure, may be carried out by preparing antibodies having the desired purity, as described in Remington's Pharmaceutical Sciences 21. stThe pharmaceutical compositions may be prepared for storage by mixing with any pharma- ceutically acceptable excipient or stabilizer described and exemplified in lyophilized formulations or aqueous solutions and / or suspensions in the form of ... suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or suspensions in the form of lyophilized formulations or Antioxidants include, for example, (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol, and m-cresol), low molecular weight (less than about 10 residues).Other exemplary pharma- ceutically acceptable excipients include polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, such as glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants, such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG).

[0451] In one exemplary embodiment, the pharmaceutical composition may optionally include pharma- ceutically acceptable auxiliary substances (pH adjusters, and buffering and toxicity adjusters, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate) as required to approximate physiological conditions. In some embodiments, the checkpoint inhibitor antibodies or antigen-binding fragments thereof of the present disclosure may be formulated, lyophilized for storage, and reconstituted with a suitable excipient prior to use according to lyophilization and reconstitution techniques known in the art. In one exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof, the composition is formulated as a sterile, preservative-free solution of one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof for intravenous or subcutaneous administration. The formulation may be supplied either as a single-use prefilled pen, as a single-use, e.g., about 1 mL prefilled glass syringe, or as a single-use institutional use vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or antigen-binding fragment thereof is clear and colorless, with a pH in the range of about 6.9 to 5.0, preferably 6.5 to 5.0, and even more preferably about 6.0 to about 5.0. In various embodiments, the formulation containing the pharmaceutical composition may contain about 500 mg to about 10 mg, or about 400 mg to about 20 mg, or about 300 mg to about 30 mg, or about 200 mg to about 50 mg of the checkpoint inhibitor antibody or antigen-binding fragment thereof per mL of solution when reconstituted and administered to a subject. Exemplary injection or infusion excipients include, for example, mannitol, citric acid monohydrate, dibasic sodium phosphate dihydrate, monobasic sodium phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration, for intravenous, intramuscular, intraperitoneal, or subcutaneous administration.

[0452] In another exemplary embodiment, the one or more immunotherapeutic agents, or antigen-binding fragments thereof, are formulated for intravenous or subcutaneous administration as a sterile aqueous solution containing 1-75 mg / mL, or more preferably, about 5-60 mg / mL, or even more preferably, about 10-50 mg / mL, or even more preferably, about 10-40 mg / mL of the antibody, along with sodium acetate, polysorbate 80, and sodium chloride, at a pH in the range of about 5 to 6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / mL of the immunotherapeutic agent, e.g., an immune checkpoint inhibitor antibody or antigen-binding fragment thereof, along with 20 mM sodium acetate, 0.2 mg / mL polysorbate 80, and 140 mM sodium chloride, at pH 5.5. Additionally, the solution containing the checkpoint inhibitor antibody or antigen-binding fragment thereof may contain, among many other compounds, histidine, mannitol, sucrose, trehalose, glycine, poly(ethylene glycol) glycol, EDTA, methionine, and any combination thereof, as well as many other compounds known in the relevant art.

[0453] In one embodiment, the pharmaceutical composition of the present disclosure comprises the following components: 5-500 mg of the immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80 at pH 5.8, together with a crystalline form or crystalline salt form of Compound 1. The composition may be provided as a lyophilized powder. When the powder is reconstituted in full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted in half volume, in which case the composition comprises 10-500 mg of the immunotherapeutic agent or antigen-binding fragment thereof of the present disclosure, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80 at pH 5.8.

[0454] In one embodiment, a portion of the dose is administered by intravenous bolus and the remainder is administered by infusion of the immunotherapeutic formulation. For example, an intravenous injection of about 0.001 to about 200 mg / kg, e.g., about 0.001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 50 mg / kg, or about 0.001 mg / kg to about 10 mg / kg of the immunotherapeutic agent or antigen-binding fragment thereof may be given as a bolus, and the remainder of the antibody dose may be administered by intravenous injection. A given dose of the immunotherapeutic agent or antigen-binding fragment thereof may be administered over a period of, for example, 1 hour to 2 hours to 5 hours.

[0455] In further embodiments, a portion of the dose is administered by subcutaneous injection and / or injection in the form of a bolus, and the remainder is administered by injection of the immunotherapeutic formulation. In some exemplary doses, the immunotherapeutic formulation can be administered subcutaneously at a dose ranging from about 0.001 to about 200 mg / kg, e.g., about 0.001 mg / kg to about 100 mg / kg, or about 0.001 mg / kg to about 50 mg / kg, or about 0.001 mg / kg to about 10 mg / kg intravenous injection of the immunotherapeutic agent or antigen-binding fragment thereof. In some embodiments, the dose may be given as a bolus, and the remainder of the immunotherapeutic dose may be administered by subcutaneous or intravenous injection. A given dose of the immunotherapeutic agent or antigen-binding fragment thereof may be administered over a period of, for example, 1 hour to 2 hours to 5 hours.

[0456] The formulations herein may also contain more than one active compound, preferably compounds with complementary activities that do not adversely affect each other, as necessary for the particular indication being treated. For example, it may be desirable to provide one or more immunotherapeutic agents with other specificities. Alternatively, or in addition, the compositions may include anti-inflammatory agents, chemotherapeutic agents, cytotoxic agents, cytokines, growth inhibitory agents, and / or small molecule antagonists. Such molecules are preferably present in combination in amounts effective for the intended purpose.

[0457] Formulations to be used for in vivo administration should be sterile or nearly sterile, which is readily accomplished by filtration through sterile filtration membranes.

[0458] In various embodiments, the exemplary formulations of pharmaceutical compositions described herein can be prepared using methods that are generally known in the field of pharmaceutical formulations.In general, such preparation methods can include the step of combining active ingredient with excipient or one or more other auxiliary ingredients, and then packaging the product into desired single or multiple dosage units, if desired.

[0459] In some embodiments, compositions comprising a crystalline form or a crystalline salt form of Compound 1 may also be delivered in vesicles, and immunotherapeutic agents may be delivered in the same liposomal formulation or in a separate formulation that is compatible with the liposomal formulation comprising the crystalline form or a crystalline salt form of Compound 1. In some illustrative examples, liposomes containing one or more liposomal surface moieties, such as polyethylene glycol, antibodies and antibody fragments thereof that target desired tumor surface antigens, receptors, growth factors, glycoproteins, glycolipids, or neoantigens that are selectively transported to specific cells or organs, thus enhancing targeted drug delivery.

[0460] In another embodiment, the crystalline form or crystalline salt form of Compound 1 can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in LIPOSOMES IN THERAPY OF INFECTIUS DISEASE AND CANCER, Lopez-Berestein and Fidler (eds.), Liss, NY, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

[0461] In yet another embodiment, a composition containing a crystalline form or crystalline salt form of Compound 1, or a combination thereof, or a composition containing an immunotherapeutic agent can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, the controlled release of the crystalline form or crystalline salt form of Compound 1 may include polymeric materials that provide sustained, intermediate, pulsatile, or alternative release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); also see Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Macromol. Sci. Rev. 20:19 (1989)). al., J. Neurosurg. 71:105 (1989). Other controlled release systems, discussed in review by Langer, Science 249:1527-1533 (1990), may also be used.

[0462] The optimal concentration of the active ingredient(s) in the selected vehicle can be determined empirically according to procedures well known to those skilled in the art and will depend on the final pharmaceutical formulation desired and the application for which it is to be used.

[0463] The present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the components of the pharmaceutical composition of the present disclosure, which at a minimum includes a crystalline form or crystalline salt form of Compound 1 and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof described herein. In other embodiments, the kit may include one or more additional containers providing a pharma-ceutically acceptable excipient, e.g., a diluent. In one embodiment, the kit may include at least one container, which may include a crystalline form or crystalline salt form of Compound 1 and a checkpoint inhibitor antibody or antigen-binding fragment thereof of the present disclosure. The kit may also include a set of instructions for preparing and administering to a subject in need thereof a final pharmaceutical composition for the treatment of a disease or disorder mediated by a checkpoint molecule.

[0464] In some embodiments of the present disclosure, the immunotherapeutic agent is a population of immune cells, which may be administered in combination with a crystalline or crystalline salt form of Compound 1 to treat a subject with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as white blood cells (nucleated white blood cells), that contain (e.g., express) a receptor that binds to an antigen of interest. The white blood cells of the present disclosure may be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the white blood cells are lymphocytes. Examples of lymphocytes include T cells, B cells, natural killer (NK) cells, or NKT cells. In some embodiments, the T cells are CD4+Th (T helper) cells, CD8+ cytotoxic T cells, γδT cells, or regulatory (suppressor) T cells. In some embodiments, the immune cells are dendritic cells.

[0465] The immune cells of the present disclosure are, in some embodiments, genetically engineered to express an antigen-binding receptor. A cell is considered to be "engineered" if it contains an engineered (exogenous) nucleic acid. The engineered nucleic acid of the present disclosure may be introduced into a cell by any known (e.g., conventional) method. For example, engineered nucleic acids can be introduced into cells by electroporation (see, e.g., Heiser WC Transscription Factor Protocols: Methods in Molecular Biology.TM. 2000;130:117-134), chemical (e.g., calcium phosphate or lipid) transfection (see, e.g., Lewis WH, et al., Sotic Cell Genet. 1980 May;6(3):333-47; Chen C., et al., Mol Cell Biol. 1987 August;7(8):2745-2752), fusion with bacterial protoplasts containing the recombinant plasmid (see, e.g., Schaffner W. Proc Natl Acad Sci USA. 1980 April;77(4):2163-7), direct microinjection of purified DNA into the nucleus of a cell (see, e.g., Capecchi MR Cell. 1980 November;22(2Pt2):479-88), or by retroviral transduction.

[0466] Some aspects of the present disclosure provide an "adoptive cell" approach, which involves isolating immune cells (e.g., T cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express an antigen-binding receptor such as a chimeric antigen receptor), expanding the cells ex vivo, and then reintroducing the immune cells into the subject. This method results in many more engineered immune cells in the subject than can be achieved by traditional gene delivery and vaccination methods. In some embodiments, the immune cells are isolated from the subject, expanded ex vivo without genetic modification, and then reintroduced into the subject.

[0467] The immune cells of the present disclosure comprise a receptor that binds to an antigen, such as an antigen encoded by an exogenously delivered nucleic acid, as provided herein. In some embodiments, the white blood cells are modified (e.g., genetically modified) to express a receptor that binds to the antigen. The receptor may be, in some embodiments, a naturally occurring antigen receptor (normally expressed on immune cells), a recombinant antigen receptor (not normally expressed on immune cells), or a chimeric antigen receptor (CAR). Naturally occurring and recombinant antigen receptors encompassed by the present disclosure include T cell receptors, B cell receptors, NK cell receptors, NKT cell receptors, and dendritic cell receptors. "Chimeric antigen receptor" refers to an artificial immune cell receptor engineered to recognize and bind to an antigen expressed by a tumor cell. Generally, CARs are engineered for T cells and are chimeras of the signaling domain of the T cell receptor (TcR) complex and an antigen recognition domain (e.g., a single chain fragment (scFv) of an antibody) (Enbland et al., Human Gene Therapy. 2015;26(8):498-505), the disclosures of which are incorporated herein by reference in their entireties.

[0468] In some embodiments, the antigen-binding receptor is a chimeric antigen receptor (CAR). T cells expressing CARs are referred to as "CAR T cells". CAR T cell receptors, in some embodiments, comprise a signaling domain of a T cell receptor (TcR) complex and an antigen recognition domain (e.g., a single chain fragment (scFv) of an antibody) (Enbland et al., Human Gene Therapy. 2015;26(8):498-505), the disclosures of which are incorporated herein by reference in their entirety.

[0469] There are four generations of CARs, each of which contains different components. First generation CARs link an antibody-derived scFv to the CD3 zeta (zeta or Z) intracellular signaling domain of the T cell receptor via a hinge and transmembrane domain. Second generation CARs incorporate additional domains, such as CD28, 4-1BB (41BB), or ICOS, to provide a costimulatory signal. Third generation CARs contain two costimulatory domains fused to the CD3 zeta chain of the TcR. Third generation costimulatory domains can include, for example, a combination of CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. A CAR, in some embodiments, comprises an ectodomain (e.g., CD3), a hinge, a transmembrane domain, and one (first generation), two (second generation), or three (third generation) endodomains (derived from CD3Z and / or costimulatory molecules), typically derived from a single chain variable fragment (scFv) (Maude et al., Blood. 2015; 125(26):4017-4023; Karkla and Gottschalk, Cancer J. 2014; 20(2):151-155, the disclosures of which are incorporated herein by reference in their entirety).

[0470] In some embodiments, the chimeric antigen receptor (CAR) is a T-cell redirected for universal cytokine killing (TRUCK), also known as the fourth generation CAR. TRUCK is a CAR-redirected T cell used as a vehicle to produce and release transgenic cytokines that accumulate in target tissues, such as target tumor tissues. The transgenic cytokines are released upon target CAR binding. TRUCK cells can deposit various therapeutic cytokines at the target. This can provide therapeutic concentrations at the target site and avoid systemic toxicity.

[0471] CARs usually differ in their functional properties. When engaged, the signaling domain of the CD3ζ T cell receptor activates and induces T cell proliferation, but can lead to anergy (lack of response by the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolerance). Lymphocytes are considered anergic when they are unable to respond to a specific antigen. The addition of a costimulatory domain in second generation CARs improved the replicative capacity and persistence of engineered T cells. Similar antitumor effects are observed in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies suggest that 4-1BB CARs may result in superior proliferation and / or persistence. Clinical trials suggest that both of these second generation CARs can induce substantial T cell proliferation in vivo, but CARs containing the 4-1BB costimulatory domain appear to persist even longer. Third generation CARs combine multiple signaling domains (costimulation) to enhance efficacy. Fourth generation CARs are further engineered with constitutive or inducible expression cassettes of transgenic cytokines that are released by the CAR T cells to modulate T cell responses. See, e.g., Enblad et al., Human Gene Therapy. 2015; 26(8):498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8):1145-1154, the disclosures of which are incorporated herein by reference in their entireties.

[0472] In some embodiments, an exemplary immunotherapeutic agent is a first generation chimeric antigen receptor CAR. In some embodiments, the chimeric antigen receptor is a second generation CAR. In some embodiments, the chimeric antigen receptor is a third generation CAR. In some embodiments, the chimeric antigen receptor is a fourth generation CAR or a T-cell redirected for universal cytokine killing (TRUCK).

[0473] In some embodiments, a chimeric antigen receptor (CAR) comprises an extracellular domain, which comprises an antigen-binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, the CAR is fully human. In some embodiments, the antigen-binding domain of the CAR is specific for one or more antigens. In some embodiments, a "spacer" domain or "hinge" domain is located between the extracellular domain (including the antigen-binding domain) and the transmembrane domain of the CAR, or between the cytoplasmic domain and the transmembrane domain of the CAR. "Spacer domain" refers to any oligopeptide or polypeptide that functions to link a transmembrane domain to an extracellular domain and / or a cytoplasmic domain in a polypeptide chain. "Hinge domain" refers to any oligopeptide or polypeptide that functions to provide flexibility to the CAR or a domain thereof, or to prevent steric hindrance of the CAR or a domain thereof. In some embodiments, a spacer domain or hinge domain may comprise up to 300 amino acids (e.g., 10-100 amino acids, or 5-20 amino acids). In some embodiments, one or more spacer domain(s) may be included in other regions of the CAR.

[0474] In some embodiments, the CARs of the present disclosure comprise an antigen binding domain, such as a single chain Fv (scFv), specific for a tumor antigen. The choice of binding domain depends on the type and number of ligands that define the surface of the target cell. For example, the antigen binding domain may be selected to recognize a ligand that serves as a cell surface marker on the target cell associated with a particular disease state, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that can act as ligands for the antigen binding domain in the CARs of the present disclosure include markers associated with cancer cells and / or other forms of diseased cells. In some embodiments, the CARs are engineered to target a tumor antigen of interest by engineering a desired antigen binding domain that specifically binds to an antigen on tumor cells encoded by an engineered nucleic acid, as provided herein.

[0475] An antigen-binding domain (e.g., scFv) that "specifically binds" to a target or epitope is a term understood in the art, and methods for determining such specific binding are also known in the art. A molecule is said to exhibit "specific binding" if it reacts or associates with a particular target antigen more frequently, more rapidly, with a longer duration and / or with a higher affinity than it does with alternative targets. An antigen-binding domain (e.g., scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. Thus, "specific binding" does not necessarily require (although it can include) exclusive binding.

[0476] In some embodiments, immune cells expressing CARs are genetically engineered to recognize multiple targets or antigens, allowing for the recognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind multiple targets include "split-signal CARs" that restrict complete immune cell activation to tumors expressing multiple antigens; "tandem CARs" (TanCARs) (comprising an ectodomain with two scFvs); and "universal ectodomain CARs" (incorporating avidin or fluorescein isothiocyanate (FITC)-specific scFvs to recognize tumor cells incubated with tagged monoclonal antibodies (Mabs)).

[0477] A CAR is considered "bispecific" if it recognizes two different antigens (has two different antigen recognition domains). In some embodiments, a bispecific CAR is composed of two separate antigen recognition domains that are in tandem on a single transgenic receptor (called TanCAR; see, for example, Grada Z et al. Molecular Therapy Nucleic Acids 2013;2:e105, which is incorporated by reference in its entirety). Thus, in some embodiments, the method includes delivering a combination comprising a crystalline form or a crystalline salt form of Compound 1 and an immunotherapeutic agent to a tumor, where the immunotherapeutic agent is an engineered nucleic acid that encodes an antigen or an engineered nucleic acid that induces the expression of an autoantigen, and delivering to the tumor an immune cell expressing a bispecific CAR that binds to two antigens, one of which is encoded by the engineered nucleic acid.

[0478] In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR), which can be used, for example, to avoid extratumoral toxicity (Fedorov, VD et al. Sci. Transl. Med. (published online December 11, 2013), incorporated herein by reference in its entirety). iCARs contain antigen-specific inhibitory receptors, for example, to block non-specific immune suppression that may result from additional tumor target expression. iCARs can be based, for example, on the inhibitory molecules CTLA-4 or PD-1. In some embodiments, these iCARs block T cell responses from T cells that are activated by either their endogenous T cell receptor or the activated CAR. In some embodiments, this inhibitory effect is temporary.

[0479] In some embodiments, CARs may be used in adoptive cell transfer, where immune cells are removed from a subject and modified to express a receptor specific for an antigen, e.g., a tumor-specific antigen. The engineered immune cells that can recognize and kill cancer cells are then reintroduced into the subject (Pule, et al., Cytotherapy. 2003; 5(3): 211-226; Maude et al., Blood. 2015; 125(26): 4017-4023, each of which is incorporated herein by reference in its entirety).

[0480] According to another aspect of the present disclosure, the tumor antigenic component in the vaccine of the present invention is any natural or synthetic tumor-associated protein or peptide, or a combination of tumor-associated proteins and / or peptides or glycoproteins or glycopeptides. In yet another aspect, the antigenic component may be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigenic component consists of a cell lysate derived from tumor tissue removed from the patient being treated. In another aspect, the lysate may be engineered from exosomes derived from tumor tissue or may be synthetic. In yet another aspect, the antigenic component consists of a cell lysate derived from tumor tissue extracted from one or more unrelated individuals or tumor cell lines.

[0481] In various embodiments, exemplary immunotherapeutic agents include one or more cancer vaccines for use in combination with the crystalline or crystalline salt forms of Compound 1. The tumor-associated antigenic components of the vaccines can be produced by any of a variety of well-known techniques. For individual protein components, the antigenic protein is isolated from tumor tissue or tumor cell lines by standard chromatographic means, such as high pressure liquid chromatography or affinity chromatography, or alternatively, it is synthesized by standard recombinant DNA techniques in a suitable expression system, such as E. coli, yeast, or plants. The tumor-associated antigenic protein is then purified from the expression system by standard chromatographic means. For peptide antigenic components, these are generally prepared by standard automated synthesis. Proteins and peptides may be modified by the addition of amino acids, lipids, and other agents to improve incorporation into vaccine delivery systems (such as multilamellar liposomes). For tumor-associated antigenic components derived from the patient's own tumor or tumors from other individuals, or cell lines, tumor tissue, or single cell suspensions derived from tumor tissue, they are typically homogenized in a suitable buffer. Homogenates can also be fractionated, such as by centrifugation, to isolate specific cellular components, such as cell membranes or soluble materials. Tumor forms can be used directly, or tumor-associated antigens can be extracted for incorporation into vaccines using buffers containing low concentrations of suitable agents, such as detergents. An example of a suitable detergent for extracting antigenic proteins from tumor tissues, tumor cells, and tumor cell membranes is diheptanoylphosphatidylcholine. Exosomes derived from tumor tissues or tumor cells, whether autologous or xenogeneic to the patient, can be used for antigenic components for incorporation into vaccines, or as starting forms for the extraction of tumor-associated antigens.

[0482] In some embodiments of the present disclosure, the combination therapy includes a crystalline form or a crystalline salt form of Compound 1 in combination with a cancer vaccine immunotherapeutic agent. In various examples, the cancer vaccine includes at least one tumor-associated antigen, at least one immunostimulatory agent, and optionally at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulatory component in the cancer vaccine of the present disclosure is any Biological Response Modifier (BRM) capable of enhancing the efficacy of the therapeutic cancer vaccine and inducing humoral and cellular immune responses against cancer cells in the patient. In one aspect, the immunostimulatory agent is a cytokine or a combination of cytokines. Examples of such cytokines include interferons such as IFN-γ, interleukins such as IL-2, IL-15 and IL-23, colony stimulating factors such as M-CSF and GM-CSF, and tumor necrosis factor. In another embodiment, the immunostimulatory component of the disclosed cancer vaccine includes one or more adjuvant-type immunostimulatory agents, such as APC Toll-like receptor agonists or costimulatory / cell adhesion membrane proteins, with or without immune stimulatory cytokines. Examples of Toll-like receptor agonists include lipid A and CpG, and costimulatory / adhesion proteins, such as CD80, CD86, ICAM-1.

[0483] In some embodiments, the immune stimulatory agent is selected from the group consisting of IFN-gamma (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or a combination thereof. According to other aspects, the cell-based immunotherapeutic agent is selected from the group consisting of dendritic cells, tumor infiltrating T lymphocytes, chimeric antigen receptor-modified T effector cells directed against the patient's tumor type, B lymphocytes, natural killer cells, myeloid cells, and any other cells of the patient's immune system, or a combination thereof. In one embodiment, the cancer vaccine immunostimulatory agent includes one or more cytokines, such as interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ), one or more Toll-like receptor agonists and / or adjuvants, such as monophosphoryl lipid A, lipid A, muramyl dipeptide (MDP) lipid complexes and double-stranded RNA, or one or more costimulatory membrane proteins and / or cell adhesion proteins, such as CD80, CD86, and ICAM-1, or any combination of the above. In one embodiment, the cancer vaccine includes an immunostimulatory agent that is a cytokine selected from the group consisting of interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ). In another embodiment, the cancer vaccine includes an immunostimulant that is a Toll-like receptor agonist and / or adjuvant selected from the group consisting of monophosphoryl lipid A, lipid A, and muramyl dipeptide (MDP) lipid complexes and double-stranded RNA. In yet another embodiment, the cancer vaccine includes an immunostimulant that is a costimulatory membrane protein and / or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[0484] In various embodiments, the immunotherapeutic agent may comprise a cancer vaccine, which incorporates any tumor antigen that may potentially be used to construct a fusion protein according to the invention, in particular the following: (a) cancer testis antigens, such as NY-ESO-1, SSX2, SCP1, and polypeptides of the RAGE, BAGE, GAGE, and MAGE families, e.g., GAGE-1, GAGE-2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, MAGE-7, MAGE-8, MAGE-9, MAGE-10, MAGE-11, MAGE-12, MAGE-13, MAGE-14, MAGE-15, MAGE-16, MAGE-17, MAGE-18, MAGE-19, MAGE-20, MAGE-21, MAGE-22, MAGE-23, MAGE-24, MAGE-25, MAGE-26, MAGE-27, MAGE-28, MAGE-29, MAGE-30, MAGE-31, MAGE-32, MAGE-33, MAGE-34, MAGE-35, MAGE-36, MAGE-37, MAGE-38, MAGE-39 ... (b) mutant antigens including p53, associated with various solid tumors, such as colorectal, lung, head and neck cancer; p21 / Ras (e.g., associated with melanoma, pancreatic and colorectal cancer); CDK4 (e.g., associated with melanoma); MUM1 (e.g., associated with melanoma); caspase-8 (e.g., associated with head and neck cancer); CIA 0205 (e.g., associated with bladder cancer); HLA-A2-R1701, beta-catenin (e.g., associated with melanoma); TCR (e.g., associated with T-cell non-Hodgkin's lymphoma); BCR-abl (e.g., associated with chronic myeloid leukemia); trioserine isomerase; KIA 0205; CDC-27, and LDLR-FUT; (c) overexpressed antigens, such as galectin 4, associated with colorectal cancer; galectin 9 (e.g., associated with Hodgkin's disease); proteinase 3 (e.g., associated with chronic myeloid leukemia); WT 1 (e.g., associated with various leukemias); carbonic anhydrase (e.g., associated with renal cancer); aldolase A (e.g., associated with lung cancer, etc.); PRAME (e.g., associated with melanoma); HER-2 / neu (e.g., associated with breast, colon, lung, and ovarian cancer); mammaglobin, alpha-fetoprotein (e.g., associated with hepatocellular carcinoma); KSA (e.g., associated with colorectal cancer); gastrin (e.g., associated with pancreatic and gastric cancer, etc.); telomerase catalytic protein, MUC-1 (e.g., associated with breast and ovarian cancer); G-250 (e.g., associated with renal cell carcinoma); p53 (e.g., associated with breast, colon, etc.);and carcinoembryonic antigens (e.g., associated with cancers of the gastrointestinal tract such as breast, lung, and colorectal cancer); (d) common antigens, such as melanoma-melanocyte differentiation antigens, such as Mart-1 / Melan A; gp100; MC1R; melanocyte stimulating hormone receptor; tyrosinase; tyrosinase-related protein-1 / TRP1 and tyrosinase-related protein-2 / TRP2 (e.g., associated with melanoma); (e) prostate-related antigens, such as PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2, associated with prostate cancer; (f) bone immunoglobulin idiotypes (associated with myeloma and B-cell lymphoma). In certain embodiments, the one or more TAAs are selected from the group consisting of pi5, Hom / Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein-Barr virus antigens, EBNA, human papillomavirus (HPV) antigens, such as E6 and E7, Hepatitis B and C virus antigens, human T-cell lymphotropic viral antigens, TSP-180, pl85erbB2, pl 80erbB-3, c-met, mn-23H1, TAG-72-4, CA19-9, CA72-4, CAM17.1, NuMa, K-ras, pi 6, TAGE, PSCA, CT7, 43-9F, 5T4, 791Tgp72, beta-HCG, BCA225, BTAA, CA125, CA15-3 (CA 27.29￥BCAA), CA195, CA242, CA-50, CAM43, CD68￥KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB / 70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 associated protein / cyclophilin C binding protein), TAAL6, TAG72, TLP, TPS, or any combination thereof;

[0485] In some embodiments, the present disclosure provides a crystalline form or a crystalline salt form of Compound 1 for use in combination with a cancer vaccine, which may include a tumor antigen comprising the entire amino acid sequence, a portion thereof, or a specific immunogenic epitope of a human protein.

[0486] In various embodiments, an exemplary immunotherapeutic agent may comprise an mRNA operable to encode any one or more of the aforementioned cancer antigens useful for synthesizing a cancer vaccine. In some exemplary embodiments, the mRNA-based cancer vaccine may have one or more of the following properties: a) the mRNA encoding each cancer antigen is interspersed with cleavage prone sites; b) the mRNA encoding each cancer antigen is directly linked to each other without a linker; c) the mRNA encoding each cancer antigen is linked to each other with a mononucleotide linker; d) each cancer antigen comprises 20-40 amino acids and contains a centrally located SNP mutation; e) at least 40% of the cancer antigens have a highest affinity for class I MHC molecules from the subject; f) at least 40% of the cancer antigens have a highest affinity for class II MHC molecules from the subject; g) at least 40% of the cancer antigens have a predicted binding affinity for HLA-A, HLA-B, and / or DRB1 of IC>500 nM; h) the mRNA encodes 1-15 cancer antigens; i) 10-60% of the cancer antigens have binding affinity for class I MHC and 10-60% of the cancer antigens have binding affinity for class II MHC. has binding affinity for MHC; and / or j) the mRNA encoding the cancer antigen is arranged such that the cancer antigen is ordered to minimize epitope splicing.

[0487] In various embodiments, the combination comprising the crystalline form or crystalline salt form of Compound 1 and the cancer vaccine immunotherapeutic agent as disclosed herein can be used to induce an immune response in a subject against a cancer antigen. The method comprises administering to a subject an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or its immunogenic fragment in combination with administration of the crystalline form or crystalline salt form of Compound 1 in either the same composition or separate compositions, administered simultaneously or sequentially, thereby inducing an immune response specific to the antigenic polypeptide or immunogenic fragment in the subject, wherein the anti-antigenic polypeptide antibody titer of the subject is increased after vaccination compared to the anti-antigenic polypeptide antibody titer in a subject vaccinated with a conventional vaccine at a prophylactically effective dose against cancer. An "anti-antigenic polypeptide antibody" is a serum antibody that specifically binds to an antigenic polypeptide.

[0488] A prophylactically effective dose is a therapeutically effective dose that prevents the progression of cancer at a clinically acceptable level. In some embodiments, a therapeutically effective dose is a dose described in the package insert of the vaccine. As used herein, a conventional vaccine refers to a vaccine other than the mRNA vaccine of the present invention. For example, a conventional vaccine includes, but is not limited to, a live microbial vaccine, a killed microbial vaccine, a subunit vaccine, a protein antigen vaccine, a DNA vaccine, and the like. In an exemplary embodiment, a conventional vaccine is a vaccine that has achieved regulatory approval and / or is registered by a national drug regulatory agency, such as the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA).

[0489] In some embodiments, the anti-antigenic polypeptide antibody titer in the subject increases by 1 log to 10 logs after vaccination compared to the anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer. In some embodiments, the anti-antigenic polypeptide antibody titer in the subject increases by 1 log after vaccination compared to the anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer. In some embodiments, the anti-antigenic polypeptide antibody titer in the subject increases by 2 logs after vaccination compared to the anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer.

[0490] Aspects of the present invention provide a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, the RNA polynucleotide being in a formulation for in vivo administration to a host, thereby conferring an antibody titer superior to the standard for seroprotection of the first antigen to an acceptable proportion of human subjects. In some embodiments, the antibody titer generated by the mRNA vaccine of the present invention is a neutralizing antibody titer. In some embodiments, the neutralizing antibody titer is greater than a protein vaccine. In other embodiments, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is greater than an adjuvanted protein vaccine. In yet other embodiments, the neutralizing antibody titer generated by the mRNA vaccine of the present invention is 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2000-10,0000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. Neutralizing titers are typically expressed as the highest serum dilution required to reduce plaque counts by 50%.

[0491] In preferred aspects, the RNA vaccine immunotherapeutic (e.g., mRNA vaccine) of the present disclosure produces prophylactically and / or therapeutically effective levels, concentrations and / or titers of antigen-specific antibodies in the blood or serum of a vaccinated subject. As defined herein, the term antibody titer refers to the amount of antigen-specific antibodies produced in a subject, e.g., a human subject. In exemplary embodiments, the antibody titer is expressed as the reciprocal of the highest dilution (in a serial dilution) that still gives a positive result. In exemplary embodiments, the antibody titer is determined or measured by enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, the antibody titer is determined or measured by a neutralization assay, e.g., a microneutralization assay. In certain aspects, the antibody titer is expressed as a ratio, such as 1:40, 1:100, etc.

[0492] In exemplary embodiments of the present invention, an effective vaccine produces antibody titers of greater than 1:40, greater than 1:100, greater than 1:400, greater than 1:1000, greater than 1:2000, greater than 1:3000, greater than 1:4000, greater than 1:500, greater than 1:6000, greater than 1:7500, greater than 1:10000. In exemplary embodiments, antibody titers are produced or achieved by 10 days after vaccination, by 20 days after vaccination, by 30 days after vaccination, by 40 days after vaccination, or by 50 days or more after vaccination. In exemplary embodiments, titers are produced or achieved after a single dose of vaccine administered to a subject. In other embodiments, titers are produced or achieved after multiple doses, for example, a first and a second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in g / ml or in IU / L (International Units per Liter) or mIU / ml (milli-International Units per ml). In exemplary embodiments of the invention, an effective vaccine produces greater than 0.5 μg / mL, greater than 0.1 μg / mL, greater than 0.2 μg / mL, greater than 0.35 μg / mL, greater than 0.5 μg / mL, greater than 1 μg / mL, greater than 2 μg / mL, greater than 5 μg / mL, or greater than 10 μg / mL. In exemplary embodiments of the invention, an effective vaccine produces greater than 10 mIU / mL, greater than 20 mIU / mL, greater than 50 mIU / mL, greater than 100 mIU / mL, greater than 200 mIU / mL, greater than 500 mIU / ml, or greater than 1000 mIU / ml. In exemplary embodiments, this antibody level or concentration is produced or achieved by 10 days after vaccination, by 20 days after vaccination, by 30 days after vaccination, by 40 days after vaccination, or by 50 days or more after vaccination. In exemplary embodiments, this level or concentration is produced or achieved after a single dose of the vaccine administered to the subject. In other embodiments, this level or concentration is produced or achieved after multiple doses, for example, one and two (e.g., booster doses). In exemplary embodiments, the antibody level or concentration is determined or measured by enzyme-linked immunosorbent assay (ELISA).In exemplary embodiments, the antibody level or concentration is determined or measured by a neutralization assay, for example, a microneutralization assay. Also provided is a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, the RNA polynucleotides having a stabilizing element or formulated with an adjuvant and present in a formulation for in vivo administration to a host to induce high antibodies that last longer than the antibody titers elicited by an mRNA vaccine encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to produce neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from a cationic peptide and an immunostimulatory nucleic acid. In some embodiments, the cationic peptide is protamine.

[0493] An immunotherapeutic agent comprising a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame, which contains at least one chemical modification or optionally no nucleotide modification, wherein the open reading frame encodes a first antigenic polypeptide or a concatemeric polypeptide, and wherein the RNA polynucleotides are present in said formulation for in vivo administration to a host such that the level of antigen expression in the host significantly exceeds the level of antigen expression produced by an mRNA vaccine encoding the first antigenic polypeptide, which has a stabilizing element or is formulated with an adjuvant.

[0494] In other aspects, a nucleic acid vaccine is provided that includes one or more RNA polynucleotides having an open reading frame that includes at least one chemical modification or, optionally, no nucleotide modification, encoding a first antigenic polypeptide or a concatemeric polypeptide, the vaccine having at least 10-fold less RNA polynucleotide than required for an unmodified mRNA vaccine to generate a comparable antibody titer. In some embodiments, the RNA polynucleotide is present in a dose of 25-100 micrograms.

[0495] Aspects of the invention also provide a unit of use vaccine comprising 10 μg to 400 μg of one or more RNA polynucleotides, comprising an open reading frame comprising at least one chemical modification or, optionally, no nucleotide modification, encoding a first antigenic polypeptide or a concatemeric polypeptide, and a pharma- ceutically acceptable excipient, formulated for delivery to a human subject. In some embodiments, the vaccine further comprises a cationic lipid nanoparticle.

[0496] Aspects of the invention provide a method of creating, maintaining, or restoring antigenic memory to a tumor in an individual or a population of individuals, comprising administering to the individual or population an antigenic memory booster nucleic acid vaccine comprising: (a) at least one RNA polynucleotide, the polynucleotide comprising at least one chemical modification or optionally no nucleotide modification, and two or more codon-optimized open reading frames, the open reading frames encoding a set of reference antigenic polypeptides; and (b) optionally a pharmaceutically acceptable excipient. In some embodiments, the vaccine is administered to the individual via a route selected from the group consisting of intramuscular administration, intradermal administration, and subcutaneous administration. In some embodiments, the administering step comprises contacting the subject's muscle tissue with a device suitable for injecting the composition. In some embodiments, the administering step comprises contacting the subject's muscle tissue with a device suitable for injecting the composition in combination with electroporation.

[0497] An embodiment of the invention provides a method of vaccinating a subject, comprising administering to the subject a single dose of 25 μg / kg to 400 μg / kg of a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, or a concatemeric polypeptide, in an amount effective to vaccinate the subject.

[0498] In another aspect, a nucleic acid vaccine is provided that includes one or more RNA polynucleotides having an open reading frame that includes at least one chemical modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, the vaccine having at least 10-fold less RNA polynucleotide than required for an unmodified mRNA vaccine to generate a comparable antibody titer. In some embodiments, the RNA polynucleotide is present in a dose of 25-100 micrograms.

[0499] In some embodiments, the crystalline or crystalline salt forms of Compound 1 may be used in combination with bispecific antibody immunotherapeutics. The bispecific antibody may comprise a protein construct having a first antigen-binding moiety and a second antigen-binding moiety that binds to cytotoxic immune cells. The first antigen-binding moiety may bind to a tumor antigen that is specifically treated with the combination of the present invention. For example, the first antigen-binding moiety may bind to non-limiting examples of tumor antigens selected from, among others, EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folate binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and tenascin. In some embodiments, the first antigen-binding moiety has specificity for a protein or peptide that is overexpressed on tumor cells compared to corresponding non-tumor cells. In some embodiments, the first antigen-binding moiety has specificity for a protein that is overexpressed on tumor cells compared to corresponding non-tumor cells. As used herein, "corresponding non-tumor cells" refers to non-tumor cells that are of the same cell type as the origin of the tumor cells. Note that such proteins are not necessarily different from tumor antigens.Non-limiting examples include carcinoembryonic antigen (CEA) (overexpressed in most colon, rectal, breast, lung, pancreatic, and gastrointestinal cancers); heregulin receptor (HER-2, neu, or c-erbB-2) (frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers); epidermal growth factor receptor (EGFR) (highly expressed in a range of solid tumors including those of the breast, head and neck, non-small cell lung, and prostate); asialoglycoprotein receptor; transferrin receptor; serpin enzyme complex receptor (expressed in hepatocytes); fibroblast growth factor receptor (FGFR) (overexpressed in pancreatic ductal adenocarcinoma cells); vascular endothelial growth factor receptor (VEGFR) for anti-angiogenic gene therapy; folate receptor (selectively overexpressed in 90% of non-mucinous ovarian cancers); cell surface glycosylation; carbohydrate receptor; and polymeric immunoglobulin receptor.

[0500] The second antigen-binding moiety is any molecule that specifically binds to an antigen or protein or polypeptide expressed on the surface of a cytotoxic immune cell (CIK cell). Exemplary non-limiting antigens expressed on the surface of cytotoxic immune cells suitable for use in the present disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptors, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In some embodiments, the second antigen binding moiety binds to CD3 of a cytotoxic immune cell, e.g., a CIK cell. In some embodiments, the second antigen binding moiety binds to CD56 of a cytotoxic immune cell. In some embodiments, the second antigen binding moiety binds to an Fc receptor of a cytotoxic immune cell. In some embodiments, the Fc region of a bispecific antibody binds to an Fc receptor of a cytotoxic immune cell. In some embodiments, the second antigen binding moiety is any molecule that specifically binds to an antigen expressed on the surface of a cytotoxic immune cell (e.g., a CIK cell). The second antigen binding moiety is specific for an antigen on a cytotoxic immune cell. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells. The second antigen binding moiety specifically binds to an antigen expressed on the surface of a cytotoxic immune cell.Exemplary non-limiting antigens expressed on the surface of cytotoxic immune cells suitable for modification in the present disclosure may include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, Fc receptors, LFA, LFA-1, TCRαβ, CCR7, macrophage inflammatory protein 1a, perforin, PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27, and Fas ligand. In other embodiments, the bispecific antibody modulator is an activator of a costimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule against OX40 and another tumor antigen or costimulatory antigen. The OX40 agonist may be administered alone or in combination with other immunomodulatory agents, for example, in combination with inhibitors (e.g., antibody constructs) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3 or LAG-3. In some embodiments, the anti-OX40 antibody molecule is a bispecific antibody that binds GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and / or -5), TIM-3 or LAG-3. In an exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., an anti-PD-1 molecule as described herein). The OX40 antibody molecule and the anti-PD-1 antibody molecule may be in the form of separate antibody compositions or as a bispecific antibody molecule.In other embodiments, the OX40 agonist may be administered in combination with an agonist of another costimulatory molecule, such as GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand. In some embodiments, the second antigen-binding moiety binds to an Fc receptor on a cytotoxic immune cell, such as a CIK cell.

[0501] In some embodiments, the bispecific antibody immunotherapeutic agent has specificity for a tumor antigen and a CIK cell, which brings the tumor antigen-expressing tumor cells into close proximity to the CIK cells, leading to the elimination of the tumor cells via the anti-tumor cytotoxicity of the CIK cells. In some embodiments, the bispecific antibody has specificity for a tumor antigen but not for a CIK cell, but the Fc region of the bispecific antibody can bind to an Fc receptor of the CIK cell, which brings the tumor cells into close proximity to the CIK cells, leading to the elimination of the tumor cells via the anti-tumor cytotoxicity of the CIK cells. In some embodiments, the bispecific antibody has specificity for a CIK cell but not for a tumor cell, but the Fc region of the bispecific antibody can bind to an Fc receptor of the tumor cell, which brings the tumor cells into close proximity to the CIK cells, leading to the elimination of the tumor cells via the anti-tumor cytotoxicity of the CIK cells.

[0502] In some embodiments, the crystalline or crystalline salt forms of Compound 1 may be used in combination with immunotherapeutic agents that are multivalent antibodies / fusion proteins / constructs that engage immune cells. In various embodiments, exemplary immunotherapeutic agents may include multivalent antibodies / fusion proteins / constructs that engage immune cells, which may include recombinant structures, e.g., all engineered antibodies that do not mimic the original IgG structure. Here, various strategies are utilized to multimerize antibody fragments. For example, scFvs are self-associated into dimers (diabodies; 55 kDa) by shortening the peptide linker between the V domains. Bispecific diabodies are formed by non-covalent binding of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This leads to the formation of heterodimers with two different binding sites. Single chain diabodies (sc diabodies) are bispecific molecules in which the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandem diabodies (Tandabs) are tetravalent bispecific antibodies generated by two sc diabodies.

[0503] Also included are di-diabodies, known in the art. This 130 kDa molecule is formed by fusing the diabody to the N-terminus of the CH3 domain of IgG, resulting in an IgG-like structure. Further diabody derivatives are triabodies and tetrabodies, which fold into trimeric and tetrameric fragments by shortening the linker to less than 5 or 0-2 residues. Exemplary are also the (scFv) known as "bispecific T cell engagers" (BITEs). 2BITE is a bispecific single chain antibody consisting of two scFv antibody fragments linked via a flexible linker that is directed to a surface antigen on target cells and CD3 on T cells. Bivalent (Fab)2 and trivalent (Fab)3 antibody formats are also exemplified. Also exemplified are minibodies and trimeric bodies generated from scFv. Exemplary constructs useful for targeting tumor antigens may include one or more of diabodies, single chain (sc)-diabodies (scFv)2, minibodies, minibodies, barnase-burster, scFv-Fc, sc(Fab)2, trimeric antibody constructs, triabody antibody constructs, trimeric body antibody constructs, tribody antibody constructs, collaborating antibody constructs, (scFv-TNFa)3, F(ab)3 / DNL. Exemplary cytotoxic immune cells include, but are not limited to, CIK cells, T cells, CD8+ T cells, activated T cells, monocytes, natural killer (NK) cells, NK T cells, lymphokine-activated killer (LAK) cells, macrophages, and dendritic cells.

[0504] In some embodiments, the crystalline forms or crystalline salt forms of Compound 1 may be used in combination with radioconjugate immunotherapeutic agents.

[0505] In various embodiments, a radioconjugate is a small or large molecule (herein referred to as a "cellular targeting agent"), such as a polypeptide, antibody, or antibody fragment thereof, that is conjugated or otherwise attached to a radionuclide, or multiple radionuclides, such that binding of the radioconjugate to its target (a protein or molecule on or in a cancer cell) results in the death or morbidity of the cancer cell. In various embodiments, the radioconjugate may be a cellular targeting agent labeled with a radionuclide, or the cellular targeting agent may be conjugated or otherwise immobilized to a particle, or microparticle, or nanoparticle, that contains multiple radionuclides, where the radionuclides are the same or different. Methods for synthesizing radioconjugates are known in the art and may include classes of immunoglobulins, or antigen-binding portions thereof, that are conjugated to toxic radionuclides.

[0506] In some embodiments, molecules that bind to cancer cells may be known as "cell targeting agents". As used herein, exemplary cell targeting agents may enable drug-containing nanoparticles or radionuclides to target specific types of cells of interest. Examples of cell targeting agents include, but are not limited to, small molecules (e.g., folic acid, adenosine, purine) and macromolecules (e.g., peptides or antibodies) that bind to or target tumor-associated antigens. Examples of tumor-associated antigens include, but are not limited to, adenosine receptor, alpha v beta 3, aminopeptidase P, alpha fetoprotein, cancer antigen 125, carcinoembryonic antigen, ccavelin-1, chemokine receptor, clusterin, carcinoembryonic antigen, CD20, epithelial tumor antigen, melanoma-associated antigen, Ras, p53, Her2 / Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate-specific antigen, purinergic receptor, radiation-induced cell surface receptor, serpin B3, serpin B4, squamous cell carcinoma antigen, thrombospondin, tumor antigen 4, tumor-associated glycoprotein 72, thiocinase, and tyrosine kinase. In some embodiments, the cell targeting agent is folic acid or a folic acid derivative that specifically binds to the folate receptor (FR). In some embodiments, the cell targeting agent is an antibody, bispecific antibody, trispecific antibody, or antigen-binding construct thereof that specifically binds to a cancer antigen selected from, inter alia, EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, mucin, TAG-72, CIX, PSMA, folate binding protein, GD2, GD3, GM2, VEGF, VEGFR, integrin αVβ3, integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, and Tenascin.

[0507] By using folic acid as a targeting agent in radioconjugates, both tumor cells and regulatory T (Treg) cells can also be targeted for destruction. It is widely accepted that large numbers of Treg cells suppress tumor immunity. Specifically, Treg cells suppress reactive T cells (foreign and autologous) without killing them through contact-dependent or cytokine (e.g., IL-10, TGF-β, etc.) secretion. FR4 is selectively upregulated in Treg cells. It has been shown that antibody blockade of FR4 depleted Treg cells and induced tumor immunity in tumor-bearing mice. Thus, folic acid-coated PBM nanoparticles carrying cytotoxic agents target FR-expressing cells for their destruction and inhibit tumor progression both directly (i.e., BrCa cells) and indirectly (i.e., breast tumor-associated and peripheral Treg cells).

[0508] In another further embodiment, the targeting agent is an antibody or peptide, or a multivalent antibody / fusion protein / construct that engages immune cells, which may bind to tumor associated antigens consisting of, but not limited to, adenosine receptor, alpha v beta 3, aminopeptidase P, alpha fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptor, clusterin, carcinoembryonic antigen, CD20, human growth factor receptor (HGFR), epithelial tumor antigen, melanoma associated antigen, MUC1, Ras, p53, Her2 / Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate specific membrane antigen, prostate specific antigen, purinergic receptor, radiation induced cell surface receptor, serpin B3, serpin B4, squamous cell carcinoma antigen, thrombospondin, tumor antigen 4, tumor associated glycoprotein 72, tyrosinase, tyrosine kinase, and the like.

[0509] In some embodiments, the crystalline or crystalline salt forms of Compound 1 described herein can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, the crystalline or crystalline salt forms of Compound 1 described herein can be used in combination with immunotherapeutic agents, such as vaccines. In various embodiments, exemplary vaccines include those used to stimulate immune responses against cancer antigens.

[0510] The amounts of both the crystalline form or crystalline salt form of Compound 1 disclosed herein and the additional one or more additional therapeutic agents (in compositions containing additional therapeutic agents as described above) that may be combined with excipient materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. In certain embodiments, the compositions of the invention are formulated to allow administration of a dosage of 0.01 to 100 mg / kg body weight / day of the compositions of the invention.

[0511] The additional therapeutic agent and the crystalline or crystalline salt form of Compound 1 disclosed herein may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or even lower doses may be used with fewer side effects for the patient. In certain embodiments, such compositions may be administered at a dosage of 0.01-10,000 μg / kg body weight / day of the additional therapeutic agent.

[0512] In some embodiments, the crystalline forms or crystalline salt forms of Compound 1 disclosed herein may be combined with inhibitors of one or more of the following kinases for the treatment of diseases disclosed herein, such as cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, 1NS-R, IGF-1R, IR-R, PDGFαR, PDGFαR, PDGFβ ... β / R, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYR, FRK, JAK, ABL, ALK, CDK7, CDK12, CDK13, KRAS, and B-Raf. In some embodiments, the crystalline or salt forms of Compound 1 disclosed herein may be combined with one or more inhibitors of CD47 and MALT1 proteins for the treatment of cancer.

[0513] In some embodiments, the crystalline forms or crystalline salt forms of Compound 1 disclosed herein may be used in combination with one or more poly ADP ribose polymerase (PARP) inhibitors for the treatment of diseases disclosed herein, such as cancer. Exemplary PARP inhibitors include, but are not limited to, olaparib (Lynparza®), rucaprib (Rubraca®), niraparib (Zejula®), tarzoparib (Talzenna®), and TPST-1120.

[0514] In some embodiments, the crystalline or crystalline salt forms of Compound 1 disclosed herein may be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, zanubrutinib, updacitinib, fedratinib, entrectinib, alpelisib, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ri ... These include nib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, gilter, larotrectinib, lorlatinib, netarsudil, osimertinib, pexidartinib, ribociclib, temsirolimus, XL-147, XL-765, XL-499, and XL-880. In some embodiments, the compounds described herein may be used in combination with an HSP90 inhibitor (e.g., XL888), a Liver X receptor (LXR) modulator, a retinoid-related orphan receptor gamma (RORy) modulator, a CK1 inhibitor, a CKI inhibitor, a Wnt pathway inhibitor (e.g., SST-215), or a mineralocorticoid receptor inhibitor (e.g., esaclenone or XL-550) for the treatment of a disease disclosed herein, such as cancer.

[0515] In some embodiments, the crystalline forms or crystalline salt forms of Compound 1 disclosed herein may be used in combination with polatuzumab vedotin for the treatment of diseases disclosed herein, such as cancer.

[0516] Labeled Compounds and Assay Methods Another aspect relates to labeled crystalline forms or crystalline salt forms (radiolabeled, fluorescently labeled, etc.) of the invention, which are useful not only in imaging techniques but also in both in vivo and ex vivo assays for localizing and quantifying TAM kinase in tissue samples, including humans, and for identifying TAM kinase ligands by inhibitory binding of the labeled compounds. Thus, the invention includes TAM kinase assays containing such labeled compounds.

[0517] The present invention further includes isotopically labeled crystalline forms or crystalline salt forms of the present invention. An "isotopically labeled" or "radiolabeled" compound is a crystalline form or crystalline salt form of the present invention in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the crystalline forms or crystalline salt forms of the present invention include: 2 H (also written as D to indicate deuterium), 3 H (also written as T for tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 The radionuclide incorporated in the present radiolabeled compounds will depend on the particular application of the radiolabeled compound. For example, in vitro metalloprotease labeling and competition assays, 3 H, 14 C. 82 Br, 125 I, 131 I, or35 Compounds incorporating S are generally most useful. For radioimaging applications, 11 C. 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful. In some embodiments, the crystalline forms or crystalline salt forms described herein have one or more hydrogens replaced with deuterium, such as hydrogens attached to carbon atoms. Such compounds have increased resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to a mammal, particularly a human.

[0518] A "radiolabel" or "labeled compound" is understood to be a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S, and 82 Br.

[0519] The present invention may further include synthetic methods for incorporating radioisotopes into the crystalline forms or crystalline salt forms of the present invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods applicable to the compounds of the present invention.

[0520] The labeled compounds of the present invention may be used in screening assays to identify / assess compounds. For example, a newly synthesized or identified compound (i.e., a test compound) that is labeled may be evaluated for its ability to bind to TAM kinase by monitoring its concentration fluctuation when contacting TAM kinase through tracking of the label. For example, a (labeled) test compound may be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) that is known to bind to TAM kinase. Thus, the ability of a test compound to compete with a standard compound for binding to TAM kinase directly correlates with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, to evaluate the competition between a standard compound and a test compound, the concentration of the labeled standard compound is monitored to determine the relative binding affinity of the test compound.

[0521] Preparation and Examples

[0522] General Experimental Techniques

[0523] Aqueous slurry experiments: Compound 1 salts found to have aqueous solubility less than 1 mg / mL were slurried in 20 mL of water at ambient temperature for 1 day. The solids were then collected by vacuum filtration and analyzed by XRPD.

[0524] Crash Cooling (CC): Concentrated solutions of compound 1 and various counterions were prepared in MeOH with stirring at elevated temperature. The capped vial containing the hot solution was transferred to a freezer (approximately -20°C) and rapidly cooled. The solids that formed were collected. If no solids were observed, further crystallization techniques were used.

[0525] Crash Precipitation (CP): Clear solutions of compound 1 and coformer were prepared in various solvents at room temperature. Various aliquots of anti-solvent were slowly added to the solution with gentle stirring until the solids crashed out of solution. The mixtures were allowed to stir for the specified time. The solids formed were collected by positive pressure filtration.

[0526] Fast Cool (FC): Concentrated solutions of compound 1 and various counterions were prepared in acetone or MeOH with stirring at elevated temperature. The capped vial containing the hot solution was transferred to a benchtop at ambient temperature. The solids that formed were collected. If no solids were present, further crystallization techniques were used.

[0527] First Evaporation (FE): Clear solutions of compound 1 and coformers were prepared in various solvents. The vials were left uncapped and the solvent was allowed to evaporate at ambient conditions.

[0528] Interconversion Slurry: A slurry of Form R of Compound 1 was prepared by adding enough solid to a given solvent system at ambient conditions such that residual solid was present. The mixture was then stirred for an extended period of time to achieve saturation. A solid of the desired form was then added to an aliquot of the saturated solution (filtered through a 0.2 μm nylon filter) such that residual solid was present. The mixture was then stirred for an extended period of time at ambient temperature to isolate the solid.

[0529] Isolation Techniques: In general, non-ambient temperature samples were isolated immediately after removal from their respective temperature controllers to minimize equilibration to ambient temperature prior to isolation of the solids.

[0530] Decant Liquid Phase: A portion of the solids isolated by solution-based crystallization techniques was recovered by centrifuging the suspension (if necessary) and discarding the liquid phase, leaving behind the moist solids. Unless otherwise specified herein as "moisture analyzed", the solids were roughly dried (e.g., air-dried or dried under nitrogen).

[0531] Positive Pressure Filtration: Solids were collected onto 0.2 μm nylon or PTFE filters by pressing the slurry through a syringe and Swinnex filter holder assembly. Generally, solids were dried briefly by blowing air through the filter with a 20 mL syringe. Where specified herein as "analyzed wet," solids were left wet with mother liquor. Some samples were briefly dried under a gentle stream of nitrogen gas prior to analysis.

[0532] Vacuum filtration: Solids were collected by vacuum filtration onto a paper or nylon filter and briefly air-dried on the filter under reduced pressure before being transferred to a vial.

[0533] Reaction Crystallization (RC): A mixture of compound 1 and various coformers was combined in a hot acetone slurry such that the molar concentration of the coformer was 2-fold higher than the API. The solution was stirred for a given period of time. When a clear solution was observed, further crystallization techniques were used.

[0534] Stability study: Various salts of Compound 1 were placed in open vials in a 75% RH chamber (saturated sodium chloride solution). The RH chamber was placed in a 40° C. oven for 15-16 days. Samples were analyzed by PLM and XRPD at the end of this time.

[0535] Slow Cooling (SC): Concentrated solutions of compound 1 and various coformers were prepared in various solvents with stirring at elevated temperatures. The vials were capped in a heated sample block, the hot plate was switched off, and the vials were slowly cooled to ambient temperature in a heated vial block. Once the clear solutions had cooled to ambient temperature, they were further cooled in a refrigerator (5-7°C) and / or freezer (approximately -20°C). If no solids were observed, further crystallization techniques were used.

[0536] Slow evaporation: Solutions were prepared with stirring in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Unless otherwise noted, each solution was evaporated at ambient conditions from a covered vial (e.g., loosely capped or covered with aluminum foil with holes). Solutions were evaporated to dryness unless specified as partial evaporation (solids with small amounts of solvent remaining), in which case the solids were isolated as described herein.

[0537] Solubility Estimation: Aliquots of various solvents were added to a measured amount of Compound 1 and stirred (usually sonicated) at the temperature stated until complete dissolution was achieved as judged visually. If dissolution occurred after the addition of the first aliquot, the value is recorded as ">". If dissolution did not occur, the value is recorded as '<'.

[0538] Estimation of water solubility: Aliquots of water were added to measured amounts of various salts of Compound 1 and subjected to sonication.

[0539] Slurry Experiments: Saturated solutions of compound 1 and various coformers were prepared in a variety of solvents and solvent mixtures. The mixtures were stirred at ambient and elevated temperatures for the times noted. Solids were recovered by the techniques described and further crystallization techniques were used as necessary.

[0540] Vacuum Oven Desolvation: Desolvation was attempted with salts of Compound 1 that were determined to be solvates by various analytical methods. Samples were placed in a vacuum oven at temperatures ranging from ambient to 80° C. for a given period of time. Samples were analyzed by XRPD and / or TGA to determine if desolvation was successful.

[0541] Vapor diffusion: Concentrated solutions were prepared in various solvents and filtered, typically through 0.2 μm nylon or PTFE filters. The filtered solutions were dispensed into small vials, which were then placed into a larger vial containing antisolvent. The small vial was left uncapped and the larger vial was capped to allow vapor diffusion to occur. Any solids present were isolated as described herein.

[0542] Steam stress: The selected solid was transferred to a small vial and then placed into a larger vial containing the solvent. The small vial was left uncapped and the larger vial was capped and subjected to steam stress at a defined temperature.

[0543] Coformer means one or more pharma- ceutically acceptable bases and / or pharma-ceutically acceptable acids disclosed herein in conjunction with Compound 1. Examples of coformers as used herein include fumaric acid, HCL, and phosphoric acid.

[0544] Equipment Technology

[0545] Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using adamantane, phenyl salicylate, indium, tin, and zinc. Samples were placed in thermally sealed or open aluminum DSC pans and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The samples were analyzed from -30°C to 250°C at a heating rate of 10°C / min. Thermograms are plotted by reference temperature (x-axis), but results are recorded according to sample temperature.

[0546] Dynamic Vapor Sorption (DVS)

[0547] a.VTI: Dynamic Vapor Sorption (VS) data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and PVP were used as calibration standards. Samples were dried prior to analysis. Sorption and desorption data were collected over a RH range of 5% to 95% in 10% RH increments under a nitrogen purge. The equilibrium criteria used for analysis was less than 0.0100 wt% change within 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0548] b. Specific: Automated water vapor sorption (VS) data were collected on a Surface Measurement System DVS intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a RH range of 5% to 95% in 10% RH increments under a nitrogen purge. The equilibration criteria used for analysis was less than 0.0100 wt.% change within 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0549] Hot Stage Microscopy (HSM): Hot stage microscopy was performed using a Linkam hot stage (FTIR600) mounted on a Leica DM LP microscope equipped with a SPOT Insight™ color digital camera. Temperature calibration was performed using USP melting point standards. Samples were placed on a cover slip and a second cover slip was placed on top of the sample. Each sample was visually observed using a 20x objective with crossed polarizers and a primary red compensator while the stage was heated. Images were taken using SPOT software (v.4.5.9).

[0550] Optical microscopy: Optical microscopy was performed using a Leica MZ12.5 stereo microscope. Samples were observed using a 0.8-10x objective with crossed polarizers and a primary red compensator. Samples were viewed in situ or with a drop of mineral oil.

[0551] Solution proton nuclear magnetic resonance spectroscopy ( 1 HNMR):Solution 1H NMR spectra were obtained by Spectral Data Services (Champaign, IL). Samples were dissolved in DMSO-d 6 Data acquisition parameters are given on the first page of each spectrum in the data section of this report.

[0552] Thermogravimetric Analysis (TGA): Thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using phenyl salicylate, indium, tin, and zinc. Samples were placed in aluminum pans. Open pans were inserted into a TG furnace. The furnace was heated under nitrogen. Each sample was heated from ambient to 350°C at a heating rate of 2, 5, or 10°C / min. Thermograms are plotted by reference temperature (x-axis), but results are recorded according to sample temperature.

[0553] X-ray powder diffraction (XRPD)

[0554] a. Reflection: XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer at room temperature (298 Kelvin) using an incident beam of Cu Kα radiation generated using a long, finely focused source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, silicon specimens (NIST SRM 640e) were analyzed to verify that the observed position of the Si 111 peak matched the NIST certified position. Sample specimens were loaded into wells. Anti-scatter slits (SS) were used to minimize background generated by air. Soller slits were used on the incident and diffracted beams to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample, and Data Collector software v.2.2b. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including divergence slit (DS) and incident beam SS.

[0555] b. Transmission: XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer at room temperature using an incident beam of Cu radiation generated using an Optix long fine focus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak matched the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter extensions, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits were used on the incident and diffracted beams to minimize spread from the axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.2.2b. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including the divergence slit (DS) in front of the mirror.

[0556] XRPD Indexing: Indexing and structure refinement are computational studies. In the figures referenced for a particular indexed XRPD pattern, agreement between the accepted peak positions marked with bars and the observed peaks indicates a consistent unit cell determination. Successful indexing of a pattern indicates that the sample is composed primarily of a single crystalline phase unless otherwise noted. The space group consistent with the assigned annihilation symbols, unit cell parameters, and derived quantities are tabulated.

[0557] 13 C solid state NMR

[0558] Instrumentation information. Solid-state NMR (SSNMR) experiments were performed on a Bruker Avance NEO spectrometer (Bruker, Billerica, MA). 13 100.52MHz for C and 1The NMR spectrum was operated at 399.71 MHz for H. Data were acquired using a RevNMR HX probe equipped with a 7 mm magic angle spinning module (Revolution NMR, Fort Collins, CO).

[0559] Data collection. 13 To limit the C background, samples were packed into 7 mm zirconia rotors using Kel-F® sample spacers. 13 A magic angle spinning (MAS) speed of 5 kHz was used to acquire all the C data. All data collection was performed at a nominal temperature of about 18.5° C. The sweep width of the data collection was about 39.7 kHz.

[0560] Relaxation parameter determination. 13 C Using the observed saturation recovery, 1 HT 1 The relaxation time was measured. 1 HT 1rho Value, 13 C Determined by observation. 1 HT 1 The measurements used a 1 second pulse delay between successive acquisitions. 1 HT 1rho The measurements used a pulse delay of 15 seconds between successive acquisitions. 1 HT 1rho Prior to the measurements, one dummy scan was used.

[0561] 13 C CPTOSS spectrum. Using a cross-polarization total sideband suppression (CPTOSS) sequence and a MAS speed of 5 kHz with a contact time of 1.5 ms. 13 C spectra were signal averaged for 12 h. Data were acquired using one dummy scan prior to acquisition, a contact time of 1.5 ms, and an acquisition time of approximately 50 ms, a pulse delay of 15 s, and 2872 acquisitions.

[0562] 13Compound setup for work on C. 3-Methylglutaric acid (MGA) was used as a calibration standard to ensure the spectrometer was working properly. 13 C chemical shifts are reported relative to the methyl peak of 3-methylglutaric acid at 18.84 ppm with an accuracy of ±0.4 ppm. 3-Methylglutaric acid was purchased from Sigma Aldrich and used as is without further purification.

[0563] Data processing. Data were processed using the Topspin® 4.0.8 (Copyright) software package from Bruker Biospin. The data were analyzed using a full FID (3960 points) with line broadening ( 13 C 0Hz for CPTOSS spectrum; 1 HT 1 and 1 HT 1rho The samples were Fourier transformed, phased (apk) and baseline corrected (abs) using a frequency of 20 Hz for the experiments. Manual phasing was performed if necessary. 1 HT 1 and 1 HT 1rho The T1 guide of the Topspin® software package was used for the measurements. Semi-automated peak picking was used to determine the chemical shifts of the spectra.

[0564] Sample preparation. The samples were received as powdered material and packed directly into a 7 mm rotor without modification. Samples were received, stored, and prepared under ambient conditions.

[0565] 19 F solid state NMR

[0566] Instrumentation information. Solid-state NMR (SSNMR) experiments were performed on a Bruker Avance NEO spectrometer (Bruker, Billerica, MA). 19 375.88MHz and F 1The NMR spectrum was operated at 399.50 MHz for H. A RevNMR HF probe equipped with a 4 mm magic angle spinning module (Revolution NMR, Fort Collins, CO) was used.

[0567] Data collection. 19 Samples were packed into 4 mm zirconia rotors using Vespel® sample spacers to limit F background. Magic angle spinning (MAS) speeds of 12 kHz and 15 kHz were used to identify spinning sidebands from isotropic chemical shifts. All other data were acquired at 15 kHz MAS unless otherwise noted. All data collection was performed at a nominal temperature of approximately 18.5° C. The sweep width of the data collection was approximately 147.1 kHz.

[0568] Relaxation parameter determination. 19 F is calculated using the observed saturation recovery rate. 1 HT 1 and 19 FT 1 The relaxation time was measured. 1 HT 1rho Value, 19 F was determined by observation. 1 HT 1 and 19 FT 1 The measurements used a 1 second pulse delay between successive acquisitions. 1 HT 1rho The measurements used a pulse delay of 10 seconds between successive acquisitions. 1 HT 1rho One dummy scan was used prior to data collection for the measurements.

[0569] 19 F cross polarization (CP) spectrum. High quality 19F spectra were signal averaged for 12 h using a cross-polarization (CP) sequence with a MAS speed of 15 kHz and a contact time of 1.0 ms. One dummy scan prior to acquisition, a contact time of 1 ms, an acquisition time of approximately 10 ms, and a pulse delay of 15 s were used, resulting in 2880 acquisitions with 12 h of signal averaging. 1 An additional spectrum was acquired in a single pulse experiment with 1 H decoupling (HPDEC) using a pulse delay of 10 seconds, 128 acquisitions, and an acquisition time of approximately 50 ms.

[0570] Data processing. Data were processed using the Topspin® 4.0.8 (Copyright) software package from Bruker Biospin. Data were Fourier transformed using full FID (2924 points) and 0 Hz line broadening (CP experiments) or 30 Hz line broadening (HPDEC experiments), phased (apk) and baseline corrected (abs). Manual phasing was performed when necessary. 19 FT 1 , 1 HT 1 , and 1 HT 1rho The T1 guide of the Topspin® software package was used for the measurements. Semi-automated peak picking was used to determine the chemical shifts of the spectra.

[0571] Sample preparation. Samples were received as powdered material and loaded directly into a 4 mm rotor without any modification. Samples were received, stored, and prepared under ambient conditions. EXAMPLES

[0572] Preparation Example 1: Synthesis of Compound 1

[0573] Step 1: N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4): [ka]

[0574] To a solution of compound 2 (10 g, 44.80 mmol, 1 equiv.) and compound 3 (5.87 g, 53.8 mmol, 1.2 equiv.) in dimethylacetamide (DMA) (60 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 equiv.). The mixture was stirred vigorously at 20° C. until the reaction was complete. The mixture was diluted with saturated NaHCO 3 Poured into aqueous Cl (400 mL) and extracted with EtOAc (4x1000 mL). The combined organic phase was washed with saturated NaCl (100 mL) and anhydrous Na 2 SO 4 It was dried over and concentrated to give compound 4 (21 g, crude) (50% purity). 1 H NMR (400MHz, DMSO-d 6 )δ 10.16(br s,1H),9.72(br s,1H),7.61(dd,2H),7.34(d,2H),7.13(t,2H)6.68(d,2H),1.42(s,4H);C 17 H 15 FN 2 O 3 MS(EI) measured value: 314.9(MH+).

[0575] Step 2: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate (6): [ka]

[0576] Compound 4 (5.99g, 9.5mmol, 1.2eq), Compound 5 (2g, 8.0mmol, 1.0eq), Pd(OAc) 2(89 mg, 397.4 μmol, 0.05 equiv.), rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl (TrixiePhos, 316.71 mg, 794.7 μmol, 0.1 equiv.) and K 3 PO 4 A mixture of (2.53 g, 11.9 mmol, 1.5 equiv) in anisole (50 mL) was stirred at 110° C. for 2 hours (h) under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (1:1 petroleum ether:EtOAc to 20:1 EtOAc:MeOH). Compound 6 was obtained (2.6 g, 61.8% yield). 1 H NMR (400 MHz, CDCl 3 )δ 9.38(s,1H),8.80(s,1H),8.63(d,2H),7.64(d,2H),7.54-7.41(m,3H),7.18(d,2H),7.09- 7.01(m,2H),6.43(d,1H),4.05(s,3H),3.97(s,3H),1.78-1.72(m,2H),1.69-1.63(m,2H);C 29 H 24 FN 3 O 6 MS(EI) measured value: 530.0(MH+).

[0577] Step 3: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (7) [ka]

[0578] To a solution of compound 6 (1.8 g, 3.4 mmol, 1 equiv.) in tetrahydrofuran (THF) (15 mL) and MeOH (15 mL) was added 2 M aqueous NaOH (7 mL, 4.1 equiv.). The mixture was stirred at 6-13 °C for 4 h. The mixture was adjusted to pH 8 with 1 M aqueous HCl and concentrated to remove the solvent. Water (50 mL) was added and the mixture was adjusted to pH 6 with 1 M aqueous HCl. The resulting precipitate was filtered, washed with water (2 × 10 mL) and dried under vacuum. Compound 7 was obtained (1.7 g, 97.0% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ 10.22(s,1H),10.08(s,1H),8.65(d,1H),8.48(s,1H),7.77(d,2H),7.64(dd,2H) )7.47(s,1H),7.25(d,2H),7.15(t,2H),6.45(d,1H),3.96(s,3H),1.47(s,4H);C 28 H 22 FN 3 O 6 MS(EI) measured value: 516.1(MH+).

[0579] Step 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (1) [ka]

[0580] A solution of compound 7 (300 mg, 582.0 μmol, 1 equiv.), HATU (332 mg, 873.2 μmol, 1.5 equiv.), and DIEA (301 mg, 2.3 mmol, 406 μL, 4 equiv.) in DMF (10 mL) was stirred at 6-10° C. for 1 h. Methanamine hydrochloride (79 mg, 1.2 mmol, 2.0 equiv.) was added and the mixture was stirred at 6-10° C. for 17 h. The mixture was filtered and the filtrate was purified by preparative HPLC (column: Waters™ Xbridge 150 mm×25 mm×5 μm, gradient: 10 mM NH 4 HCO3 The mixture was purified with 33-63% acetonitrile in water (flow rate: 25 mL / min). Compound 1 was obtained (105.4 mg, yield 34.3%). 1 H NMR (400 MHz, DMSO-d 6 )δ 10.20(s,1H),10.06(s,1H),8.65(d,1H),8.61(s,1H),8.42-8.33(m,1H),7.77(d,2H),7.68-7.61(m, 2H),7.51(s,1H),7.25(d,2H),7.19-7.11(m,2H),6.46(d,1H),4.02(s,3H),2.84(d,3H)1.47(s,4H);C 29 H 25 FN 4 O 5 MS(EI) measured value: 529.1(MH+).

[0581] Preparative Example 2: Alternative Synthesis of Compound 1 [ka]

[0582] Synthesis of 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (8) [ka]

[0583] A suspension of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 5 (2 g, 8 mmol) in THF (20 mL) was treated with methylamine in EtOH (33% w / w, 8 M, 20 mL, 160 mmol) and H 20 (10 mL) was added. The resulting mixture was stirred at room temperature. The mixture became a clear solution in about 10 min and remained a clear solution for the duration of the reaction. Stirring was continued until the starting material was completely consumed as evidenced by LCMS and HPLC. This took about 3 h. The mixture was then concentrated and the residue was slurried in 20 mL of water and filtered. Some EtOAc was used to transfer the material from the flask to the filter funnel. The product was dried to give 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide as a white solid (yield 1.8 g, 90%, HPLC purity >97%).

[0584] Synthesis of 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (9) [ka]

[0585] A 5 L, 3-necked round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-chloro-7-methoxy-N-methylquinoline-6-carboxamide (8; 300 g; 1 equiv.), 4-aminophenol (195.9 g; 1.5 equiv.), and DMA (1500 mL). The resulting solution was stirred at room temperature and a solution of sodium t-pentoxide (184.52 g; 1.4 equiv.) dissolved in anhydrous THF (313 mL) was added over 5 min with stirring. The reaction mixture was then heated to 75-80° C. and stirred for an additional 2-6 h. The reaction mixture was then cooled to room temperature and charged with water (3 L) and stirred for at least an additional 1 h. The product was filtered and washed twice with 600 mL of 1:1 DMA / water and then once with 1200 mL of water. The product was transferred to a crystallization dish and dried in a vacuum oven at 40-45 °C for a minimum of 18 h to give a light brown glossy solid (370-377 g; 96-97%).

[0586] Synthesis of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carbonyl chloride (10) [ka]

[0587] A 250 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (2, 19.11 g; 1.3 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved and cooled to 5-10 °C before being charged with oxalyl chloride (7.13 mL; 1.28 equiv.). The resulting mixture was aged at 10-15 °C for 2-3 h and completion of the reaction was confirmed by IPC (in-process control). Upon completion of the reaction, the resulting product mixture was used in the next step without further purification.

[0588] Synthesis of 1-(4-fluorophenylcarbamoyl)cyclopropane-1-carbonyl chloride (10) [Alternative Method]

[0589] A 250 mL three-necked round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (2, 19.11 g; 1.3 equiv.), 75 mL of anhydrous THF, and 0.25 mL of DMF (catalyst). The mixture was stirred until all solids were dissolved and cooled to 5-15 °C before being charged with oxalyl chloride (7.13 mL; 1.28 equiv.). The resulting mixture was allowed to warm to room temperature and then stirred for 2-4 h. The resulting product mixture was used in the next step without further purification.

[0590] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [ka]

[0591] A 500 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (9, 21.3 g; 1.0 equiv.), 210 mL of anhydrous THF, and a solution of potassium carbonate (27.32 g; 3 equiv.) in 100 mL of water. 2 CO 3 The aqueous solution was rinsed with an additional 6.4 mL of water. The reaction mixture containing compound 10 from the previous example was transferred to the reaction mixture over 30 min with vigorous stirring, maintaining the internal temperature at 20-25°C. The transfer equipment was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 h. The resulting mixture was warmed to 35-40°C and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic phase was warmed to 55-60°C, then polish filtered and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3-neck round bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirrer and charged with water at 55-60°C. The resulting solution was seeded with compound 1, and water was added as an anti-solvent to the resulting seed bed over 4-4.5 h while maintaining the temperature at 50-55°C. The resulting slurry was cooled to 20-25°C and aged for 2 h or more. The product was then filtered, washed with water / THF and dried.

[0592] Synthesis of N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide (1) [Alternative Method]

[0593] A 500 mL three-neck round bottom flask equipped with a thermometer, nitrogen inlet, and magnetic stirrer was charged with 4-(4-aminophenoxy)-7-methoxy-N-methylquinoline-6-carboxamide (9, 21.3 g; 1.0 equiv.), 210 mL of anhydrous THF, and a solution of potassium carbonate (27.32 g; 3 equiv.) in 100 mL of water. 2 CO 3The aqueous solution was rinsed with an additional 6.4 mL of water. The reaction mixture containing compound 10 from the previous example was transferred to the reaction mixture over 0.5-1 hour with vigorous stirring while maintaining the internal temperature below 27° C. The transfer equipment was rinsed with 32 mL of anhydrous THF. The reaction mixture was stirred at ambient temperature for 0.5-1 hour. The resulting mixture was warmed to 35-40° C. and the phases were allowed to separate. The lower aqueous layer was discarded and the upper organic phase was warmed to 45-50° C., then filtered through filter paper and rinsed with 21 mL of THF. The filtered organic phase was transferred to a 1 L 3-neck round bottom flask equipped with a thermometer, nitrogen inlet, and mechanical stirrer and charged with 694 mL of filtered water over a minimum of 1 hour. The resulting mixture was stirred at 20-25° C. for a minimum of 12 hours, then the product was filtered and rinsed twice with 42 mL of a 2:1 mixture of water:THF. The product was then dried on the filter at room temperature or in a vacuum oven at 40-45° C. to give a white-beige solid (31.36 g; 90%).

[0594] Example 1: Preparation of Form R of Compound 1

[0595] A slurry of 106.8 mg of compound 1 in 5 mL of p-dioxane (Sigma-Aldrich, lot SHBL5393) was heated until a clear solution was achieved. The solution was filtered through a 0.2 μm nylon filter, allowed to cool to ambient temperature, and then placed in a refrigerator until solidified. The sample was removed from the refrigerator, allowed to thaw, and the precipitant was isolated by water suction vacuum filtration.

[0596] Example 2: Preparation of Form S of Compound 1

[0597] A slurry of 244.9 mg of Compound 1 in 7 mL of N-methyl-2-pyrrolidone (Sigma-Aldrich, lot SHBG9647V) was heated until a clear solution was achieved. The solution was filtered through a 0.2 μm nylon filter into 15 mL of ELGA ultrapurified water (8264-99-01) at room temperature. The precipitant was isolated by positive pressure filtration using a Swinnex® filter assembly and a 0.2 μm nylon filter.

[0598] Example 3: Preparation of Form T of Compound 1

[0599] A slurry of 87.28 mg of compound 1 in 39 mL of methylene chloride (Thermo Scientific, Lot 188785) was provided at 38° C. The hot slurry was filtered through a 0.2 μm PTFE filter to obtain a clear solution. The solution was allowed to evaporate to dryness at ambient temperature in a vial covered with needle-pierced aluminum foil. The resulting solid was exposed to 105-120° C. under vacuum for approximately 2 hours.

[0600] Example 4: Preparation of Form U of Compound 1

[0601] A cloudy solution of 67.3 mg of Compound 1 in 20 mL of methylene chloride (Thermo Scientific, Lot 188785) was sonicated and heated. The hot cloudy solution was filtered through a 0.2 μm PTFE filter to obtain a clear solution. The solution was allowed to evaporate to dryness at ambient temperature in an open vial.

[0602] Example 5: Preparation of Form V of Compound 1

[0603] The hemifumarate salt of compound 1 (1617.7 mg) was washed twice with 15 mL aliquots of water (Honeywell) and then dried under vacuum at 45-55° C. for approximately 1 day. A slurry of 51.5 mg of the washed hemifumarate salt in 2 mL of isopropyl alcohol (Supelco) and 1.2 mL of N,N-dimethylformamide (Acros) was heated to 50° C. and filtered through a 0.2 μm nylon filter to give a clear solution. The solution was cooled to freezer temperature and the precipitant was isolated by decantation. The solid was dried under vacuum at 80° C. for approximately 1 day.

[0604] Example 7: Preparation of Form W of Compound 1

[0605] The hemifumarate salt of compound 1 (1617.7 mg) was washed twice with 15 mL aliquots of water (Honeywell, lot DW046) and then dried under vacuum at 45-55° C. for approximately 1 day. A slurry of 46.1 mg of the washed hemifumarate salt in 2 mL of cyclopentyl methyl ether (Alfa Aesar, lot 10201006) and 1.2 mL of 1,1,1,3,3,3-hexafluoro-2-propanol (Sigma-Aldrich, lot WXBC8784V) was stirred at 50° C. for approximately 1 day. The solid was collected by vacuum filtration aspirating the water and then dried under vacuum at 80° C. for approximately 1 day.

[0606] Example 8: Preparation of Form X of Compound 1

[0607] A clear solution of 81.4 mg of compound 1 in 19 mL of tetrahydrofuran (Sigma-Aldrich, lot SHBM5527) was prepared at 60° C. The solution was filtered through a 0.2 μm nylon filter and then rotary evaporated to dryness. The residue was further dried under vacuum at ambient temperature for about 1 day. 5 mL of diethyl ether (Sigma-Aldrich, lot SHBL6577) was added to the residue and the slurry was sonicated briefly. The solid was isolated by water suction vacuum filtration.

[0608] Example 9: Preparation of Form Y of Compound 1

[0609] Compound 1 hemifumarate salt (1617.7 mg) was washed twice with 15 mL aliquots of water (Honeywell, lot DW046) and then dried under vacuum at 45-55°C for approximately 1 day. A slurry of 51.5 mg of the washed hemifumarate salt in 2 mL of 1-butanol (Sigma-Aldrich, lot SHBG0160V) and 1.2 mL of dimethylsulfoxide (Sigma-Aldrich, lot MKCH9235) was stirred at 50°C for approximately 1 day. The suspension was filtered through a 0.2 μm nylon filter to obtain a clear solution and allowed to cool to room temperature. The solution was stored at freezer temperature for approximately 8 days. The precipitant was isolated by water suction vacuum filtration and then dried under vacuum at 75°C for approximately 1 day.

[0610] Example 10: Preparation of amorphous Compound 1

[0611] Amorphous Compound 1 was successfully produced by rotary evaporation from DCM, THF, or chloroform. A clear solution of 81.4 mg of Compound 1 in 19 mL of tetrahydrofuran (Sigma-Aldrich, lot SHBM5527) was prepared at 60° C. The solution was filtered through a 0.2 μm nylon filter and then rotary evaporated to dryness. The residue was further dried under vacuum at ambient temperature for about 1 day.

[0612] Example 11: Preparation of Hemi-edisylate Form A of Compound 1

[0613] A slurry containing 37.7 mg of ethane-1,2-disulfonic acid and 88.4 mg of compound 1 in 9 mL of ethanol was stirred at room temperature for several hours. The solid was collected by vacuum filtration, sucking out the water, and then exposed to 45° C. under vacuum for 1 day.

[0614] Example 12: Preparation of Hemina Padisylate Form A of Compound 1

[0615] A slurry containing 84.4 mg of naphthalene-1,5-disulfonic acid and 123.5 mg of compound 1 in 5 mL of ethanol was sonicated for approximately 10 minutes. The solids were collected by water suction vacuum filtration, rinsed with 1 mL of ethanol, and briefly dried under a nitrogen purge.

[0616] Example 13: Preparation of napsylate salt form A of compound 1

[0617] A slurry of 50.2 mg naphthalene-2-sulfonic acid and 115.8 mg compound 1 in 11 mL tetrahydrofuran was stirred at 65° C. for several minutes. The slurry was removed from the heat and an additional 46.0 mg naphthalene-2-sulfonic acid was added to give a nearly clear solution. As the solution was sonicated, turbidity increased and a thick slurry was obtained after about 5 minutes. The solids were collected by water suction vacuum filtration and the wet cake was dried briefly under a nitrogen purge.

[0618] Example 14: Preparation of Hemifumarate Salt Form C of Compound 1

[0619] The hemifumarate form C was dissolved in acetic acid, 2 O, and ACN.

[0620] Example 15: Preparation of Hemifumarate Salt Form D of Compound 1

[0621] Hemi-fumarate form D was obtained from a polymorphism experiment using EGEE.

[0622] Example 16: Preparation of Hemifumarate Salt Form E of Compound 1

[0623] Hemi-fumarate Form E was obtained from a polymorphism experiment involving TFE and nitromethane.

[0624] Following a similar procedure from the polymorph screening experiment, hemifumarate Form E was produced in bulk. Approximately 0.5 g of hemifumarate Form B of compound 1 was stirred in 2:1 TFE / nitromethane at 60° C. to form a solution containing trace particles. The sample was filtered, cooled to ambient temperature, and subsequently evaporated to dryness at ambient conditions. The solid produced was consistent with hemifumarate Form E.

[0625] Alternatively, about 3 g of Compound 1 hemifumarate Form B was first stirred in 2:1 TFE / nitromethane at 60° C. However, the solid did not completely dissolve. Additional TFE was added to the sample at 60° C. to make a 4:1 TFE / nitromethane solution. The sample was filtered, cooled to ambient temperature, and then evaporated to dryness at ambient conditions to obtain hemifumarate Form E.

[0626] In another procedure, the hemifumarate salt of compound 1 (approximately 1 g) was solubilized in a mixture of 2:1 TFE:nitromethane (6 mL). The mixture was then stirred and heated at 60° C. for 24 hours to dissolve the solid material, resulting in a cloudy solution. After complete dissolution, the solution was cooled to room temperature. The solvent was evaporated by rotary evaporation at 40° C. and −0.09 Mpa. Small particles and irregularly shaped aggregates were observed by PLM. The material was birefringent, indicating that the material was crystalline. SEM data was consistent with the PLM analysis, showing the presence of large aggregates and very small particles attached to the surface of larger particles. Needle-like particle morphology was observed, as shown in FIG. 36. The collected solid was confirmed to be Form E as assessed by XRPD using a Rigaku diffractometer with CuKα (1.541837 Å) radiation at a voltage and current of 40 kV and 15 mA.

[0627] The DSC and TGA of the material are shown in Figure 37. DSC analysis was performed on a TA Instruments DSC2500. Sample sizes of approximately 1-3 mg were weighed into Tzero aluminum DSC pans with sealed lids and the pans were crimped. The samples were heated at 10°C / min from ambient to 260°C under dry nitrogen at 50 mL / min. TGA analysis was performed using a Discovery TGA 550 analyzer (TA Instruments) where 3-10 mg of material was heated at a heating rate of 10°C / min in an open aluminum pan under a dry nitrogen purge. Temperature calibration was performed using Alumel® and nickel. Weight calibration was performed using standard weights of 100 mg and 1 g. A broad endotherm was observed by DSC at 100.9°C reflecting the presence of solvent in the material. A weight loss of 9.86% was observed by TGA.

[0628] Other embodiments The foregoing disclosure has been described in some detail by way of illustrations and examples for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. It will be apparent to those skilled in the art that changes and modifications may be practiced within the scope of the appended claims. It should therefore be understood that the above description is intended to be illustrative, and not restrictive.

[0629] Therefore, the scope of the invention should be determined not with reference to the above description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. A crystalline solid of Compound 1, 【Chemistry 17】 The crystalline solid of Compound 1, wherein the crystalline solid of Compound 1 is selected from Compound 1 Form R, Compound 1 Form S, Compound 1 Form T, Compound 1 Form U, Compound 1 Form V, Compound 1 Form W, Compound 1 Form X, Compound 1 Form Y, and mixtures thereof.

2. Form R of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 10.69, 16.09, 16.41, 16.51, 17.39, 18.78, 19.24, 19.93, 21.44, 22.66, 22.99, and 26.48°2θ (±0.20°); Form S of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 8.37, 12.49, 12.83, 13.69, 16.85, 18.69, 19.62, 20.11, 20.70, 21.65, 23.79, 24.58, 25.12, and 25.89 degrees 2θ (±0.20 degrees); Form T of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 10.56, 12.29, 14.31, 18.27, 19.36, 21.16, 21.58, 22.52, 24.74, 27.47, and 28.66°2θ (±0.20°); Form U of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 9.24, 10.62, 14.34, 17.04, 17.34, 17.72, 19.43, 19.57, 20.08, 20.25, 21.25, 23.23, 23.62, 23.97, and 24.89; Form V of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 9.21, 10.45, 14.32, 16.86, 19.31, 19.41, 20.28, 21.36, 21.54, 23.34, 23.96, 24.90, and 28.25°2θ (±0.20°); Form W of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 8.82, 11.21, 11.44, 11.57, 13.16, 13.22, 14.40, 16.74, 17.95, 18.13, 19.16, 19.37, 19.56, 19.91, 21.84, 22.98, and 24.10°2θ (±0.20°); Form X of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 5.34, 5.88, 9.45, and 10.71 degrees 2θ (±0.20 degrees); and 2. The crystalline solid of claim 1, wherein Form Y of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 10.22, 11.09, 11.60, 13.71, 14.57, 18.12, 19.17, 19.85, 21.41, 21.59, 23.47, 24.54, 24.73, 25.34, 28.32, and 28.77 degrees 2θ (±0.20 degrees).

3. Form R of Compound 1 has the following peaks: 4.65, 5.33, 6.55, 7.56, 9.31, 10.69, 11.38, 14.63, 15.17, 15.74, 16.09, 16.41, 16.51, 17.05, 17.39, 17.93, 18.24, 18.78, 19.24, 19.93, 20.15, 21.06, 22.07, 23.09, 24.09, 25.09, 26.09, 27.09, 28.09, 29.09, 30.09, 31.09, 32.09, 33.09, 34.09, 35.09, 36.09, 37.09, 38.09, 39.09, 40.09, 41.09, 42.09, 43.09, 44.09, 45.09, 46.09, 47.09, 48.09, 49.09, 50.09, 51.09, 52.09, 53.09, 54.09, 55.09, 56.09, 57.09, 58.09, 59.09, 60.09, 61.09, 62.09, 63.09, 64.09, 65.09, 66.09, 67.09, 68.09, 69.09, 70.09, characterized by an XRPD pattern including all of the following: 0.71, 21.44, 22.22, 22.66, 22.99, 23.39, 24.06, 24.38, 24.70, 25.75, 26.15, 26.48, 27.05, 27.24, 27.54, 27.88, and 28.71 degrees 2θ (±0.20 degrees); Form S of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 5.56, 8.37, 11.22, 12.49, 12.83, 13.69, 16.85, 17.60, 17.98, 18.69, 19.62, 20.11, 20.70, 21.03, 21.65, 21.89, 22.90, 23.79, 24.58, 25.12, 25.89, 26.20, 26.94, 27.43, 28.15, 29.73, and 30.22 °2θ (±0.20°); Form T of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 7.15, 8.92, 9.59, 10.56, 11.20, 12.29, 13.44, 13.87, 14.31, 15.72, 16.85, 17.48, 17.95, 18.27, 18.48, 19.36, 21.16, 21.58, 22.02, 22.52, 23.34, 24.74, 25.97, 26.41, 27.01, 27.47, 28.66, 29.07, 29.43, and 30.25 °2θ (±0.20°); Form U of Compound 1 was identified by the following peaks: 6.12, 8.64, 9.24, 9.66, 10.62, 11.48, 12.27, 13.06, 13.70, 14.34, 14.70, 16.05, 17.04, 17.34, 17.72, 18.61, 18.96, 19.43, 19.57, 20.08, 20.25, 20.98, 21.25, 21.43, 22.06, 23.08, 24.06, 25.08, 26.06, 27.06, 28.06, 29.06, 30.06, 31.06, 32.06, 33.06, 34.06, 35.06, 37.06, 38.06, 39.06, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06, 63.06, 64.06, 65.06, 66.06, 67.06, 68.06, 69.06, 70. characterized by an XRPD pattern which includes all of the following: 2.23, 22.39, 22.83, 23.23, 23.62, 23.97, 24.89, 25.70, 26.21, 26.48, 27.35, 27.94, 28.22, 28.55, 28.93, 29.27, 29.45, 29.85, 29.98, and 30.24 degrees 2θ (±0.20 degrees); Form V of Compound 1 was detected by the following peaks: 6.05, 9.21, 9.66, 10.45, 11.45, 11.58, 12.14, 12.29, 12.86, 13.62, 14.32, 16.08, 16.86, 17.40, 17.66, 18.26, 18.45, 18.79, 19.31, 19.41, 20.28, 20.98, 21. 36, 21.54, 21.85, 22.23, 22.45, 22.78, 23.00, 23.34, 23.96, 24.90, 25.69, 25.90, 26.38, 27.18, 28.02, 28.25, 28.54, 29.24, and 29.89 °2θ (±0.20°); Form W of Compound 1 was detected by the following peaks: 8.82, 9.58, 10.50, 10.85, 11.21, 11.44, 11.57, 13.16, 13.22, 14.22, 14.40, 14.91, 15.81, 16.74, 17.10, 17.55, 17.95, 18.13, 18.35, 18.73, 19.16, 19.37, 19.56, 19.91, 20.65, 21.02, 21.30, 21.54, characterized by an XRPD pattern including all of the following: 21.84, 22.34, 22.62, 22.98, 23.27, 23.53, 24.10, 24.66, 25.08, 25.36, 25.62, 25.90, 26.41, 26.85, 27.07, 27.24, 27.70, 28.27, 28.73, 28.94, 29.25, 29.54, 30.11, and 30.53 °2θ (±0.20°); Form X of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 5.34, 5.88, 9.45, 10.71, 11.84, 13.36, 15.06, 16.55, 17.99, 18.80, 21.69, 22.60, 23.59, 25.54, and 26.98 °2θ (±0.20°); and Form Y of Compound 1 was identified as follows: 9.77, 10.22, 11.09, 11.60, 12.83, 13.20, 13.71, 14.57, 14.99, 16.06, 16.55, 17.43, 18.12, 18.45, 18.98, 19.17, 19.62, 19.85, 20.56, 20.78, 20.89, 21.13, 21.41, 21.59, 22.02, 22.28, 22.72, 22. 93, 23.47, 24.06, 24.22, 24.54, 24.73, 25.34, 25.68, 26.01, 26.41, 27.04, 27.47, 27.78, 28.12, 28.32, 28.77, 29.41, 30.31, 31.01, 31.24, 31.54, and 32.18 °2θ (±0.20°).

4. Form R of Compound 1 is characterized in a DSC thermogram by an endotherm with a first onset temperature of about 110°C and a second onset temperature of about 226°C, or in a TGA thermogram by a weight loss of about 27.5 wt% between temperatures of 46 and 177°C; and 10. The crystalline solid of claim 1, wherein Form U of Compound 1 is characterized by an endotherm with an onset temperature of about 199°C in a DSC thermogram.

5. A crystalline salt of Compound 1 having the structure: [Chemistry 18] A crystalline salt of Compound 1, wherein the crystalline salt of Compound 1 is selected from hemi-edisylate Form A of Compound 1, heminapadisylate Form A of Compound 1, napsylate Form A of Compound 1, napsylate Form B of Compound 1, napsylate Form C of Compound 1, and mixtures thereof.

6. Compound 1 hemi-edisylate Form A is characterized by an XRPD pattern containing all of the following peaks: 4.99, 5.99, 12.11, 13.49, 18.64, 20.09, 21.00, 22.30, 24.53, and 27.28°2θ (±0.20°); Compound 1 hemina padisylate Form A is characterized by an XRPD pattern containing all of the following peaks: 4.74, 8.03, 10.50, 12.27, 16.33, 16.96, 18.72, 19.13, 21.11, 22.96, 23.83, 24.89, and 25.68 °2θ (±0.20°); and 6. The crystalline salt form of claim 5, wherein napsylate Form A of Compound 1 is characterized by an XRPD pattern containing all of the following peaks: 4.74, 8.12, 8.60, 13.39, 13.80, 15.08, 16.32, 16.85, 18.40, 21.25, 21.42, 22.91, 24.12, 24.36, 26.99, and 28.95 °2θ (±0.20°).

7. Compound 1 hemi-edisylate Form A is characterized by an XRPD pattern containing all of the following peaks: 4.99, 5.99, 10.05, 10.37, 12.11, 13.49, 15.30, 16.20, 17.62, 18.64, 20.09, 21.00, 22.30, 23.44, 24.53, 25.23, 27.28, 27.96, and 28.70°2θ (±0.20°); Compound 1 hemina padisylate Form A is characterized by an XRPD pattern containing all of the following peaks: 4.74, 8.03, 10.50, 12.27, 12.72, 14.37, 15.38, 15.92, 16.33, 16.96, 18.16, 18.72, 19.13, 20.01, 21.11, 22.96, 23.83, 24.89, 25.68, 26.69, 27.53, and 28.24 degrees 2θ (±0.20 degrees); and The napsylate salt form A of Compound 1 was detected by the following peaks: 4.74, 6.88, 8.12, 8.60, 9.52, 10.65, 10.91, 11.42, 12.36, 13.39, 13.80, 14.32, 15.08, 16.32, 16.85, 17.29, 17.68, 18.40, 18.54, 19.26, 19.51, 19.72, 20.01, 20.31, 20.

6. The crystalline salt form of claim 5, characterized by an XRPD pattern comprising all of the following angles: 2θ (±0.20°): 21.55, 21.25, 21.42, 21.95, 22.23, 22.91, 23.26, 24.12, 24.36, 25.13, 25.57, 26.07, 26.25, 26.99, 27.48, 27.84, 28.17, 28.95, and 30.05°2θ (±0.20°).

8. Hemi-edisylate Form A of Compound 1 is characterized by an endotherm with an onset temperature of about 259°C in the DSC thermogram; Compound 1 hemina padisylate Form A is characterized by an endotherm with an onset temperature of about 205° C. in a DSC thermogram; and 6. The crystalline salt form of claim 5, wherein napsylate Form A of Compound 1 is characterized by an endotherm at about 63°C in a DSC thermogram.

9. The hemi-edisylate salt Form A of Compound 1, characterized by a weight loss of about 0.6 wt % up to a temperature of 135° C. in a TGA thermogram; Compound 1 hemina padisylate Form A is characterized by a weight loss of about 1.5 wt % up to a temperature of 144° C. in a TGA thermogram; and 6. The crystalline salt form of claim 5, wherein napsylate Form A of Compound 1 is characterized by a weight loss of about 5.2 wt % up to a temperature of 165°C in a TGA thermogram.

10. A crystalline fumarate salt of Compound 1, 【Chemistry 19】 The crystalline fumarate salt of Compound 1 is selected from hemifumarate Form C of Compound 1, hemifumarate Form D of Compound 1, hemifumarate Form E of Compound 1, hemifumarate Form F of Compound 1, and mixtures thereof.

11. Hemi-fumarate form E of compound 1 described in claim 10, characterized by an XRPD pattern including all of the following peaks: 7.07, 9.64, 11.44, 15.41, 16.20, 16.47, 19.54, 20.51, 22.18, 22.72, 23.81, 26.14, and 27.18°2θ (±0.20°).

12. The following peaks are present: 5.17, 5.46, 7.07, 9.64, 10.37, 10.95, 11.44, 12.38, 13.86, 14.17, 14.71, 15.41, 15.57, 16.20, 16.47, 17.89, 18.09, 18.87, 19.54, 20.51, 21.34, 21.65, 22.18, 22.72, 23.17, 23.

11. The hemifumarate form E of compound 1 of claim 10, characterized by an XRPD pattern comprising all of the following angles 2θ (±0.20°): 41, 23.81, 24.42, 25.23, 25.64, 26.14, 27.18, 27.64, 28.02, 28.90, 29.26, 29.72, 30.48, 30.96, 31.72, and 32.84°2θ (±0.20°).

13. 170.6 ppm chemical shift with peaks at 171.3, 170.6, 167.1, 167.0, 165.5, 164.2, 164.0, 160.9, 160.0, 157.8, 149.9, 147.0, 138.2, 136.1, 129.5, 128.1, 125.3, 123.5, 121.2, 120.3, 120.0, 114.9, 114.0, 102.3, 64.2, 62.7, 61.4, 56.0, 55.5, 26.6, and 21.6±0.2 ppm. １３ 11. The hemifumarate form E of compound 1 according to claim 10, characterized by a C NMR spectrum.

14. A solid with peaks at 85.7, 84.8, 79.1, 44.9, 41.8, 5.0, 2.0, 1.3, −35.0, −38.0, −38.7, −43.0, −70.7, −72.6, −74.8, −77.6, −77.9, −78.5, −82.9, −114.8, −115.9, −117.8, −118.5, −122.9, −154.6, −155.8, −157.7, −158.4, −162.8, −194.5, −195.8, −197.6, −198.3, and −202.7±0.2 ppm relative to the −118.5 ppm chemical shift from cross-polarization experiments. １９ 11. The hemifumarate form E of compound 1 according to claim 10, characterized by F NMR spectrum.

15. Solid with peaks at 45.1, 5.0, 2.1, −34.9, −38.1, −38.7, −74.3, −74.8, −77.7, −114.7, −115.9, −117.9, −118.8, −122.8, −154.6, −155.9, −157.8, −158.4, −162.8, −194.5, −197.7, and −198.5 ± 0.2 ppm relative to the −118.8 ppm chemical shift from the HPDEC experiment. １９ 11. The hemifumarate form E of compound 1 according to claim 10, characterized by F NMR spectrum.

16. A pharmaceutical composition comprising the crystalline form or crystalline salt form of any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. A composition for treating cancer, comprising a crystalline solid of compound 1 described in any one of claims 1 to 4, a crystalline salt of compound 1 described in any one of claims 5 to 9, or a crystalline fumarate salt of compound 1 described in any one of claims 10 to 15.

18. The pharmaceutical composition of claim 16 for treating cancer.

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