Crystalline and salt forms of kinase inhibitors

Abstract

To provide crystalline forms and salt forms of kinase inhibitors.SOLUTION: The present invention relates to crystalline forms of the free base of the c-Met inhibitor, Compound 1. The present invention also relates to crystalline forms of salts of Compound 1. The 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 a disease, disorder or syndrome mediated, at least in part, by modulating the invivo activity of a protein kinase.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 779,430 and U.S. Provisional Patent Application No. 62 / 856,469, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to crystalline forms of the free base of the c-Met inhibitor, Compound 1. The present invention also relates to crystalline forms of 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. [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 numerous tumor cell types and was originally cloned from a patient with chronic myeloid leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is believed to drive tumor growth through activation of proliferation and anti-apoptotic 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 in patients with the indicated cancers.

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

[0005] Therefore, there is a need for compounds that inhibit TAM receptor tyrosine kinases, such as Axl and Mer, for the treatment of selected cancers. Summary of the Invention [Means for solving the problem]

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

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

[0008] Specific crystalline forms of an active pharmaceutical ingredient (API), such as Compound 1, may have several advantages over other crystalline or amorphous forms, such as increased stability during storage or processing, better solubility, and increased bioavailability. Several stable crystalline forms of Compound 1 and selected salts of Compound 1 are reported herein.

[0009] In one aspect, the present invention relates to a crystalline solid form of Compound 1 or a hydrate or solvate thereof.

[0010] In another aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1HCl salt The present invention relates to a crystalline hydrochloride salt form of Compound 1 having the formula:

[0011] In one aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 hemifumarate or a hydrate or solvate thereof, wherein the crystalline salt form is hemifumarate Compound 1·0.5 fumarate characterized as Compound 1 hemifumarate Form B.

[0012] In another aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 Fumarate or a hydrate or solvate thereof, wherein the crystalline salt form is fumarate Compound 1·fumaric acid.

[0013] In one aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 Phosphate Form A or a hydrate or solvate thereof, wherein the crystalline phosphate form is characterized as Compound 1 Phosphate Form A.

[0014] In yet another aspect, the present invention relates to a method for 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 of treatment a crystalline form or crystalline salt form described herein, or a pharmaceutical composition described herein.

[0015] In another aspect, the invention relates to a method of inhibiting a protein kinase comprising contacting the protein kinase with a crystalline form or crystalline salt form described herein.

[0016] In yet another aspect, the present invention relates to a process for preparing Compound 1 hemifumarate Form B, comprising contacting Compound 1 with fumaric acid in an organic solvent to form a mixture, and stirring the mixture. [Brief explanation of the drawings]

[0017] [Figure 1] 1 is an XRPD pattern of Compound 1 Form A. [Figure 2] 1 is a DSC thermogram of Compound 1 Form A. [Figure 3] 1 is a TGA thermogram of Compound 1 Form A. [Figure 4] 1 is a DVS isotherm plot of Compound 1 Form A from 5% relative humidity to 95% relative humidity. [Figure 5]1A-1D are hot stage micrographs showing Compound 1 Form A at (A) 28.6°C with no change in crystalline form, (B) 210.0°C with no change in crystalline form, (C) 230.0°C with some melting and decomposition, and (D) 231.3°C with complete melting and decomposition. [Figure 6] 1 is an XRPD pattern of Compound 1 Form B. [Figure 7] 1 is a TGA thermogram of Compound 1 Form B. [Figure 8] 1 is an XRPD pattern of Compound 1 Form C. [Figure 9] 1 is a TGA thermogram of Compound 1 Form C. [Figure 10] 1 is an XRPD pattern of Compound 1 Form D. [Figure 11] 1 is a TGA thermogram of Compound 1 Form D. [Figure 12] 1 is an XRPD pattern of Compound 1 Form E. [Figure 13] 1 is a TGA thermogram of Compound 1 Form E. [Figure 14] 1 is an XRPD pattern of Compound 1 Form F. [Figure 15] 1 is a TGA thermogram of Compound 1 Form F. [Figure 16] 1 is an XRPD pattern of Compound 1 Form G. [Figure 17] 1 is a TGA thermogram of Compound 1 Form G. [Figure 18] 1 is an XRPD pattern of Compound 1 Form H. [Figure 19] 1 is an XRPD pattern of Compound 1 Form K. [Figure 20] 1 is a DSC thermogram of Compound 1 Form K. [Figure 21] 1 is a TGA thermogram of Compound 1 Form K. [Figure 22] 1 is an XRPD pattern of Compound 1 Form O. [Figure 23] 1 is an XRPD pattern of Compound 1 Form P. [Figure 24]1 is a DSC thermogram of Compound 1 Form P. [Figure 25] 1 is an XRPD pattern of Compound 1 Form Q. [Figure 26] 1 is a DSC thermogram of Compound 1 Form Q. [Figure 27] 1 is a TGA thermogram of Compound 1 Form Q. [Figure 28] FIG. 1 is an XRPD pattern of Compound 1 fumarate Form A+Compound 1 Form A (free base form). [Figure 29] 1 is an XRPD pattern of Compound 1 hemifumarate Form B. [Figure 30] 1 is a DSC thermogram of Compound 1 hemifumarate Form B. [Figure 31] 1 is a TGA thermogram of Compound 1 hemifumarate Form B. [Figure 32] 1 is a DVS isotherm plot of Compound 1 hemifumarate Form B. [Figure 33] 1A-1D are hot stage micrographs showing Compound 1 hemifumarate Form B at (A) 26.4°C with no change in crystalline form, (B) 209.6°C with no change in crystalline form, (C) 222.1°C with some melting, and (D) 223.1°C with complete melting and some darkening indicative of decomposition. [Figure 34] 1 is an XRPD pattern of Compound 1HCl Form A. [Figure 35] 1 is an XRPD pattern of Compound 1HCl Form B. [Figure 36] 1 is an XRPD pattern of Compound 1HCl Form C. [Figure 37] 1 is an XRPD pattern of Compound 1HCl Form D. [Figure 38] 1 is the indexing results for Compound 1 Form A, including assigned annihilation symbols, unit cell parameters, and tabulated space groups consistent with derived quantities. [Figure 39] 1 is the indexing results for Compound 1 Form B, including the tabulated space group matching assigned annihilation symbols, unit cell parameters, and derived quantities. [Figure 40] 1 is the indexing results for Compound 1 Form D, including the tabulated space group matching assigned annihilation symbols, unit cell parameters, and derived quantities. [Figure 41] 1 is an indexing result for Compound 1 Form H, including assigned annihilation symbols, unit cell parameters, and tabulated space group matching derived quantities. [Figure 42] 1 is an indexing result for Compound 1 Form O, including tabulated space group matching with assigned annihilation symbols, unit cell parameters, and derived quantities. [Figure 43] 1 is an indexing result for Compound 1 Form P, including assigned annihilation symbols, unit cell parameters, and tabulated space group matching derived quantities. [Figure 44] 1 is the indexing results for Compound 1 Form Q, including the tabulated space group matching assigned annihilation symbols, unit cell parameters, and derived quantities. [Figure 45] 1 is the indexing results for Compound 1 hemifumarate Form B, including assigned annihilation symbols, unit cell parameters, and tabulated space group matching derived quantities. [Figure 46] 1 is the indexing results for Compound 1HCl Form A, including assigned annihilation symbols, unit cell parameters, and tabulated space group matching derived quantities. [Figure 47] 1 is the indexing results for Compound 1HCl Form B, including assigned annihilation symbols, unit cell parameters, and tabulated space group matching derived quantities. [Figure 48] 1 is an XRPD pattern of Compound 1 phosphate Form A. [Figure 49] 1 is an XRPD pattern of Compound 1 Form I. [Figure 50] 1 is an XRPD pattern of Compound 1 Form J. [Figure 51] 1 is an XRPD pattern of Compound 1 Form L. [Figure 52] 1 is an XRPD pattern of Compound 1 Form M. [Figure 53]1 is an XRPD pattern of Compound 1 Form N. [Figure 54] 1H NMR spectrum of Compound 1 hemifumarate Form B in DMSO-d6. [Figure 55] 1 is a 1H NMR spectrum of Compound 1 Form A in DMSO-d6. [Figure 56] 1H NMR spectrum of Compound 1 Form K in DMSO-d6. DETAILED DESCRIPTION OF THE INVENTION

[0018] Definitions, Abbreviations and Acronyms analysis technology [Table 18]

[0019] Experimental Techniques [Table 19]

[0020] others [Table 20]

[0021] solvent [Table 21]

[0022] As used herein, the following definitions apply unless otherwise indicated.

[0023] For purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry," 2000, the entire contents of which are incorporated herein by reference. nd Ed., 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.

[0024] As used herein, the term "low / limited / significant moisture absorption" refers to a material that exhibits <0.5 / <2.0 / ≧2.0 wt % water uptake over a specified RH range.

[0025] As used herein, the term "stoichiometric hydrate" refers to a crystalline material having a defined water content over a wide RH range. Typical stoichiometric hydrates are hemihydrates, monohydrates, sesquihydrates, dihydrates, etc.

[0026] As used herein, the term "variable hydrate" refers to a crystalline material that has variable water content over a wide RH range, yet does not undergo a phase change.

[0027] As used herein, chemical terms designated as "forms" refer to chemical compounds or salts that consist of a single phase.

[0028] As used herein, the terms "low / limited / medium / good / high solubility" refer to materials with a solubility of <1 / 1-20 / 20-100 / 100-200 / >200 mg / mL.

[0029] As used herein, the term "crystalline" refers to a material that produces an XRPD pattern with sharp peaks (as well as measured peak widths) and diffuse scattering that is weak relative to such peaks.

[0030] As used herein, the term "disordered crystalline" refers to a material that produces an XRPD pattern with broad peaks (compared to the measured peak widths) and / or strong diffuse scattering compared to such peaks. 1) Microcrystalline, 2) Crystallinity with a large defect density; 3) a mixture of crystalline and X-ray amorphous phases, or 4) A combination of the above It may be.

[0031] As used herein, the term "insufficient signal" means that spectroscopic analysis of a sample produces a spectrum or pattern (output) that has insufficient signal above the expected background noise.

[0032] As used herein, the term "single crystalline phase" refers to an XRPD pattern that is determined to contain evidence of a single crystalline form due to Bragg peaks being indexed by a single unit cell. Indexing is the process of assigning Miller index labels to each peak in a diffraction pattern. The size and shape of the crystalline unit cell are also determined during the indexing process.

[0033] 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. A typical slurry involves agitation (typically by stirring or shaking), an action also referred to as "slurrying," in a sealed vial at a given temperature for an extended period of time. Typically, the solids are recovered after a given period of time using the methods described herein.

[0034] As used herein, the terms "X-ray amorphous" or "amorphous" refer to a material in which there is diffuse scattering but no evidence of Bragg peaks in an XRPD pattern.

[0035] As used herein, the term "crystalline" refers to a compound in the solid state 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 rigid long-range order. The term crystalline does not necessarily mean that the compound exists as a crystal, but rather that it has this crystal-like internal structural arrangement.

[0036] As used herein, the term "substantially crystalline" refers to a solid material that is primarily arranged in a fixed geometric pattern or lattice with rigid 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). Note that the term "substantially crystalline" also includes the descriptor "crystalline" defined in the preceding paragraph.

[0037] For purposes of the present invention, a "patient" includes humans and any other animals, particularly mammals, and other organisms. As such, the methods are applicable to both human therapy and veterinary use. In preferred embodiments, the patient is a mammal, and in most preferred embodiments, the patient is human. Examples of preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, and primates.

[0038] "Kinase-dependent diseases or conditions" refer to pathological conditions that depend on the activity of one or more kinases. Kinases are either directly or indirectly involved in the signal transduction pathways of various cellular activities, including proliferation, adhesion, migration, differentiation, and invasion. Diseases associated with kinase activity include those that support tumor growth, solid tumor growth, and other diseases involving excessive local angiogenesis, such as angiogenesis associated with ocular diseases (e.g., diabetic retinopathy, age-related macular degeneration) and inflammation (e.g., psoriasis, rheumatoid arthritis).

[0039] A "therapeutically effective amount" is an amount of a crystalline form or crystalline salt form of the present invention that, when administered to a patient, ameliorates the symptoms of the disease. The amount of a crystalline form or crystalline salt form of the present 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. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0040] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit-risk ratio.

[0041] As used herein, the phrase "pharmaceutically acceptable excipient" refers to a compound that is pharmaceutically acceptable. "Pharmaceutically acceptable" refers to an acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients generally include excipients that are safe, non-toxic, and not biologically or otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable," as defined herein. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of '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 Prescription and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0042] "Cancer" refers to a cell proliferative disease state, including, but not limited to: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Head and Neck: squamous cell carcinoma of the head and neck, pharyngeal and hypopharyngeal carcinoma, nasal and paranasal carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral and pharyngeal carcinoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, non-small cell lung carcinoma), alveolar (bronchial) carcinoma, alveolar sarcoma, alveolar soft part sarcoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; Colon: colorectal carcinoma, adenocarcinoma, esophageal car ... Cancer, gastrointestinal stromal tumor, lymphoma, carcinoid, Turcot's syndrome; Gastrointestinal: gastric cancer, gastroesophageal junction adenocarcinoma, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (pancreatic 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 tract: kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], 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), testicle (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriomas, sarcomas, stromal cell carcinoma, fibromas, fibroadenomas, adenoid tumors, lipomas), specific cystic carcinoma, papillary carcinoma, penile carcinoma, penile squamous cell carcinoma; liver: hepatocellular carcinoma (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 chordoma, osteochondroma (osteochondroid 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, germ cell tumor [pinealoma], 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 cancer [serous cystadenocarcinoma]) , mucinous cystadenocarcinoma, unclassified carcinoma], granulosa theca cell tumor, sertolioid 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); hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), myelofibrosis, polycythemia vera; Cancer cells include: thyroid cancer, essential thrombocythemia, Hodgkin's disease, non-Hodgkin's lymphoma; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentiginous dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. Therefore, the term "cancer cells" as used herein includes cells affected by any one of the above conditions. In some embodiments, the compounds or combinations disclosed herein can 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.

[0043] 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 appearing on a carbon, oxygen, or nitrogen in the structures herein indicates the presence of a hydrogen atom.

[0044] Embodiment

[0045] In one aspect, the present invention provides compound 1, which is 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. [ka] compound 1 or a crystalline solid form of a salt, solvate, or hydrate thereof.

[0046] In some embodiments of this aspect, the salt is an inorganic salt, an organic salt, a pharmaceutically acceptable salt, or a chiral salt.

[0047] In one aspect, the present invention provides compound 1, which is 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. [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof.

[0048] In one embodiment of this aspect, the crystalline solid form of Compound 1 is characterized as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form K, Form O, or Form Q.

[0049] In one embodiment, the crystalline solid is characterized as Compound 1 Form A.

[0050] In still further embodiments, Compound 1 Form A is characterized by one or more of the following peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the one or more peaks are 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 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 9.09, 19.34, 19.60, 20.00, 20.46, 20.85, 21.45, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56.

[0051] In another embodiment, Compound 1 Form A is characterized by one or more peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the one or more peaks are selected from 5.48, 9.93, 11.36, 11.79, 12.04, 12.62, 14.33, 14.67, 15.33, 16.51, 18.07, 19.09, 20.00, 21.55, 22.35, 22.58, 24.29, 24.35, 24.87, 28.19, and 28.56.

[0052] In another embodiment, Compound 1 Form A is characterized by one or more peaks in an XRPD pattern at ±0.20 2θ scale, wherein the one or more peaks are selected from 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19.

[0053] In a further embodiment, Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2θ scale, the peaks being 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19.

[0054] In still further embodiments, Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, the peaks being 5.48, 9.93, 11.36, 11.79, 12.04, 12.62, 14.33, 14.67, 15.33, 16.51, 18.07, 19.09, 20.00, 21.55, 22.35, 22.58, 24.29, 24.35, 24.87, 28.19, and 28.56.

[0055] In still further embodiments, Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, said peaks being 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.08, 20.09, 21.09, 22.09, 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, 7 9.09, 19.34, 19.60, 20.00, 20.46, 20.85, 21.45, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56.

[0056] In still further embodiments, Compound 1 Form A is characterized by an XRPD pattern substantially identical to FIG.

[0057] In one embodiment, Compound 1 Form A is characterized by an endotherm in a DSC thermogram at a temperature greater than 200° C. In one embodiment, Compound 1 Form A is characterized by an endotherm in a DSC thermogram with an onset temperature greater than 200° C.

[0058] In another embodiment, Compound 1 Form A is characterized by weight loss at temperatures above 200° C. in a TGA thermogram.

[0059] In another embodiment, Compound 1 Form A is characterized by a weight gain of about 0.8 to about 1.0 wt % as determined by DVS analysis when collected in a 5% relative humidity environment to a 95% relative humidity environment.

[0060] In one embodiment, the crystalline solid is characterized as Compound 1 Form B.

[0061] In one embodiment, Compound 1 Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are: 4.76, 9.58, 10.49, 10.97, 11.27, 12.10, 13.26, 13.52, 14.52, 15.15, 15.42, 16.69, 17.29, 17.92, 18.02, 19.02, 20.02, 21.02, 22.02, 23.02, 24.02, 25.02, 26.02, 27.02, 28.02, 29.02, 30.02, 31.02, 32.02, 33.02, 34 8.34, 19.05, 19.25, 19.48, 20.04, 20.59, 20.90, 21.39, 21.84, 22.25, 22.68, 22.84, 23.12, 23.32, 23.60, 24.03, 24.79, 25.32, 25.65, 25.88, 26.50, 26.79, 27.25, 28.55, and 29.49.

[0062] In one embodiment, Compound 1 Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 9.58, 10.49, 11.27, 12.10, 13.26, 13.52, 15.15, and 16.69.

[0063] In another embodiment, Compound 1 Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 10.49, 12.10, 13.26, and 13.52.

[0064] In a further embodiment, Compound 1 Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 10.49, 12.10, 13.26, and 13.52.

[0065] In still further embodiments, Compound 1 Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 9.58, 10.49, 11.27, 12.10, 13.26, 13.52, 15.15, and 16.69.

[0066] In still further embodiments, Compound 1 Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the peaks are: 4.76, 9.58, 10.49, 10.97, 11.27, 12.10, 13.26, 13.52, 14.52, 15.15, 15.42, 16.69, 17.29, 17.92, 18.34, 19.05, 19.25, 19.48, 20.04, 20.59, 20.9 0, 21.39, 21.84, 22.25, 22.68, 22.84, 23.12, 23.32, 23.60, 24.03, 24.79, 25.32, 25.65, 25.88, 26.50, 26.79, 27.25, 28.55, and 29.49.

[0067] In still a further embodiment, Compound 1 Form B is characterized by an XRPD pattern substantially identical to FIG.

[0068] In one embodiment, Compound 1 Form B is characterized by a first weight loss of about 0.3 wt % between temperatures of 38 and 92°C and a second weight loss of about 11.2 wt % between temperatures of 92 and 188°C in a TGA thermogram.

[0069] In one embodiment, the crystalline solid is characterized as Compound 1 Form C.

[0070] In one embodiment, Compound 1 Form C is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are: 3.89, 4.63, 7.95, 9.31, 10.54, 10.87, 11.14, 11.31, 11.49, 11.75, 12.22, 12.96, 13.59, 13.84, 14.01, 14.62, 14.79, 15.46, 15.87, 16.01 ... 0.86, 16.07, 16.61, 16.73, 16.88, 17.64, 18.13, 18.73, 19.10, 19.42, 19.75, 20.09, 20.47, 21.00, 21.65, 21.95, 22.47, 23.11, 23.46, 23.77, 24.84, 25.17, 26.14, 26.48, 26.88, 27.72, 28.35, 28.70, and 28.96.

[0071] In one embodiment, Compound 1 Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 3.89, 7.95, 9.31, 10.54, 12.96, 16.61, 17.64, and 20.47.

[0072] In another embodiment, Compound 1 Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 3.89, 7.95, 9.31, and 17.64.

[0073] In a further embodiment, Compound 1 Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 3.89, 7.95, 9.31, and 17.64.

[0074] In still further embodiments, Compound 1 Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 3.89, 7.95, 9.31, 10.54, 12.96, 16.61, 17.64, and 20.47.

[0075] In still further embodiments, Compound 1 Form C is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 3.89, 4.63, 7.95, 9.31, 10.54, 10.87, 11.14, 11.31, 11.49, 11.75, 12.22, 12.96, 13.59, 13.84, 14. .01, 14.62, 14.79, 15.46, 15.86, 16.07, 16.61, 16.73, 16.88, 17.64, 18.13, 18.73, 19.10, 19.42, 19.75, 20.09, 20.47, 21.00, 21.65, 21.95, 22.47, 23.11, 23.46, 23.77, 24.84, 25.17, 26.14, 26.48, 26.88, 27.72, 28.35, 28.70, and 28.96.

[0076] In still a further embodiment, Compound 1 Form C is characterized by an XRPD pattern substantially identical to FIG.

[0077] In one embodiment, Compound 1 Form C is characterized in a TGA thermogram by a first weight loss of about 0.4 wt% between temperatures of 40 and 75°C, a second weight loss of about 13.8 wt% between temperatures of 75 and 154°C, and a third weight loss of about 1.9 wt% between temperatures of 190 and 220°C.

[0078] In one embodiment, the crystalline solid is characterized as Compound 1 Form D.

[0079] In one embodiment, Compound 1 Form D is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are 5.08, 5.43, 7.00, 9.62, 10.21, 10.90, 12.31, 13.66, 14.06, 14.70, 15.35, 16.06, 16.39, 17.89, 18.17, 18.35, 18.53, 18.80, 18.96 , 19.15, 19.50, 20.09, 20.37, 20.58, 20.93, 21.31, 21.79, 21.97, 22.30, 22.91, 23.12, 23.26, 23.62, 23.93, 24.37, 24.77, 24.99, 25.39, 25.96, 26.62, 27.10, 27.53, 28.05, 28.38, 28.78, 29.09, 29.38, and 29.64.

[0080] In one embodiment, Compound 1 Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.43, 7.00, 10.21, 18.96, 23.62, 24.99, 26.62, 27.10, and 29.64.

[0081] In another embodiment, Compound 1 Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 5.43, 7.00, 10.21, and 29.64.

[0082] In a further embodiment, Compound 1 Form D is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 5.43, 7.00, 10.21, and 29.64.

[0083] In still further embodiments, Compound 1 Form D is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 5.43, 7.00, 10.21, 18.96, 23.62, 24.99, 26.62, 27.10, and 29.64.

[0084] In still further embodiments, Compound 1 Form D is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 5.08, 5.43, 7.00, 9.62, 10.21, 10.90, 12.31, 13.66, 14.06, 14.70, 15.35, 16.06, 16.39, 17.89, 18.09, 19.09, 20.09, 21.09, 22.09, 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 .17, 18.35, 18.53, 18.80, 18.96, 19.15, 19.50, 20.09, 20.37, 20.58, 20.93, 21.31, 21.79, 21.97, 22.30, 22.91, 23.12, 23.26, 23.62, 23.93, 24.37, 24.77, 24.99, 25.39, 25.96, 26.62, 27.10, 27.53, 28.05, 28.38, 28.78, 29.09, 29.38, and 29.64.

[0085] In still further embodiments, Compound 1 Form D is characterized by an XRPD pattern substantially identical to FIG.

[0086] In another embodiment, Compound 1 Form D is characterized by a weight loss of about 13.5 wt % between temperatures of 38 and 130° C. in a TGA thermogram.

[0087] In one embodiment, the crystalline solid is characterized as Compound 1 Form E.

[0088] In one embodiment, Compound 1 Form E is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.16, 6.13, 9.77, 10.37, 10.82, 11.69, 13.73, 14.34, 14.79, 15.47, 15.79, 16.33, 16.64, 16.82, 17.60, 17.89, 18.16, 18.72, 19.09, 19.59, 20.65, 21.73, 22.10, 22.72, 23.23, 23.54, 23.79, 24.78, 25.13, 26.37, 26.91, 29.12, and 29.95.

[0089] In one embodiment, Compound 1 Form E is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.13, 9.77, 10.37, 13.73, 14.79, 26.37, 29.12, and 29.95.

[0090] In another embodiment, Compound 1 Form E is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 10.37, 14.79, 26.37, and 29.95.

[0091] In a further embodiment, Compound 1 Form E is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 10.37, 14.79, 26.37, and 29.95.

[0092] In still further embodiments, Compound 1 Form E is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.13, 9.77, 10.37, 13.73, 14.79, 26.37, 29.12, and 29.95.

[0093] In still further embodiments, Compound 1 Form E is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 5.16, 6.13, 9.77, 10.37, 10.82, 11.69, 13.73, 14.34, 14.79, 15.47, 15.79, 16.33, 16.64, 16.82, 17.60, 17.89, 18.16, 18.72, 19.09, 19.59, 20.65, 21.73, 22.10, 22.72, 23.23, 23.54, 23.79, 24.78, 25.13, 26.37, 26.91, 29.12, and 29.95.

[0094] In still further embodiments, Compound 1 Form E is characterized by an XRPD pattern substantially identical to FIG.

[0095] In another embodiment, Compound 1 Form E is characterized by a weight loss of about 8.2 wt % between temperatures of 60 and 130° C. in a TGA thermogram.

[0096] In one embodiment, the crystalline solid is characterized as Compound 1 Form F.

[0097] In one embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.85, 7.44, 8.56, 10.95, 11.75, 12.28, 13.65, 14.48, 14.94, 15.61, 16.27, 16.68, 17.84, 18.39, 19.25, 19.52, 20.30, 21.62, 22.07, 22.83, 23.58, 24.33, 25.93, 26.20, 26.48, 27.79, 29.2, and 29.9.

[0098] In one embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 7.44, 8.56, 13.65, 16.27, 19.25, 25.93, 29.2, and 29.9.

[0099] In another embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 7.44, 8.56, 13.65, and 29.9.

[0100] In a further embodiment, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 7.44, 8.56, 13.65, and 29.9.

[0101] In still further embodiments, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 7.44, 8.56, 13.65, 16.27, 19.25, 25.93, 29.2, and 29.9.

[0102] In still further embodiments, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 5.85, 7.44, 8.56, 10.95, 11.75, 12.28, 13.65, 14.48, 14.94, 15.61, 16.27, 16.68, 17.84, 18.39, 19.25, 19.52, 20.30, 21.62, 22.07, 22.83, 23.58, 24.33, 25.93, 26.20, 26.48, 27.79, 29.2, and 29.9.

[0103] In one embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.85, 7.44, 8.56, 10.95, 11.75, 12.28, 13.65, 14.48, 14.94, 15.61, 16.27, 16.68, 17.84, 18.39, 19.25, 19.52, 20.30, 21.62, 22.07, 22.83, 23.58, 24.33, 25.93, 26.20, 26.48, and 27.79.

[0104] In one embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 7.44, 8.56, 13.65, 16.27, 19.25, and 25.93.

[0105] In another embodiment, Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are , 8.56, and 13.65.

[0106] In a further embodiment, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 7.44, 8.56, and 13.65.

[0107] In still further embodiments, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 7.44, 8.56, 13.65, 16.27, 19.25, and 25.93.

[0108] In still further embodiments, Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 5.85, 7.44, 8.56, 10.95, 11.75, 12.28, 13.65, 14.48, 14.94, 15.61, 16.27, 16.68, 17.84, 18.39, 19.25, 19.52, 20.30, 21.62, 22.07, 22.83, 23.58, 24.33, 25.93, 26.20, 26.48, and 27.79.

[0109] In still further embodiments, Compound 1 Form F is characterized by an XRPD pattern substantially identical to FIG.

[0110] In another embodiment, Compound 1 Form F is characterized by a first weight loss of about 0.1 wt % between temperatures of 38 and 77°C, and a second weight loss of about 14.4 wt % between temperatures of 77 and 178°C in a TGA thermogram.

[0111] In one embodiment, the crystalline solid is characterized as Compound 1 Form G.

[0112] In one embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 4.72, 6.71, 9.47, 11.51, 11.84, 13.04, 14.40, 15.12, 16.03, 16.28, 16.51, 17.04, 17.85, 18.04, 18.73, 19.29, 19.49, 19.73, 20.72, 21.10, 22.61, 23.16, 24.10, 25.49, 26.47, 27.25, 27.84, 30.3, and 30.7.

[0113] In one embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.71, 9.47, 14.40, 17.04, 17.85, 21.10, 30.3, and 30.7.

[0114] In another embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.71, 9.47, 30.3, and 30.7.

[0115] In a further embodiment, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.71, 9.47, 30.3, and 30.7.

[0116] In still further embodiments, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.71, 9.47, 14.40, 17.04, 17.85, 21.10, 30.3, and 3 It is 0.7.

[0117] In still further embodiments, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 4.72, 6.71, 9.47, 11.51, 11.84, 13.04, 14.40, 15.12, 16.03, 16.28, 16.51, 17.04, 17.85, 18.04, 18.73, 19.29, 19.49, 19.73, 20.72, 21.10, 22.61, 23.16, 24.10, 25.49, 26.47, 27.25, 27.84, 30.3, and 30.7.

[0118] In one embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 4.72, 6.71, 9.47, 11.51, 11.84, 13.04, 14.40, 15.12, 16.03, 16.28, 16.51, 17.04, 17.85, 18.04, 18.73, 19.29, 19.49, 19.73, 20.72, 21.10, 22.61, 23.16, 24.10, 25.49, 26.47, 27.25, and 27.84.

[0119] In one embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.71, 9.47, 14.40, 17.04, 17.85, and 21.10.

[0120] In another embodiment, Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.71 and 9.47.

[0121] In a further embodiment, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.71 and 9.47.

[0122] In still further embodiments, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.71, 9.47, 14.40, 17.04, 17.85, and 21.10.

[0123] In still further embodiments, Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 4.72, 6.71, 9.47, 11.51, 11.84, 13.04, 14.40, 15.12, 16.03, 16.28, 16.51, 17.04, 17.85, 18.04, 18.73, 19.29, 19.49, 19.73, 20.72, 21.10, 22.61, 23.16, 24.10, 25.49, 26.47, 27.25, and 27.84.

[0124] In still a further embodiment, Compound 1 Form G is characterized by an XRPD pattern substantially identical to FIG.

[0125] In one embodiment, Compound 1 Form G is characterized by a weight loss of about 20.8 wt % between temperatures of 40 and 165° C. in a TGA thermogram.

[0126] In one embodiment, the crystalline solid is characterized as Compound 1 Form H.

[0127] In another embodiment, Compound 1 Form H is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are: 6.30, 10.79, 11.42, 11.73, 12.63, 14.01, 14.29, 14.67, 15.74, 16.41, 17.23, 17.52, 18.01, 18.31, 18.56, 19.04, 19.67, 19.80, 20.32, 20.72, 21.53, 21.69, 21.95, 22.47, 23.14, 23.53, 24.33, 24.84, 25.13, 25.38, 25.69, 26.75, 27.48, 28.19, 28.70, 29.09, and 29.60.

[0128] In another embodiment, Compound 1 Form H is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 6.30, 11.42, 11.73, 17.52, 18.01, 18.56, 21.95, and 25.69.

[0129] In another embodiment, Compound 1 Form H is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 6.30, 17.52, 18.56, and 25.69.

[0130] In a further embodiment, Compound 1 Form H is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.30, 17.52, 18.56, and 25.69.

[0131] In still further embodiments, Compound 1 Form H is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 6.30, 11.42, 11.73, 17.52, 18.01, 18.56, 21.95, and 25.69.

[0132] In still further embodiments, Compound 1 Form H is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 6.30, 10.79, 11.42, 11.73, 12.63, 14.01, 14.29, 14.67, 15.74, 16.41, 17.23, 17.52, 18. 01, 18.31, 18.56, 19.04, 19.67, 19.80, 20.32, 20.72, 21.53, 21.69, 21.95, 22.47, 23.14, 23.53, 24.33, 24.84, 25.13, 25.38, 25.69, 26.75, 27.48, 28.19, 28.70, 29.09, and 29.60.

[0133] In still further embodiments, Compound 1 Form H is characterized by an XRPD pattern substantially identical to FIG.

[0134] In one embodiment, the crystalline solid is characterized as Compound 1 Form I.

[0135] In a further embodiment, Compound 1 Form I is characterized by an XRPD pattern substantially identical to FIG.

[0136] In one embodiment, the crystalline solid is characterized as Compound 1 Form J.

[0137] In a further embodiment, Compound 1 Form J is characterized by an XRPD pattern substantially identical to FIG.

[0138] In one embodiment, the crystalline solid is characterized as Compound 1 Form K.

[0139] In one embodiment, Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.73, 6.39, 8.10, 11.53, 11.78, 12.83, 14.36, 15.56, 16.25, 17.42, 18.17, 19.07, 19.70, 19.89, 20.53, 21.11, 21.55, 22.34, 22.50, 23.24, 23.76, 24.50, 25.94, 26.42, 27.76, and 28.28.

[0140] In one embodiment, Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42.

[0141] In another embodiment, Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 6.39, 8.10, 22.34, and 24.50.

[0142] In a further embodiment, Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.39, 8.10, 22.34, and 24.50.

[0143] In still further embodiments, Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42.

[0144] In still further embodiments, Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 5.73, 6.39, 8.10, 11.53, 11.78, 12.83, 14.36, 15.56, 16.25, 17.42, 18.17, 19.07, 19.70, 19.89, 20.53, 21.11, 21.55, 22.34, 22.50, 23.24, 23.76, 24.50, 25.94, 26.42, 27.76, and 28.28.

[0145] In still further embodiments, Compound 1 Form K is characterized by an XRPD pattern substantially identical to FIG.

[0146] In another embodiment, Compound 1 Form K is characterized by an endotherm at a temperature of about 226° C. in a DSC thermogram.

[0147] In another embodiment, Compound 1 Form K is characterized by a weight loss of about 0.2 wt % between temperatures of 40 and 180° C. in a TGA thermogram.

[0148] In one embodiment, the crystalline solid is characterized as Compound 1 Form L.

[0149] In a further embodiment, Compound 1 Form L is characterized by an XRPD pattern substantially identical to FIG.

[0150] In one embodiment, the crystalline solid is characterized as Compound 1 Form M.

[0151] In a further embodiment, Compound 1 Form M has an XRPD pattern substantially identical to that of Figure 52. It is characterized by

[0152] In one embodiment, the crystalline solid is characterized as Compound 1 Form N.

[0153] In a further embodiment, Compound 1 Form N is characterized by an XRPD pattern substantially identical to FIG.

[0154] In one embodiment, the crystalline solid is characterized as Compound 1 Form O.

[0155] In one embodiment, Compound 1 Form O is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are 6.10, 9.01, 9.83, 10.68, 11.12, 11.33, 12.25, 12.99, 13.93, 14.51, 14.92, 15.55, 15.79, 17.14, 17.43, 17.58 , 18.15, 18.42, 19.35, 19.77, 20.24, 20.71, 20.90, 21.49, 21.68, 22.04, 22.36, 22.78, 23.37, 23.96, 24.39, 24.92, 25.62, 26.20, 26.64, 26.93, 27.32, 27.68, 27.96, 28.26, 28.60, and 28.81.

[0156] In one embodiment, Compound 1 Form O is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are selected from 6.10, 9.01, 14.92, 17.14, 17.58, 23.96, 25.62, and 27.96.

[0157] In another embodiment, Compound 1 Form O is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.10, 14.92, 17.14, and 23.96.

[0158] In a further embodiment, Compound 1 Form O is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.10, 14.92, 17.14, and 23.96.

[0159] In still further embodiments, Compound 1 Form O is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.10, 9.01, 14.92, 17.14, 17.58, 23.96, 25.62, and 27.96.

[0160] In still further embodiments, Compound 1 Form O is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 6.10, 9.01, 9.83, 10.68, 11.12, 11.33, 12.25, 12.99, 13.93, 14.51, 14.92, 15.55, 15.79, 17.14, 17.43, 1 7.58, 18.15, 18.42, 19.35, 19.77, 20.24, 20.71, 20.90, 21.49, 21.68, 22.04, 22.36, 22.78, 23.37, 23.96, 24.39, 24.92, 25.62, 26.20, 26.64, 26.93, 27.32, 27.68, 27.96, 28.26, 28.60, and 28.81.

[0161] In still further embodiments, Compound 1 Form O is characterized by an XRPD pattern substantially identical to FIG.

[0162] In one embodiment, the crystalline solid is characterized as Compound 1 Form P.

[0163] In one embodiment, Compound 1 Form P is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are: 5.99, 8.78, 9.40, 10.12, 11.99, 14.61, 14.87, 15.61, 15.98, 16.32, 16.62, 17.56, 17.62, 17.84, 18.05, 18.06, 18.07, 18.08, 18.10, 18.12, 18.14, 18.16, 18.18, 18.18, 18.19, 18.20, 18.21, 18.22, 18.23, 18.24, 18.2 0.43, 18.88, 19.22, 19.72, 19.85, 20.32, 20.91, 21.67, 22.04, 22.39, 22.93, 23.46, 23.71, 23.98, 24.11, 24.43, 24.84, 25.74, 26.39, 26.64, 26.85, 27.77, 28.74, 29.26, 29.55, and 30.07.

[0164] In one embodiment, Compound 1 Form P is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 11.99, 14.61, 14.87, 20.91, 21.67, 22.04, 22.93, and 26.85.

[0165] In still further embodiments, Compound 1 Form P is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 11.99, 14.61, 14.87, 20.91, 21.67, 22.04, 22.93, and 26.85.

[0166] In still further embodiments, Compound 1 Form P is characterized by all of the following peaks in an XRPD pattern at 2-theta scale ±0.2, said peaks being 5.99, 8.78, 9.40, 10.12, 11.99, 14.61, 14.87, 15.61, 15.98, 16.32, 16.62, 17.56, 17.62, 17.84, 18.0 5, 18.43, 18.88, 19.22, 19.72, 19.85, 20.32, 20.91, 21.67, 22.04, 22.39, 22.93, 23.46, 23.71, 23.98, 24.11, 24.43, 24.84, 25.74, 26.39, 26.64, 26.85, 27.77, 28.74, 29.26, 29.55, and 30.07.

[0167] In a further embodiment, Compound 1 Form P is characterized by an XRPD pattern substantially identical to FIG.

[0168] In one embodiment, the crystalline solid is characterized as Compound 1 Form Q.

[0169] In one embodiment, Compound 1 Form Q is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are 6.11, 8.61, 9.06, 9.74, 10.64, 10.89, 11.24, 11.33, 12.06, 12.24, 12.91, 13.82, 14.46, 14.83, 15.69, 15.76, 16.07, 17.05, 17.31, 17.40, 17.78, 18.16, 18.42, 18.88 , 19.08, 19.28, 19.56, 19.84, 20.07, 20.70, 21.04, 21.38, 21.59, 21.91, 22.18, 22.30, 22.58, 22.78, 23.04, 23.23, 23.50, 23.81, 24.01, 24.32, 24.86, 25.43, 25.80, 26.05, 26.20, 26.69, 27.02, 27.44, 27.63, 27.99, 28.48, 28.75, 29.17, and 29.36.

[0170] In one embodiment, Compound 1 Form Q has an XRPD pattern at ±0.2 2θ scale. The compound is characterized by one or more peaks in the spectrum, the one or more peaks being selected from 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01.

[0171] In another embodiment, Compound 1 Form Q is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 8.61, 9.74, 16.07, and 20.04.

[0172] In a further embodiment, Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 8.61, 9.74, 16.07, and 20.04.

[0173] In still further embodiments, Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01.

[0174] In still further embodiments, Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the peaks are: 6.11, 8.61, 9.06, 9.74, 10.64, 10.89, 11.24, 11.33, 12.06, 12.24, 12.91, 13.82, 14.46, 14.83, 15.69, 15.76, 16.07, 17.05, 17.31, 17.40, 17.78, 18.16, 18.42, 18.51, 18.61, 18.70, 18.82, 18.91, 19.05, 20.09, 20.10, 20.20, 20.30, 20.40, 20.51, 20.60, 20.70, 20.82, 20.91, 21.09, 21.10, 21.20, 21.30, 21.40, 21.51, 21.60, 21.70, 21.82, 21.91, 22.09, 22.20, 22.30, 22.40, 22.51, 22.60, 22.70, 22.82, 22.91, 23.09, 23.09, 23.10, 23.20, 23.30, 23.40, 23.51, 24.09, 24.10, 24 0.88, 19.08, 19.28, 19.56, 19.84, 20.07, 20.70, 21.04, 21.38, 21.59, 21.91, 22.18, 22.30, 22.58, 22.78, 23.04, 23.23, 23.50, 23.81, 24.01, 24.32, 24.86, 25.43, 25.80, 26.05, 26.20, 26.69, 27.02, 27.44, 27.63, 27.99, 28.48, 28.75, 29.17, and 29.36.

[0175] In still further embodiments, Compound 1 Form Q is characterized by an XRPD pattern substantially identical to FIG.

[0176] In another embodiment, Compound 1 Form Q is characterized by an endotherm in a DSC thermogram at a temperature between 194 and 195° C. In another embodiment, Compound 1 Form Q is characterized by an endotherm with an onset temperature between about 194 and 195° C. in a DSC thermogram.

[0177] In another embodiment, Compound 1 Form Q is characterized by a weight loss of about 11-12 wt% between temperatures of 120-160°C in a TGA thermogram.

[0178] In another aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1HCl salt The present invention relates to a crystalline hydrochloride salt form of Compound 1 having the formula:

[0179] In one embodiment, the crystalline solid is characterized as Compound 1 HCl Form A, Compound 1 HCl Form B, Compound 1 HCl Form C, or Compound 1 HCl Form D. In one embodiment, the crystalline solid is characterized as Compound 1 HCl Form A.

[0180] In one embodiment, Compound 1 HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are: 5.19, 8.17, 9.84, 10.10, 10.42, 11.07, 12.52, 12.76, 12.98, 13.49, 13.69, 13.89, 14.31, 14.84, 15.12 , 15.68, 16.34, 16.68, 17.08, 17.47, 17.96, 18.49, 19.23, 19.78, 20.31, 20.91, 21.16, 21.42, 22.10, 22.81, 23.18, 23.89, 24.39, 25.20, 25.87, 26.34, 27.06, 27.59, 28.07, 28.4, and 30.0.

[0181] In one embodiment, Compound 1 HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, 28.07, 28.4, and 30.0.

[0182] In another embodiment, Compound 1HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 13.49, 17.47, 18.49, and 30.0.

[0183] In a further embodiment, Compound 1HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 13.49, 17.47, 18.49, and 30.0.

[0184] In still further embodiments, Compound 1 HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, 28.07, 28.4, and 30.0.

[0185] In still further embodiments, Compound 1 HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the peaks are: 5.19, 8.17, 9.84, 10.10, 10.42, 11.07, 12.52, 12.76, 12.98, 13.49, 13.69, 13.89, 14.31, 14.84, 15.08, 16.09, 17.10, 17.11, 17.12, 17.13, 17.14, 17.15, 17.16, 17.17, 17.18, 17.19, 17.19, 17.20, 17.21, 17.22, 17.23, 17.24, 17.25, 17.26, 17.27, 17.28, 17.30, 17.31, 17.32, 17.33, 17.34, 17.35, 17.40, 17.41, 17.42, 17.46, 17.49, 17.50, 17.51, 17.52, 17.53, 17.56, 17.60, 17.70, 17.71, 17.72, 17.73, 17.74, 17.75, 17.76, 17.80, 17.90, 18.00, 18.01, 18.02, 18.03, 18.04, .12, 15.68, 16.34, 16.68, 17.08, 17.47, 17.96, 18.49, 19.23, 19.78, 20.31, 20.91, 21.16, 21.42, 22.10, 22.81, 23.18, 23.89, 24.39, 25.20, 25.87, 26.34, 27.06, 27.59, 28.07, 28.4, and 30.0.

[0186] In one embodiment, Compound 1 HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are: 5.19, 8.17, 9.84, 10.10, 10.42, 11.07, 12.52, 12.76, 12.98, 13.49, 13.69, 13.89, 14.31, 14.84, 14.86, 15.04, 16.02, 17.06, 18.08, 19.06, 20.04, 21.06, 22.08, 23.09, 24.09, 25.06, 26.08, 27.09, 28.09, 29.08, 30.08, 31.08, 32.08, 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, 5.12, 15.68, 16.34, 16.68, 17.08, 17.47, 17.96, 18.49, 19.23, 19.78, 20.31, 20.91, 21.16, 21.42, 22.10, 22.81, 23.18, 23.89, 24.39, 25.20, 25.87, 26.34, 27.06, 27.59, and 28.07.

[0187] In one embodiment, Compound 1 HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, and 28.07.

[0188] In another embodiment, Compound 1HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 13.49, 17.47, and 18.49.

[0189] In a further embodiment, Compound 1HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 13.49, 17.47, and 18.49.

[0190] In still further embodiments, Compound 1 HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, and 28.07.

[0191] In still further embodiments, Compound 1 HCl Form A is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 5.19, 8.17, 9.84, 10.10, 10.42, 11.07, 12.52, 12.76, 12.98, 13.49, 13.69, 13.89, 14.31, 14. 84, 15.12, 15.68, 16.34, 16.68, 17.08, 17.47, 17.96, 18.49, 19.23, 19.78, 20.31, 20.91, 21.16, 21.42, 22.10, 22.81, 23.18, 23.89, 24.39, 25.20, 25.87, 26.34, 27.06, 27.59, and 28.07.

[0192] In still a further embodiment, Compound 1HCl Form A is characterized by an XRPD pattern substantially identical to FIG.

[0193] In one embodiment, the crystalline solid is characterized as Compound 1HCl Form B.

[0194] In one embodiment, Compound 1 HCl Form B is characterized by one or more peaks in an XRPD pattern at the 2θ scale ±0.2, wherein the one or more peaks are 8.20, 9.72, 9.81, 10.04, 10.56, 12.52, 12.97, 13.32, 13.48, 13.81, 14.35, 14.95, 15.89, 16.63, 17.37, 17. 83, 17.99, 18.32, 19.15, 19.31, 19.51, 19.72, 20.17, 20.84, 21.04, 21.15, 21.30, 21.81, 22.02, 22.65, 23.11, 23.40, 23.75, 24.76, 25.34, 25.74, 26.20, 26.90, 27.71, 27.98, 28.34, and 28.98.

[0195] In one embodiment, Compound 1HCl Form B has an XRP peak at 2θ scale ±0.2. The compound is characterized by one or more peaks in a D pattern, the one or more peaks being selected from 9.72, 15.89, 16.63, 17.37, 18.32, 19.51, 21.04, 21.30, 21.81, 23.40, 24.76, 26.20, and 27.71.

[0196] In another embodiment, Compound 1HCl Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.72, 17.37, 18.32, and 19.51.

[0197] In a further embodiment, Compound 1HCl Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 9.72, 17.37, 18.32, and 19.51.

[0198] In still further embodiments, Compound 1 HCl Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 9.72, 15.89, 16.63, 17.37, 18.32, 19.51, 21.04, 21.30, 21.81, 23.40, 24.76, 26.20, and 27.71.

[0199] In still further embodiments, Compound 1 HCl Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, said peaks being 8.20, 9.72, 9.81, 10.04, 10.56, 12.52, 12.97, 13.32, 13.48, 13.81, 14.35, 14.95, 15.89, 16.63, 17.37, 17.83, 17.99, 18.32, 19.15, 19.31, 19.51, 19.72, 20.17, 20.84, 21.04, 21.15, 21.30, 21.81, 22.02, 22.65, 23.11, 23.40, 23.75, 24.76, 25.34, 25.74, 26.20, 26.90, 27.71, 27.98, 28.34, and 28.98.

[0200] In still a further embodiment, Compound 1HCl Form B is characterized by an XRPD pattern substantially identical to FIG.

[0201] In one embodiment, the crystalline solid is characterized as Compound 1HCl Form C.

[0202] In still further embodiments, Compound 1 HCl Form C is characterized by one or more of the following peaks in an XRPD pattern at ±0.2 2θ scale: 2.5, 3.0, 4.3, 5.1, 6.2, 6.8, 7.3, 7.8, 8.8, 10.6, 11.6, 12.5, 13.3, 13.8, 15.3, 15.7, 17.1, 17.8, 19.0, 19.4, 20.0, 20.5, 20.8, 21.5, 22.2, 22.6, 23.0, 23.5, 23.9, 25.2, 26.2, 26.8, 27.2, 28.0, 28.9, and 29.5.

[0203] In one embodiment, Compound 1 HCl Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, and 29.5.

[0204] In another embodiment, Compound 1 HCl Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 2.5, 3.0, 4.3, 11.6, 17.1, 19.0, 20.5, 26.8, and 29.5.

[0205] In one embodiment, Compound 1HCl Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, and 29.5.

[0206] In still further embodiments, Compound 1 HCl Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, 8.8, 11.6, 17.1, 19.0, 20.5, 26.8, and 29.5.

[0207] In still further embodiments, Compound 1 HCl Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 2.5, 3.0, 4.3, 5.1, 6.2, 6.8, 7.3, 7.8, 8.8, 10.6, 11.6, 12.5, 13.3, 13.8, 15.3, 15.7, 17.1, 17.8, 19.0, 19.4, 20.0, 20.5, 20.8, 21.5, 22.2, 22.6, 23.0, 23.5, 23.9, 25.2, 26.2, 26.8, 27.2, 28.0, 28.9, and 29.5.

[0208] In still a further embodiment, Compound 1HCl Form C is characterized by an XRPD pattern substantially identical to FIG.

[0209] In one embodiment, the crystalline solid is characterized as Compound 1HCl Form D.

[0210] In still further embodiments, Compound 1 HCl Form D is characterized by one or more of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 3.47, 5.27, 6.93, 8.21, 8.97, 9.86, 10.16, 10.44, 10.69, 11.28, 12.26, 12.75, 13.27, 13.92, 14.23, 14.5 4, 14.95, 15.44, 15.58, 15.80, 16.08, 16.25, 17.84, 18.44, 18.65, 19.34, 19.75, 20.13, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.15, 24.39, 24.60, 24.91, 25.16, 26.27, 27.03, 27.61, and 28.37.

[0211] In one embodiment, Compound 1 HCl Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 3.47, 5.27, 10.16, 10.69, 12.26, 14.54, 14.95, 17.84, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.91, and 25.16.

[0212] In a further embodiment, Compound 1 HCl Form D is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 3.47, 5.27, 10.16, 10.69, 12.26, 14.54, 14.95, 17.84, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.91, and 25.16.

[0213] In still further embodiments, Compound 1 HCl Form D is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 3.47, 5.27, 6.93, 8.21, 8.97, 9.86, 10.16, 10.44, 10.69, 11.28, 12.26, 12.75, 13.27, 13.92, 14.23, 14.54, 14.95, 15.44, 15.58, 15.80, 16.08 , 16.25, 17.84, 18.44, 18.65, 19.34, 19.75, 20.13, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.15, 24.39, 24.60, 24.91, 25.16, 26.27, 27.03, 27.61, and 28.37.

[0214] In a further embodiment, Compound 1HCl Form D is characterized by an XRPD pattern substantially identical to FIG.

[0215] In one aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 hemifumarate or a hydrate or solvate thereof, wherein the crystalline salt form is hemifumarate compound 1·0.5 fumarate.

[0216] In another aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 Fumarate or a hydrate or solvate thereof, wherein the crystalline salt form is fumarate Compound 1·fumaric acid.

[0217] In one embodiment, the crystalline solid is characterized as Compound 1 fumarate Form A.

[0218] In a further embodiment, Compound 1 fumarate Form A is characterized by an XRPD pattern substantially identical to FIG.

[0219] In one aspect, the present invention provides a method for producing a compound of the structure [ka] Compound 1 hemifumarate The present invention includes a crystalline fumarate salt of Compound 1 having the formula:

[0220] In one embodiment of this aspect, the crystalline fumarate salt is characterized as Compound 1 hemifumarate Form B.

[0221] In one embodiment, the crystalline solid is characterized as Compound 1 hemifumarate Form B.

[0222] In one embodiment, Compound 1 hemifumarate Form B is characterized by one or more of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are 7.55, 7.92, 9.08, 9.40, 10.81, 11.18, 13.24, 13.35, 14.47, 14.90, 15.14, 15.89, 16.64, 16.95, 17. 14, 17.29, 17.44, 17.79, 18.24, 18.34, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 24.97, 25.17, 25.69, 26.34, 26.75, 27.05, 27.35, 27.50, and 27.88.

[0223] In one embodiment, Compound 1 hemifumarate Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88.

[0224] In one embodiment, Compound 1 hemifumarate Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05.

[0225] In one embodiment, Compound 1 hemifumarate Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05.

[0226] In one embodiment, Compound 1 hemifumarate Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88.

[0227] In one embodiment, Compound 1 hemifumarate Form B is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are: 7.55, 7.92, 9.08, 9.40, 10.81, 11.18, 13.24, 13.35, 14.47, 14.90, 15.14, 15.89, 16.64, 16.95, 17.1 4, 17.29, 17.44, 17.79, 18.24, 18.34, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 24.97, 25.17, 25.69, 26.34, 26.75, 27.05, 27.35, 27.50, and 27.88.

[0228] In still a further embodiment, Compound 1 hemifumarate Form B is characterized by an XRPD pattern substantially identical to FIG.

[0229] In one embodiment, Compound 1 hemifumarate Form B is characterized by an endotherm in a DSC thermogram at about 226° C. In one embodiment, Compound 1 hemifumarate Form B is characterized by an endotherm in a DSC thermogram with an onset temperature of about 226° C.

[0230] In one embodiment, Compound 1 hemifumarate Form B is characterized by negligible weight loss at a temperature of about 220° C. in a TGA thermogram.

[0231] In one embodiment, Compound 1 hemifumarate Form B is characterized by a weight gain of about 0.2 wt % as measured by DVS in an environment containing 5% relative humidity to 95% relative humidity.

[0232] In one aspect, the present invention provides a method for producing a compound having the general structure [ka] Compound 1 Phosphate Form A or a hydrate or solvate thereof, wherein the crystalline phosphate form is characterized as Compound 1 Phosphate Form A.

[0233] In one embodiment, Compound monophosphate Form A is characterized by one or more of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.3, 6.8, 10.3, 10.5, 11.4, 12.7, 13.8, 14.7, 15.7, 16.1, 17.3, 17.5, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 22.7, 23.2, 23.6, 24.7, 25.5, 27.4, 27.8, 28.5, 29.1, and 29.3.

[0234] In one embodiment, Compound 1 Phosphate Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are 6.3, 6.8, 10.5, 12.7, 13.8, 16.1, 17.3, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 23.2, 24.7, 27. 4, 27.8, and 28.5.

[0235] In another embodiment, Compound monophosphate Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.3, 6.8, 13.8, 16.1, 19.4, 20.3, 23.2, and 24.7.

[0236] In a further embodiment, Compound monophosphate Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.3, 6.8, 13.8, 16.1, 19.4, 20.3, 23.2, and 24.7.

[0237] In still further embodiments, Compound monophosphate Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 6.3, 6.8, 10.5, 12.7, 13.8, 16.1, 17.3, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 23.2, 24.7, 27.4, 27.8, and 28.5.

[0238] In still further embodiments, Compound monophosphate Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 6.3, 6.8, 10.3, 10.5, 11.4, 12.7, 13.8, 14.7, 15.7, 16.1, 17.3, 17.5, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 22.7, 23.2, 23.6, 24.7, 25.5, 27.4, 27.8, 28.5, 29.1, and 29.3.

[0239] In still a further embodiment, Compound monophosphate Form A is characterized by an XRPD pattern substantially identical to FIG.

[0240] In one aspect, the present invention provides a compound 1 [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) In one or more peaks in the XRPD pattern at 2θ scale ±0.20, the following peaks were observed: 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.0 ...2, 20.02, 20.02, 20.51, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20. one or more peaks selected from .46, 20.85, 21.45, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56; (ii) an endotherm with an onset temperature greater than 200°C in the DSC thermogram; (iii) weight loss at temperatures above 200°C in the TGA thermogram; (iv) a weight gain of about 0.8 to about 1.0 wt % as determined by DVS analysis when collected in a 5% relative humidity environment to a 95% relative humidity environment; and (v) Substantially identical to Figure 55 1 H NMR spectrum The present invention also includes the crystalline solid form characterized as Compound 1 Form A by at least one of:

[0241] In one aspect, the present invention provides a compound 1 [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) In one or more peaks in the XRPD pattern at 2θ scale ±0.20, the following peaks were observed: 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.0 ...2, 20.02, 20.02, 20.51, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20.00, 20. one or more peaks selected from .46, 20.85, 21.45, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56; (ii) an endotherm with an onset temperature greater than 200°C in the DSC thermogram; (iii) weight loss at temperatures above 200°C in the TGA thermogram; (iv) a weight gain of about 0.8 to about 1.0 wt % as determined by DVS analysis when collected in a 5% relative humidity environment to a 95% relative humidity environment; and (v) Substantially identical to Figure 55 1 H NMR spectrum The present invention includes the above crystalline solid form characterized by at least one of:

[0242] In one embodiment of this aspect, the crystalline solid form of Compound 1 is characterized as Form A.

[0243] In one embodiment, Compound 1 Form A is characterized by one or more peaks in an XRPD pattern at ±0.20 2θ scale, wherein the one or more peaks are selected from 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19.

[0244] In another embodiment, Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, the peaks being 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19.

[0245] In one embodiment, Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the peaks are: 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.00, 20.46, 20.85, 21.45, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56.

[0246] In one embodiment, Compound 1 Form A is characterized as Compound 1 Form A by at least two of (i), (ii), (iii), and (iv).

[0247] In further embodiments, Compound 1 Form A is characterized as Compound 1 Form A by at least three of (i), (ii), (iii), and (iv).

[0248] In still further embodiments, Compound 1 Form A is characterized as Compound 1 Form A by all of (i), (ii), (iii), and (iv).

[0249] In another aspect, the present invention provides a compound of formula I. [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.20 selected from 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42; (ii) an endotherm with an onset temperature of about 226°C in the DSC thermogram; (iii) a weight loss of about 0.2 wt % between temperatures of 40 and 180°C in a TGA thermogram; and (v) Substantially identical to Figure 56 1 H NMR spectrum The present invention also includes the crystalline solid form characterized as Compound 1 Form K by at least one of:

[0250] In another aspect, the present invention provides a compound of formula I. [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.20 selected from 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42; (ii) an endotherm with an onset temperature of about 226°C in the DSC thermogram; (iii) a weight loss of about 0.2 wt % between temperatures of 40 and 180°C in a TGA thermogram; and (v) Substantially identical to Figure 56 1 H NMR spectrum The present invention includes the above crystalline solid form characterized by at least one of:

[0251] In one embodiment of this aspect, the crystalline solid form of Compound 1 is characterized as Form K.

[0252] In one embodiment, Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.39, 8.10, 22.34, and 24.50.

[0253] In another embodiment, Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.39, 8.10, 22.34, and 24.50.

[0254] In another embodiment, Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, the peaks being 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42.

[0255] In another embodiment, Compound 1 Form K is characterized as Compound 1 Form K by at least two of (i), (ii), and (iii).

[0256] In further embodiments, Compound 1 Form K is characterized as Compound 1 Form K by all of (i), (ii), and (iii).

[0257] In another aspect, the present invention provides a compound of formula I. [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.20 selected from 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01; (ii) an endotherm with an onset temperature of about 194-195°C in a DSC thermogram; and (iii) A weight loss of approximately 11-12 wt% between 120 and 160°C in the TGA thermogram The present invention also includes the crystalline solid form described above, characterized as Compound 1 Form Q by at least one of:

[0258] In another aspect, the present invention provides a compound of formula I. [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.20 selected from 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01; (ii) an endotherm with an onset temperature of about 194-195°C in a DSC thermogram; and (iii) A weight loss of approximately 11-12 wt% between 120 and 160°C in the TGA thermogram The present invention includes the above crystalline solid form characterized by at least one of:

[0259] In one embodiment of this aspect, the crystalline solid form of Compound 1 is characterized as Form K.

[0260] In one embodiment, Compound 1 Form Q is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 8.61, 9.74, 16.07, and 20.04.

[0261] In another embodiment, Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, the peaks being 8.61, 9.74, 16.07, and 20.04.

[0262] In another embodiment, Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale: 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01.

[0263] In one embodiment, Compound 1 form Q is characterized as Compound 1 form Q by at least two of (i), (ii), and (iii).

[0264] In further embodiments, Compound 1 form Q is characterized as Compound 1 form Q by all of (i), (ii), and (iii).

[0265] In one aspect, the present invention provides a compound 1 [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.2 selected from 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88; (ii) an endotherm with an onset temperature of approximately 226°C in the DSC thermogram; (iii) negligible weight loss at temperatures of about 220°C in the TGA thermogram; (iv) a weight gain of about 0.2 wt % as measured by DVS in an environment purported to be between 5% relative humidity and 95% relative humidity; and (v) Substantially identical to Figure 54 1 H NMR spectrum The crystalline solid form is characterized as Compound 1 hemifumarate Form B by at least one of:

[0266] In one aspect, the present invention provides a compound 1 [ka] compound 1 or a crystalline solid form of a hydrate or solvate thereof, comprising: (i) one or more peaks in an XRPD pattern at a 2θ scale of ±0.2 selected from 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88; (ii) an endotherm with an onset temperature of approximately 226°C in the DSC thermogram; (iii) negligible weight loss at temperatures of about 220°C in the TGA thermogram; (iv) a weight gain of about 0.2 wt % as measured by DVS in an environment purported to be between 5% relative humidity and 95% relative humidity; and (v) Substantially identical to Figure 54 1 H NMR spectrum The present invention includes the above crystalline solid form characterized by at least one of:

[0267] In one embodiment of this aspect, the crystalline solid form of Compound 1 is characterized as hemifumarate Form B.

[0268] In one embodiment, Compound 1 hemifumarate Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05.

[0269] In one embodiment, Compound 1 hemifumarate Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are: 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05.

[0270] In another embodiment, Compound 1 hemifumarate Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale: 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88.

[0271] In one embodiment, Compound 1 hemifumarate Form B is characterized as Compound 1 hemifumarate Form B by at least two of (i), (ii), (iii), and (iv).

[0272] In further embodiments, Compound 1 hemifumarate Form B is characterized as Compound 1 hemifumarate Form B by at least three of (i), (ii), (iii), and (iv).

[0273] In still further embodiments, Compound 1 hemifumarate Form B is characterized as Compound 1 hemifumarate Form B by all of (i), (ii), (iii), and (iv).

[0274] In another aspect, the invention relates to a pharmaceutical composition comprising a crystalline form or a crystalline salt form described herein and a pharmaceutically acceptable excipient.

[0275] In yet another aspect, the present invention relates to a method for 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 of treatment a crystalline form or crystalline salt form described herein, or a pharmaceutical composition described herein.

[0276] In one embodiment of this aspect, the disease, disorder or syndrome mediated at least in part by modulating the in vivo activity of a protein kinase is cancer.

[0277] In one aspect, the invention relates to a method of inhibiting a protein kinase comprising contacting the protein kinase with a crystalline form or crystalline salt form described herein.

[0278] In one embodiment of this aspect, the protein kinase is Axl, Mer, c-Met, KDR, or a combination thereof.

[0279] In yet another aspect, the present invention relates to a process for preparing Compound 1 hemifumarate Form B, comprising contacting Compound 1 with fumaric acid in an organic solvent to form a mixture, and stirring the mixture.

[0280] In one embodiment of this aspect, the organic solvent is acetone.

[0281] In another embodiment, the mixture is stirred at a temperature of about 50°C.

[0282] In another embodiment, the mixture is stirred for about 6 days.

[0283] Crystalline Forms of the Present Invention

[0284] Compound 1 Form A

[0285] Compound 1 Form A is the predominant thermodynamically stable anhydrous / nonsolvated form of Compound 1 at RT. Characterization of Compound 1 Form A is provided herein by XRPD, DSC, TGA, DVS, and hot-stage microscopy.

[0286] The XRPD pattern for Compound 1 Form A is provided in Figure 1 and a list of peaks from the pattern is provided in Table 1 below.

[0287] Table 1: XRPD peaks of Compound 1 Form A [Table 1-1] [Table 1-2]

[0288] The XRPD pattern for Compound 1 Form A was successfully indexed, suggesting that the material consists primarily or exclusively of a single crystalline phase. The unit cell volume is consistent with anhydrous / unsolvated Compound 1.

[0289] Unit cell data for Compound 1 Form A: [Table 22]

[0290] The DSC and TGA thermograms for Compound 1 Form A are provided in Figures 2 and 3, respectively. Negligible weight loss was observed by TGA up to 220°C, consistent with an anhydrous / nonsolvated material. The sharp endotherm at approximately 230°C (onset) in the DSC thermogram likely corresponds to simultaneous melting and decomposition. The DSC thermograms of various samples of Compound 1 Form A show inconsistencies in the onset temperature of the endotherm. The variation in the onset temperature of the endotherm is , possibly due to concomitant decomposition. Due to interference from decomposition, these endothermic onset temperatures do not represent true melting points.

[0291] Compound 1 Form A was further analyzed by hot-stage microscopy (Figures 5A-5D). Observations upon heating are consistent with the DSC and TGA data described herein. An onset of melting accompanied by decomposition was noted at approximately 230°C, and a discoloration was observed at approximately 231°C.

[0292] Limited hygroscopicity of Compound 1 Form A was observed by DVS (Figure 4). The material steadily took up water vapor to approximately 0.91 wt% from 5% to 95% RH. All of this weight was lost upon desorption, exhibiting very little hysteresis. XRPD of the sample after DVS showed no change in crystalline form.

[0293] Determination of pKa and logP values ​​for Compound 1 Form A was performed by Pion Inc. / Sirius Analytical Instruments Ltd. Thus, Compound 1 Form A was determined to have a pKa of 5.43±0.4, a neutral logP of 4.50±0.5, and a cationic logP of 1.79±0.8.

[0294] Compound 1 Form B

[0295] Compound 1 Form B is an acetic acid solvate obtained from vapor diffusion experiments in acetic acid with diethyl ether.

[0296] The XRPD pattern for Compound 1 Form B is provided in Figure 6 and a list of peaks from the pattern is provided in Table 2 below.

[0297] Table 2: XRPD peaks of Compound 1 Form B [Table 2-1] [Table 2-2]

[0298] The XRPD pattern was successfully indexed, and the unit cell volume is large enough to accommodate the solvate 1.

[0299] Unit cell data for Compound 1 Form B [Table 23]

[0300] The proton NMR spectrum for Compound 1 Form B is consistent with the chemical structure of Compound 1 having 1 mole of acetic acid per mole of API present.

[0301] The TGA thermogram for Compound 1 Form B shows a weight loss of approximately 11.2% between 92° C. and 188° C. (FIG. 7), which equates to approximately 1.1 mol / mol if the weight loss corresponds exclusively to the loss of acetic acid.

[0302] Based on the TGA data, a drying experiment was set up for Compound 1 Form B by heating the material for about 5 minutes at about 200° C. The solid was observed to turn black, indicating decomposition under these conditions.

[0303] Compound 1 Form C

[0304] Compound 1 Form C is an HFIPA solvate obtained by anti-solvent precipitation from HFIPA with MTBE.

[0305] The XRPD pattern for Compound 1 Form C is provided in Figure 8 and a list of peaks from the pattern is provided in Table 3 below.

[0306] Table 3: XRPD peaks of Compound 1 Form C [Table 3-1] [Table 3-2]

[0307] The proton NMR spectrum of Compound 1 Form C is consistent with the chiral structure of Compound 1 and indicates the presence of 0.6 moles of HFIPA and 0.05 moles of MTBE per mole of API.

[0308] TGA analysis of Compound 1 Form C shows a weight loss of about 13.8% between 75°C and 154°C (Figure 9). If the weight loss corresponds to the loss of HFIPA, it equates to approximately 0.5 mol / mol. An additional weight loss step of about 1.9% is noted between 190°C and 220°C, likely due to the onset of decomposition.

[0309] Compound 1 Form D

[0310] Compound 1 Form D is a MeOH solvate obtained as a minor component of a mixture with Compound 1 Form A from a crush-cool experiment in MeOH from a slurry at sub-ambient conditions in MeOH.

[0311] The XRPD pattern for Compound 1 Form D is provided in Figure 10 and a list of peaks from the pattern is provided in Table 4 below.

[0312] Table 4: XRPD peaks of Compound 1 Form D [Table 4-1] [Table 4-2]

[0313] The XRPD pattern was successfully indexed, and the unit cell volume can accommodate up to 3 moles of solvate of 1 with MeOH.

[0314] Unit cell data for Compound 1 Form D [Table 24]

[0315] The proton NMR spectrum for Compound 1 Form D is consistent with the chiral structure of Compound 1, with 2 moles of MeOH present per mole of API.

[0316] TGA analysis of Compound 1 Form D shows that the material readily desolvates upon heating, losing approximately 13.5 wt% at temperatures between 38° C. and 130° C. (FIG. 11). This weight loss is equivalent to approximately 2.6 moles of MeOH, more than the 2 moles detected by proton NMR. Therefore, the weight loss by TGA can be attributed to the loss of MeOH and additional volatiles, such as water.

[0317] Drying Compound 1 Form D under vacuum at about 80-81° C. for 1 day resulted in conversion to an amorphous material with a few small peaks by XRPD.

[0318] Compound 1 Form E

[0319] Compound 1 Form E is a THF solvate obtained from crush-cooling experiments in THF and from crush-precipitation experiments from THF / water with heptane. Note that the solid collected from the crush-cooling experiments was white, whereas nearly all other Compound 1 forms exhibited colors such as tan, brown, or reddish-brown.

[0320] The XRPD pattern for Compound 1 Form E is provided in Figure 12 and a list of peaks from the pattern is provided in Table 5 below.

[0321] Table 5: XRPD peaks of Compound 1 Form E [Table 5-1] [Table 5-2]

[0322] The proton NMR spectrum is consistent with the chiral structure of compound 1, with 0.7 moles of THF present per mole of API.

[0323] The TGA thermogram shows a weight loss of approximately 8.2% between 60 and 130 °C (Figure 13). When THF is considered the only volatile, this weight loss corresponds to approximately 0.7 mol / mol, in agreement with the proton NMR spectrum.

[0324] Based on this data, drying Compound 1 Form E under vacuum at about 77° C. for 1 day resulted in its conversion to a new disordered material, designated Compound 1 Form M.

[0325] Compound 1 Form F

[0326] Compound 1 Form F is a chloroform solvate (approximately 0.7 moles of chloroform) obtained by slow evaporation from chloroform and from a RT slurry in chloroform (mixture with Compound 1 Form L).

[0327] The XRPD pattern for Compound 1 Form F is provided in Figure 14 and a list of peaks from the pattern is provided in Table 6 below.

[0328] Table 6: XRPD peaks of Compound 1 Form F [Table 6]

[0329] The proton NMR spectrum for Compound 1 Form F is consistent with the chemical structure of Compound 1 with 0.7 moles of chloroform per mole of API present.

[0330] The TGA thermogram for Compound 1 Form F showed a weight loss of approximately 14.4% between 77° C. and 178° C., equivalent to a loss of 0.7 mol / mol of chloroform when it was the only volatile (FIG. 15).

[0331] Based on the TGA data, a drying experiment was set up in which Compound 1 Form F was heated to about 175° C. for about 13 minutes. The material completely converted to a new material designated Compound 1 Form K. Note that discoloration to yellow and brown was observed during the heating experiment.

[0332] Compound 1 Form G

[0333] Similar to Compound 1 Form F, Compound 1 Form G is also a chloroform solvate (approximately 1 mole of chloroform) obtained by precipitation from chloroform at subambient temperatures.

[0334] The XRPD pattern for Compound 1 Form G is provided in Figure 16 and a list of peaks from the pattern is provided in Table 7 below.

[0335] Table 7: XRPD peaks of Compound 1 Form G [Table 7]

[0336] The proton NMR spectrum for Compound 1 Form G is consistent with the chiral structure of Compound 1 in the presence of 0.9 mol / mol chloroform.

[0337] The TGA thermogram for Compound 1 Form G, shown in Figure 17, shows a weight loss of approximately 20.8% between 40°C and 165°C. If chloroform is the only volatile, this equates to approximately 1.2 moles, slightly higher than the 0.9 moles detected by proton NMR. This may indicate a small amount of additional volatiles, such as water, or that the material was partially dried prior to NMR analysis. Note that the TGA weight loss for Compound 1 Form G begins at a lower temperature than that for Compound 1 Form F (40°C vs. 77°C), indicating that partial drying at ambient conditions may be possible.

[0338] A sample of Compound 1 Form G was heated at about 175° C. for about 10 minutes, similar to the drying conditions for Compound 1 Form F. This experiment resulted in conversion to the same form, Compound 1 Form K.

[0339] Compound 1 Form H

[0340] Compound 1 Form H is a potent DCM solvate obtained by steam stressing amorphous Compound 1 with DCM.

[0341] The XRPD pattern for Compound 1 Form H is provided in Figure 18 and a list of peaks from the pattern is provided in Table 8 below.

[0342] Table 8: XRPD peaks of Compound 1 Form H [Table 8-1] [Table 8-2]

[0343] The XRPD pattern was successfully indexed, and the unit cell volume can accommodate up to 1 mole of compound 1 with DCM.

[0344] Unit cell data for compound 1 form H [Table 25]

[0345] The sample was first analyzed by XRPD while wet with solvent. The solid was air-dried at ambient conditions for approximately 2 hours to remove residual solvent that interfered with characterization; however, the material partially desolvated and converted to a disordered material with peaks similar to a mixture of Compound 1 Form H and Compound 1 Form A. Therefore, Compound 1 Form H exhibited poor physical stability at ambient conditions and was not further characterized.

[0346] Compound 1 Form K

[0347] Compound 1 Form K consists of anhydrous / unsolvated Compound 1 and is obtained by drying two different chloroform solvates, Compound 1 Forms F and G, at about 175°C.

[0348] The XRPD pattern for Compound 1 Form K is provided in Figure 19, and a list of peaks from the pattern is provided in Table 9 below.

[0349] Table 9: XRPD peaks of Compound 1 Form K [Table 9]

[0350] The proton NMR spectrum for Compound 1 Form K is consistent with the chiral structure of Compound 1 and shows no signs of decomposition (negligible chloroform is detected).

[0351] The DSC and TGA thermograms for Compound 1 Form K are presented in Figures 20 and 21, respectively. Negligible weight loss was observed by TGA up to 180°C, indicating that the anhydrous / insoluble The DSC endotherm at approximately 220°C (onset) likely corresponds to simultaneous melting and decomposition.

[0352] Compound 1 form O

[0353] Compound 1 Form O is a potential TFE solvate of Compound 1 obtained from one or more salt screening experiments in TFE-containing solvent systems.

[0354] The XRPD pattern for Compound 1 Form O is provided in Figure 22 and a list of peaks from the pattern is provided in Table 10 below.

[0355] Table 10: XRPD peaks of Compound 1 Form O [Table 10-1] [Table 10-2]

[0356] The XRPD pattern was successfully indexed, and the unit cell volume was capable of accommodating up to 1 mole of TFE with compound 1. The material was not further characterized.

[0357] Unit cell data for compound 1 form O [Table 26]

[0358] Compound 1 Form P

[0359] Compound 1 Form P is the predominant hydrate of Compound 1, observed only in admixture with small amounts of Compound 1 Form A.

[0360] The XRPD pattern for Compound 1 Form P is provided in Figure 22 and a list of peaks from the pattern is provided in Table 11 below.

[0361] Table 11: XRPD peaks of Compound 1 Form P [Table 11-1] [Table 11-2]

[0362] Despite existing as a mixture, the XRPD pattern of Compound 1 Form P was successfully indexed. The peaks at 11.36°, 14.35°, and 28.18° did not fit the indexing solution and were attributed to Compound 1 Form A. The unit cell volume per molecule is larger than that of Compound 1 Form A and can potentially accommodate up to 2 mol / mol of water.

[0363] Unit cell data for compound 1 form P [Table 27]

[0364] The proton NMR spectrum of the mixture is consistent with the chiral structure of compound 1, with negligible THF present.

[0365] The DSC thermogram is shown in Figure 24. Small, overlapping, broad endotherms were observed at 90°C and 109°C, consistent with dehydration. No other thermal events, such as recrystallization or melting, were observed after these events, suggesting a loss of crystallinity after dehydration.

[0366] Compound 1 Form Q

[0367] Compound 1 form Q was characterized by XPRD, DSC, TGA, and SEM (not shown).

[0368] The XRPD pattern for Compound 1 Form Q is provided in Figure 25 and a list of peaks from the pattern is provided in Table 12 below.

[0369] Table 12: XRPD peaks of Compound 1 Form Q [Table 12-1] [Table 12-2]

[0370] The XRPD pattern for Compound 1 Form Q was successfully indexed using a unit cell that is isostructural with the 2,2,2-trifluoroethanol (TFE) solvate, Compound 1 Form O.

[0371] Unit cell data for compound 1 form Q [Table 28]

[0372] DSC (Figure 26) showed a small shallow peak followed by a broad peak consistent with weight loss in thermogravimetric analysis and a final sharp endotherm with an onset of approximately 194-195°C.

[0373] The TGA weight loss, consistent with the broad endotherm in DSC, was approximately 11-12% (Figure 27).

[0374] Scanning electron microscope images were obtained for two Compound 1 Form Q samples at magnifications ranging from 100x to over 5000x. The first sample contained aggregates greater than 200 μm composed of flakes smaller than 20 μm. The second sample consisted of blades at least 50 μm long and 5 μm wide or less.

[0375] Compound 1 fumarate form A

[0376] Compound 1 fumarate Form A was made from a hot slurry consisting of acetone, fumaric acid, and the free base of Compound 1. The hot slurry was stirred for 4 days, followed by a RT slurry stirred for an additional day.

[0377] The XRPD pattern of Compound 1 fumarate Form A is provided in FIG.

[0378] Compound 1 hemifumarate form B

[0379] Compound 1 hemifumarate Form B is an anhydrous salt of Compound 1. This form is physically stable at 40°C and 75% RH for 15 days, and no disproportionation was evident in either acetone or water. This form is also not hygroscopic by DSC analysis. By DSC and hot-stage microscopy, Compound 1 hemifumarate Form B exhibits a higher melting onset near 225°C compared to the other crystalline salts identified in this study.

[0380] Compound 1 hemifumarate Form B was prepared by the method described below.

[0381] Compound 1 (199.0 mg) was combined with 2 molar equivalents of fumaric acid (88.8 mg). The mixture was slurried in 10 mL of acetone at approximately 50° C. Compound 1 hemifumarate form A spatula filled with seeds from B was added to the slurry. After 6 days at about 50° C., the pale pink solid was collected by vacuum filtration, dried on filter paper, and exposed to air under reduced pressure for approximately 5 minutes.

[0382] The XRPD pattern for Compound 1 hemifumarate Form B is provided in Figure 29, and a list of peaks from the pattern is provided in Table 13 below.

[0383] Table 13: XRPD peaks of Compound 1 hemifumarate salt Form B [Table 13-1] [Table 13-2]

[0384] The XRPD pattern of Compound 1 hemifumarate Form B was successfully indexed, indicating that the material is composed of a single crystalline phase. It has a triclinic unit cell containing two molecules of Compound 1 and one molecule of fumaric acid. The formula unit volume calculated from the indexing solution is consistent with the anhydrous form.

[0385] Unit cell data for compound 1 hemifumarate form B [Table 29]

[0386] 1 The H NMR spectrum is consistent with the chiral structure of Compound 1. Based on peak integration, there are approximately 0.5 moles of fumaric acid per mole of Compound 1, consistent with Compound 1 hemifumarate. Negligible amounts of residual acetone are also evident.

[0387] The TGA thermogram trace (Figure 31) shows negligible weight loss upon decomposition. The DSC thermogram trace (Figure 30) shows a single endotherm with an onset of approximately 225°C (132.6 J / g).

[0388] Hot stage micrographs for Compound 1 hemifumarate Form B (Figures 33A-33D) confirm the event as melting with simultaneous decomposition.

[0389] The DVS isotherm (Figure 32) shows that the form is not hygroscopic. Compound 1 hemifumarate Form B exhibits less than 0.2% weight gain / loss during sorption / desorption experiments without hysteresis.

[0390] The material recovered from the experiment remained unchanged and was identified as Compound 1 hemifumarate Form B by XRPD.

[0391] The physical stability of hemifumarate Form B was investigated. Compound 1 hemifumarate Form B was slurried in water at ambient conditions for approximately 24 hours. In separate experiments, the material was repeatedly washed with acetone. Both recovered materials were identified as Compound 1 hemifumarate Form B by XRPD analysis, indicating that these conditions did not cause disproportionation of the salt. Additionally, material exposed to 75% RH / 40°C for approximately two weeks remained unchanged by XRPD.

[0392] Compound 1 hemifumarate Form B was successfully reproduced at 200 and 1 g laboratory scale, suggesting that Compound 1 hemifumarate Form B can be produced relatively easily and reproducibly.

[0393] Compound 1HCl Form A

[0394] Compound 1 HCl Form A was made by slurrying Compound 1 and HCl in TGF at room temperature.

[0395] The XRPD pattern for Compound 1HCl Form A is provided in Figure 34, and a list of peaks from the pattern is provided in Table 14 below.

[0396] Table 14: XRPD peaks of Compound 1 HCl Form A [Table 14-1] [Table 14-2]

[0397] The XRPD pattern for Compound 1HCl Form A was successfully indexed.

[0398] Unit cell data for Compound 1 Form A [Table 30]

[0399] Compound 1HCl Form B

[0400] Compound 1 HCl Form B was made by slurrying Compound 1 and HCl in chloroform at elevated temperature.

[0401] The XRPD pattern for Compound 1HCl Form B is provided in Figure 35 and a list of peaks from the pattern is provided in Table 15 below.

[0402] Table 15: XRPD peaks of Compound 1 HCl Form B [Table 15-1] [Table 15-2]

[0403] Compound 1HCl Form C

[0404] Compound 1HCl Form C was made by a procedure involving crystallization from methanol using MTBE as an anti-solvent.

[0405] The XRPD pattern of Compound 1HCl Form C is provided in FIG.

[0406] The XRPD pattern of Compound 1 HCl Form C contains the following peaks on the ±0.2 degree 2θ scale: 2.5, 3.0, 4.3, 5.1, 6.2, 6.8, 7.3, 7.8, 8.8, 10.6, 11.6, 12.5, 13.3, 13.8, 15.3, 15.7, 17.1, 17.8, 19.0, 19.4, 20.0, 20.5, 20.8, 21.5, 22.2, 22.6, 23.0, 23.5, 23.9, 25.2, 26.2, 26.8, 27.2, 28.0, 28.9, and 29.5.

[0407] Compound 1HCl Form D

[0408] Compound 1 HCl Form D was made by first slurrying Compound 1 in acetone at about 50° C., adding 2 molar equivalents of acid, and stirring the resulting acidic slurry for 5 days at about 50° C. The product was collected by positive pressure filtration.

[0409] The XRPD pattern for Compound 1HCl Form D is provided in Figure 37, and a list of peaks from the pattern is provided in Table 16 below.

[0410] Table 16: XRPD peaks of Compound 1 HCl Form D [Table 16-1] [Table 16-2]

[0411] Compound 1 Phosphate Form A

[0412] Compound 1 phosphate Form A was made by adding 1 molar equivalent of phosphoric acid to a slurry of Compound 1 in chloroform and slurrying at elevated temperature for 3 days.

[0413] The XRPD pattern of Compound 1 Phosphate Form A is provided in Figure 48 and a list of peaks from the pattern is provided below.

[0414] The XRPD pattern of Compound 1 phosphate Form A contains the following peaks on the 2θ scale ±0.2 degrees: 6.3, 6.8, 10.3, 10.5, 11.4, 12.7, 13.8, 14.7, 15.7, 16.1, 17.3, 17.5, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 22.7, 23.2, 23.6, 24.7, 25.5, 27.4, 27.8, 28.5, 29.1, and 29.3.

[0415] General Administration

[0416] Administration of the crystalline forms or crystalline salt forms of the present invention in pure form or in a suitable pharmaceutical composition can be via any acceptable mode of administration or agent to provide similar utilities, such as oral, nasal, parenteral (intravenous, intramuscular, or subcutaneous), topical, transdermal, vaginal, intravesical, intracisternal, or rectal, in 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 easy administration of precise dosages.

[0417] The compositions contain conventional pharmaceutical excipients and the crystalline form or crystalline salt form of the present invention as an active agent, and may also contain other medicinal agents, pharmaceuticals, excipients, adjuvants, etc. The compositions of the present invention may be used in combination with anticancer drugs or other drugs commonly administered to patients undergoing cancer treatment. Adjuvants include preservatives, wetting agents, suspending agents, sweeteners, flavorings, perfumes, 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 achieved by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[0418] If desired, the pharmaceutical compositions of the present invention 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.

[0419] Compositions suitable for parenteral injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, , suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous excipients, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate. The appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0420] One preferred route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state being treated.

[0421] 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 conventional excipient, such as sodium citrate or dicalcium phosphate, or (a) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; (c) a humectant, such as glycerol; (d) a disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia; In the case of capsules, tablets, and pills, the dosage form may contain buffering agents, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.

[0422] The solid dosage forms described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. These may contain soothing agents and may be of a composition that releases the active compound(s) in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active compound can also be in microencapsulated form, if appropriate, using one or more of the above-mentioned excipients.

[0423] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.Such dosage forms can be prepared by dissolving or dispersing the crystalline form or crystalline salt form of Compound 1 and optional pharmaceutical adjuvants in excipients such as water, saline, aqueous dextrose, glycerol, ethanol, etc.; solubilizers and emulsifiers 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.

[0424] Suspensions may contain, in addition to the active compound, 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.

[0425] Compositions for rectal administration are, for example, suppositories which can be prepared by mixing a crystalline form or crystalline salt form of Compound 1 with a suitable non-irritating excipient, such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and will melt while in a suitable body cavity and release the active ingredient therein.

[0426] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vehicle and, if necessary, preservatives, buffers, or propellants. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated within the scope of the present invention.

[0427] Generally, depending on the intended mode of administration, a pharmaceutically acceptable composition contains from about 1% to about 99% by weight of the crystalline form or crystalline salt form of Compound 1 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 the crystalline form or crystalline salt form of Compound 1, with the remainder being suitable pharmaceutical excipients.

[0428] Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, 21 st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). The composition to be administered will, in any event, contain a therapeutically effective amount of a crystalline form or crystalline salt form of Compound 1, or a pharmaceutically acceptable salt thereof, in accordance with the teachings of the present invention.

[0429] The crystalline or crystalline salt forms of Compound 1 are administered in therapeutically effective amounts that vary depending on a variety of factors, including the activity of Compound 1, the metabolic stability and duration of action of Compound 1, age, body weight, overall health, sex, diet, mode and time of administration, rate of excretion, drug combinations, the severity of the specific disease state, and current treatments of the host. The crystalline or crystalline salt forms of Compound 1 may be administered to a patient at dosage levels ranging from about 0.1 to about 1,000 mg / day. For a normal human adult weighing approximately 70 kilograms, for example, dosages range from about 0.01 to about 100 mg / kg body weight / day. However, the specific dosages used may vary. For example, dosages may depend on numerous factors, including the patient's needs, the severity of the condition being treated, and the pharmacological activity of the compound being used. Determining optimal dosages for a particular patient is within the skill of one of ordinary skill in the art.

[0430] Combination therapy

[0431] The crystalline forms or crystalline salt forms of Compound 1 disclosed herein can be administered as a sole therapy or can be administered in combination with one or more additional therapies ("co-administered") for the treatment of a disease or disorder, such as a hyperproliferative disease or disorder, such as cancer. Treatments that can be used in combination with the compounds disclosed herein include: (i) surgery; (ii) radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CART cell therapy; and (v) other chemotherapeutic agents.

[0432] The term "co-administered" ("co-administer") refers to either simultaneous administration or any separate, sequential administration method of a crystalline form or crystalline salt form of Compound 1 disclosed herein and an active pharmaceutical ingredient(s), including cytotoxic agents and radiation treatment. When administration is not simultaneous, the compounds are administered in close temporal proximity to each other. Furthermore, when the compounds are administered in the same It does not matter if they are administered in the same dosage form, for example one compound may be administered topically and another compound may be administered orally.

[0433] Typically, any agent active against the disease or condition being treated may be co-administered. Examples of such agents for cancer treatment are found, for example, at https: / / www.cancer.gov / about-cancer / treatment / drugs (last accessed January 22, 2019), and in publicly available sources, such as Cancer Principles and Practice of Oncology by V.T.Devita 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 agents would be useful based on the particular characteristics of the drugs and diseases involved.

[0434] In one embodiment, the method of treatment comprises co-administration of a crystalline form or crystalline salt form of Compound 1 disclosed herein and at least one immunotherapy. Immunotherapy (also called biological response modifier therapy, biologic therapy, biological therapy, immunotherapy, or biological therapy) is a treatment that uses parts of the immune system to fight disease. Immunotherapy can help the immune system recognize or improve its 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 produced outside the body.

[0435] Examples of active immunotherapies include vaccines, including, but not limited to, cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or tumor infiltrating lymphocyte (TIL) vaccines with interleukin-2 (IL-2) or lymphokine-activated killer (LAK) cell therapy.

[0436] Examples of passive immunotherapy include, but are not limited to, targeted therapies involving monoclonal antibodies and toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies have no drug or radioactive material attached, while conjugated monoclonal antibodies are bound to, for example, chemotherapy drugs (chemical labels), radioactive particles (radiolabels), or toxins (antitoxins). Examples of these naked monoclonal antibody drugs include, but are not limited to, rituximab (Rituxan), an antibody against the CD20 antigen, used, for example, to treat B-cell non-Hodgkin's lymphoma; trastuzumab (Herceptin), an antibody against the HER2 protein, used, for example, to treat advanced breast cancer; alemtuzumab (Campath), an antibody against the CD52 antigen, used, for example, to treat B-cell chronic lymphocytic leukemia (B-CLL); cetuximab (Erbitux), an antibody against the EGFR protein, used, for example, in combination with irinotecan to treat advanced colon cancer and head and neck cancer; and bevacizumab (Avastin), an anti-angiogenic drug that acts against the VEGF protein and is used, for example, in combination with chemotherapy, to treat metastatic colon cancer. Examples of conjugated monoclonal antibodies include, but are not limited to, the radiolabeled antibody ibritumomab tiuxetan (Zevalin), which delivers radiation directly to cancerous B lymphocytes and is used, for example, to treat B-cell non-Hodgkin's lymphoma; the radiolabeled antibody tositumomab (Bexxar), which is used, for example, to treat certain types of non-Hodgkin's lymphoma; and the antitoxin gemtuzumab ozogamicin (Mylotarg), which contains calicheamicin and is used, for example, to treat acute myeloid leukemia (AML). For example, conjugated monoclonal antibodies for treating hairy cell leukemia, antitoxins for treating leukemia, lymphoma, and brain tumors, and radiolabeled antibodies, for example, OncoScint for colon and ovarian cancer, and ProstaScint for prostate cancer.

[0437] Further examples of therapeutic antibodies that may be used include, but are not limited to, HERCEPTIN™ (trastuzumab), a humanized anti-HER2 monoclonal antibody (Genentech, Calif.), for the treatment of patients with metastatic breast cancer; REOPRO™, an anti-glycoprotein IIb / IIIa receptor on platelets, for the prevention of blood clot formation.(abciximab) (Centocor); ZENAPAX™ (daclizumab), an immunosuppressive humanized anti-CD25 monoclonal antibody for the prevention of acute renal allograft rejection (Roche Pharmaceuticals, Switzerland); PANOREX™, a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Wellcome / Centocor); BEC2 (ImClone System), a murine anti-idiotypic (GD3 epitope) IgG antibody; IMC-C225 (ImClone System), a chimeric anti-EGFR IgG antibody; VITAXIN™, a humanized anti-alpha V beta 3 integrin antibody (Applied Molecular Evolution / MedImmune); Campath 1H / LDP-03 (Leukosite), a humanized anti-CD52 IgG1 antibody; Smart M195 (Protein Design Lab / Kanebo), a humanized anti-CD33 IgG antibody; and chimeric anti-CD20 RITUXAN™, an 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 (anti-CD3; Protein Design Labs); CM3 (ICOS Pharm), a humanized anti-ICAM3 antibody; IDEC-114 (IDEC Pharm / Mitsubishi), a primatized anti-CD80 antibody; ZEVALIN™, a radiolabeled murine anti-CD20 antibody (IDEC / Schering) AG); IDEC-131 (IDEC / Eisai), a humanized anti-CD40L antibody; IDEC-151 (IDEC), a primatized anti-CD4 antibody; IDEC-152 (IDEC / Seikagaku), a primatized anti-CD23 antibody; SMART anti-CD3 (Protein Design Lab), a humanized anti-CD3 IgG; and 5G1, a humanized anti-complement factor 5 (C5) antibody.1 (Alexion Pharm); D2E7 (CAT / BASF), a humanized anti-TNF-alpha antibody; CDP870 (Celltech), a humanized anti-TNF-alpha Fab fragment; IDEC-151 (IDEC Pharm / SmithKline Beecham), a primatized anti-CD4 IgG1 antibody; MDX-CD4 (Medarex / Eisai / Genmab), a human anti-CD4 IgG antibody; CD20-streptavidin (+biotin-yttrium 90; NeoRx); CDP571 (Celltech), a humanized anti-TNF-alpha IgG4 antibody; LDP-02 (LeukoSite / Genentech), a humanized anti-alpha4beta7 antibody; OrthoClone OKT4A (Ortho Biotech), a humanized anti-CD4 IgG antibody; ANTOVA™ (Biogen), a humanized anti-CD40L IgG antibody; and humanized anti-VLA-4 ANTEGREN™ (Elan), an IgG antibody; and CAT-152 (Cambridge AbTech), a human anti-TGF-beta 2 antibody. Others are provided in the following paragraphs.

[0438] Immunotherapies that may be used in combination with the crystalline forms or crystalline salt forms of Compound 1 disclosed herein include adjuvant immunotherapy, such as cytokines, e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (GM-CSF), and granulocyte-colony stimulating factor (GC-CSF). (G-CSF), macrophage inflammatory protein (MIP)-1-alpha, 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-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); bacillus Calmette-Guerin (BCG); keyhole limpet hemocyanin (KLH); Freund's incomplete 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-alpha.

[0439] In various embodiments, the crystalline form or crystalline salt form of Compound 1 may be combined with an immunological therapy and / or immunotherapeutic agent. In various embodiments, the immunological therapy and / or immunotherapeutic agent may include one or more of the following: adoptive immune cell transfer, angiogenesis inhibitors, bacillus Calmette-Guérin 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. Immunological therapies or immunotherapeutic agents are collectively referred to herein as "immunotherapeutic agents."

[0440] The present disclosure provides methods for preventing, treating, reducing, 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 synergistic anti-tumor activity and / or anti-tumor activity that is stronger than the additive effect of administering the crystalline form or crystalline salt form of Compound 1 or the immunotherapeutic agent alone.

[0441] 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 tumor suppressive potential due to its broad ability and exquisite specificity to respond to diverse tumor antigens. Furthermore, the immune system demonstrates considerable plasticity and memory components. Successful exploitation of all these attributes of the adaptive immune system makes immunotherapy unique among all cancer treatment methods.

[0442] The present disclosure provides combinations of a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent. These exemplary combinations can be used to treat subjects with cancer. In various embodiments, immunotherapeutic agents that find utility in the present compositions, formulations, and methods can include one or more agents or therapies, including adoptive immune cell transfer, angiogenesis inhibitors, bacillus Calmette-Guérin therapy, biochemotherapy, cancer vaccines, chimeric antigen receptor (CAR) T-cell therapy, cytokine therapy, gene therapy, immune checkpoint modulators, e.g., immune checkpoint inhibitors, immunoconjugates, radioconjugates, oncolytic virus therapy, or targeted drug therapy.

[0443] In certain embodiments of the present disclosure, the therapeutically effective combination comprises a crystalline form or a crystalline salt form of Compound 1 and an immunotherapeutic agent. The crystalline form or crystalline salt form of Compound 1 enhances the activity of immunotherapeutic agents.

[0444] In certain embodiments of each of the above aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of a crystalline form or crystalline salt form of Compound 1 of the invention.

[0445] In certain embodiments of each of the above aspects, as well as other aspects and embodiments described elsewhere herein, the crystalline form 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.) modulating agent selected from agonists or activators of costimulatory molecules, and which is a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen-binding sites, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct, as known in the art. In some embodiments, the immunotherapeutic agent can be an antibody that modulates a costimulatory molecule that binds to an antigen on the surface of an immune cell or cancer cell. In each of these different embodiments, the antibody modulating agent 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 barstar, a scFv-Fc, a sc(Fab)2, a trimeric antibody construct, a triabody antibody construct, a trimericbody antibody construct, a Tribody antibody construct, a Collabody antibody construct, a (scFv-TNFα)3, or a F(ab)3 / DNL antibody construct.

[0446] In certain embodiments of each of the above aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulates an 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 increases 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.

[0447] In some embodiments, the treatment method may include administering a crystalline form or 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 may be any molecule, agent, treatment, and / or method that inhibits an immune checkpoint and / or promotes an inhibitor of an immune checkpoint, e.g., by promoting endogenous immune checkpoint inhibitors; inhibiting transcription factors involved in immune checkpoint expression; and / or acting in concert with some additional exogenous factor. For example, a checkpoint inhibitor may include a treatment that inhibits a transcription factor involved in the expression of an immune checkpoint gene or promotes the expression 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). Checkpoint inhibitors may also inhibit the transcription of immune checkpoint genes; the modification and / or processing of immune checkpoint mRNA; the translation of immune checkpoint proteins; and / or the activation of molecules involved in immune or immune checkpoint pathways, such as PD-1 transcription factors, HIF-1, STAT3, NF-κB, and AP-1, or general oncogenic pathways, such as JAK / STAT, RAS / ERK, or PI3K / AKT / mTOR (Zerdes et al., Genetic, tra Inscriptional 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.

[0448] Checkpoint inhibitors can include treatments, molecules, agents, and / or methods that regulate immune checkpoints at the transcriptional level, for example, using RNA interference pathway co-suppression and / or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNAs; silencing-RNAs, small-interfering RNAs, or short-interfering RNAs (siRNAs)). Transcriptional regulation of checkpoint molecules has been shown to involve mir-16, which has been shown to target the 3'UTRs 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 (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).

[0449] T cell-specific aptamer-siRNA chimeras have been suggested as a method for highly specific inhibition of molecules in immune checkpoint pathways (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).

[0450] Alternatively, members of immune checkpoint pathways can be inhibited using treatments that affect related pathways, such as metabolism. For example, CAD macrophage-promoted expression of PD-L1 via induction of the bone morphogenetic protein 4 / phosphorylated SMAD1 / 5 / IFN regulatory factor 1 (BMP4 / p-SMAD1 / 5 / IRF1) signaling pathway results in an oversupply of the glycolytic intermediate pyruvate in mitochondria. Thus, administering treatments that modulate metabolic pathways can result in subsequent modulation of the immune inhibitory 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).

[0451] Checkpoint immunity can be controlled through oncolytic viruses, which selectively replicate in tumor cells and induce acute immune responses in the tumor microenvironment, i.e., act as gene vectors to deliver specific agents (e.g., antibodies, miRNA, siRNA, etc.) to cancer cells, and induce oncolysis and secretion of cytokines and chemokines, synergizing with immune checkpoint blockade (Shi et al., Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints, Int J Mol Sci. 2018 May;19(5):1389). Currently, the following viruses are being investigated: poliovirus, measles virus, and rabies virus. Clinical trials are underway utilizing 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); as checkpoint inhibitors.

[0452] Checkpoint inhibitors may act at the translational stage of checkpoint immunity. Translation of mRNA into protein represents a key event in the regulation of gene expression, and therefore, inhibiting immune checkpoint translation is a way in which immune checkpoint pathways can be inhibited.

[0453] 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 the 3' end). Inhibition can occur by targeting the anticodon of the initiator methionyl-transfer RNA (tRNA) (Met-tRNAi), its base pairing with the initiation codon, or the 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 stage 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.

[0454] Checkpoint inhibition can be achieved by preventing the formation of the preinitiation complex (PIC) through destabilization of eIF2α, preventing its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by preventing TCs from associating with the 40S ribosome and / or other initiation factors; by inhibiting the eIF4F complex and / or the cap-binding protein eIF4E, the scaffolding protein eIF4G, or the eIF4A helicase. Methods for examining translational regulation in cancer are described 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.

[0455] Checkpoint inhibitors can also include treatments, molecules, agents, and / or methods that regulate immune checkpoints at the cellular and / or protein level, for example, by inhibiting immune checkpoint receptors. Checkpoint inhibition can be achieved through the use of antibodies, antibody fragments, antigen-binding fragments, small molecules, and / or other drugs, agents, treatments, and / or methods.

[0456] Immune checkpoints refer to inhibitory pathways in the immune system that are involved in maintaining self-tolerance and regulating the magnitude of the immune system's response to minimize surrounding tissue damage. However, tumor cells can also activate immune system checkpoints to reduce the effectiveness of the immune response against tumor tissue ("block" the immune response). In contrast to most anticancer drugs, checkpoint inhibitors do not directly target tumor cells, but rather target lymphocyte receptors or their ligands to enhance the immune system's intrinsic antitumor activity. (Pardoll, 2012, Nature Reviews Cancer 12:252-264)

[0457] 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 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-beta modulator, a TIM-3 modulator, a SIRP-alpha 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, which may be in the form of a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding sites, a trispecific antibody, or an immune cell engaging multivalent antibody / fusion protein / construct, as known in the art).

[0458] 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.

[0459] PD-1 (also known as programmed death 1, CD279, or PDCD1) is a cell surface receptor that plays an important role in controlling the balance between stimulatory and inhibitory signals in the immune system and maintaining peripheral tolerance (Ishida, Y et al. 1992 EMBO J. 11 3887; Kier, Mary E et al. 2008 Annu 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, homologous to CD28. PD-1 is a monomeric type 1 transmembrane protein consisting of an immunoglobulin variable-like extracellular domain and a cytoplasmic domain containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based switch motifs (ITSMs). PD-1 expression can be induced, for example, on T cells, B cells, natural killer (NK) cells, and monocytes upon lymphocyte activation 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 and then binds to the TCR or BCR. It dephosphorylates effector molecules activated by signal transduction (Chemnitz, J et al. 2004 J Immunol 173:945-954; Riley, James L 2009 Immunological Reviews 229:114-125). Thus, PD-1 transduces inhibitory signals into T and B cells only when simultaneously engaged with the TCR or BCR.

[0460] 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 a state of unresponsiveness in T cells, resulting in cells that are unable to clonally expand or produce optimal levels of effector cytokines. PD-1 can also induce apoptosis in T cells through its ability to inhibit survival signals from costimulation, resulting in 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 (Tregs). For example, PD-L1 expressed on dendritic cells has been shown to synergize with TGF-β to promote the induction of CD4+FoxP3+ Tregs with enhanced suppressor function (Francisco, Loise M, et al. 2008 Annu Rev Immunol 26:677-704). et al. 2009 J Exp Med 206:3015-3029).

[0461] 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 single-pass type 1 membrane protein of approximately 33.4 kDa that is involved in immune responses (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance, Nat. Immunol. 4:1093-1101(2003)).

[0462] TIM-3 is selectively expressed in Th1 cells and phagocytes (e.g., macrophages and dendritic cells). Reducing human TIM-3 expression using siRNA or a blocking antibody resulted in increased interferon-γ (IFN-γ) secretion from CD4-positive T cells, suggesting an inhibitory role of TIM-3 in human T cells. Analysis of clinical samples from patients with autoimmune diseases did not demonstrate TIM-3 expression in CD4-positive cells. In particular, TIM-3 expression levels were lower and IFN-γ secretion was higher in T cell clones derived from the cerebrospinal fluid of patients with multiple sclerosis than in clones derived from normal healthy individuals (Koguchi K et al., J Exp Med. 203:1413-8. (2006)).

[0463] TIM-3 is the receptor for the ligand galectin-9, a member of the galectin family, a molecule ubiquitously expressed in various cell types, and a β-galactoside; phosphatidylserine (PtdSer) (DeKryff et al. 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-infiltrate 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 carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, also known as BGP, BGP1, BGP1, 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).

[0464] 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 (herpesvirus 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, a member of the CD28 family of the immunoglobulin superfamily, with the costimulatory tumor necrosis factor (TNF) receptor (TNFR), HVEM, is unique in that it defines 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 BTLA's ability to recruit either SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in a manner distinct from PD-1 and that both tyrosine-based motifs are required to block T cell activation. The BTLA cytoplasmic tail also contains a third conserved tyrosine-containing motif within the cytoplasmic domain, similar to the sequence of the Grb-2 recruitment site (YXN). Furthermore, phosphorylated peptides containing this BTLA N-terminal tyrosine motif can interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain to be investigated 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.

[0465] 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 MMP2 activation (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).

[0466] LAG-3 (lymphocyte-activation gene 3, also known as LAG3, CD223, and lymphocyte activation 3) is a protein involved in lymphocyte activation that also binds to HLA class-II antigens. LAG-3 is a single-pass type I membrane protein of approximately 57.4 kDa that contributes to the regulation of immune responses in 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., 2013). LAG-3 is expressed in the chromosome 12 of the thymocyte, thymocyte, and thymocytes (Huard 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 an important 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 domain 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). Additionally, CD4+CD25+ regulatory T cells (Tregs) have been shown to express LAG-3 upon activation, contributing 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).

[0467] 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).

[0468] In addition, several kinases, such as CHEK-1, CHEK-2, and A2aR, are known to be checkpoint inhibitors.

[0469] 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 non-replicating DNA.

[0470] CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, and checkpoint kinase 2) is an approximately 60.9 kDa serine / threonine-protein kinase involved in checkpoint-mediated cell cycle arrest, DNA repair activation, and double-strand break-mediated apoptosis. is.

[0471] A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) is an approximately 44.7 kDa multipass membrane receptor for adenosine and other ligands.

[0472] 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, TGF-beta, 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 natural killer (NK) cell activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppression of an immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or treatment that inhibits Treg activity, hi some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of an inhibitory immune checkpoint receptor.

[0473] In some embodiments, the disclosed combination comprises a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent, wherein the immunotherapeutic agent comprises a T cell modulating agent selected from an agonist or activator of a costimulatory molecule. In one embodiment, the costimulatory molecule agonist is selected from an agonist (e.g., an agonist antibody or antigen-binding fragment thereof, or a soluble fusion) of 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 CD83 ligand. 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)).

[0474] 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 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.

[0475] 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 an inhibitor of: 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 TGFbeta, 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.

[0476] In one embodiment, the immunotherapeutic agent is an agonist of a protein that stimulates 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.

[0477] In some embodiments, the immunotherapeutic agent used in the combinations disclosed herein (e.g., in combination with a crystalline form 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 an agonist (e.g., an agonist antibody or antigen-binding fragment thereof, or a soluble fusion) of 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 CD83 ligand.

[0478] 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 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 sites, a trispecific antibody, or an immune cell-engaging multivalent antibody / fusion protein / construct, known in the art, that binds to an 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.

[0479] In some embodiments, the combination comprises a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent, wherein 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 that binds both hepatocyte growth factor receptor (HGFR) and an immune checkpoint modulator described herein, e.g., PD-1, PD-L1, PD-L2, or an antibody that binds to 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. It specifically binds to proteins and one of PD-1, PD-L1, and CTLA-4.

[0480] 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.

[0481] 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 to PD-1 is described in PCT Publication 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).

[0482] 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), albemab (MSB0010718C; Merck KGaA), KD033 (Kadmon), an antibody portion of KD033, or STI-A1014 (Sorrento Therapeutics). In some embodiments, the antibody that binds to 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 comprising the CDR regions of any of these antibodies, the disclosure of which is incorporated herein by reference in its entirety.

[0483] In some embodiments, the CTLA-4 antagonist is an antibody that specifically binds to 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.).

[0484] 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).

[0485] 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).

[0486] 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.

[0487] In some embodiments of any of the above aspects or those described anywhere else herein, the cancer is selected from the group consisting of lung cancer (e.g., non-small cell lung cancer (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, leukocyte ... sarcoma, osteosarcoma, chondrosarcoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, leiomyosarcoma, or rhabdomyosarcoma), prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia, or chronic lymphocytic leukemia (CLL)), lymphoma (e.g., Hodgkin's lymphoma or non-Hodgkin's lymphoma (NHL)), myeloma (e.g., multiple myeloma (MM)), mycosis fungoides, Merkel cell carcinoma, malignant blood disorders, blood group tissue cancer, B-cell carcinoma, bronchial carcinoma, gastric cancer, brain or central nervous system cancer, peripheral nervous system cancer, uterine or endometrial cancer, oral or pharyngeal cancer, liver cancer, testicular cancer, biliary tract cancer, small intestine or appendix cancer, salivary gland cancer, adrenal gland cancer, adrenocortical carcinoma, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), polycythemia vera, chordoma, synovial tumor, Ewing's tumor, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatic carcinoma, bile duct carcinoma, choriomas, seminoma, embryonal 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 thrombocytemia, primary myelofibrosis, hypereosinophilic syndrome, systemic mastocytosis, familial hypereosinophilia, neuroendocrine carcinoma, or carcinoid tumor.

[0488] In some embodiments of any of the above aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, e.g., a PD-1 antagonist or a PD-L1 antagonist), or the subject's cancer or tumor progresses after an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, e.g., a PD-1 antagonist or a PD-L1 antagonist).

[0489] In various embodiments, immunotherapeutic agents may include antibodies or antigen-binding fragments thereof. Within this definition, immune checkpoint inhibitors include those known in the art. Including bispecific antibodies and multivalent immune cell-engaging antibodies / fusion proteins / constructs. In some embodiments, immunotherapeutics comprising bispecific antibodies may be bivalent and include bispecific antibodies binding 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.

[0490] Several bispecific antibody formats known in the art can be implemented by one of skill 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.

[0491] In various embodiments, the immunotherapeutic agent may comprise an immune cell engaging multivalent antibody / fusion protein / construct.

[0492] In embodiments of the disclosure, checkpoint inhibitors in combination with crystalline forms or crystalline salt forms of Compound 1 inhibit or reduce tumor or cancer recurrence or tumor or cancer progression by reducing or inhibiting the metastasis of the primary tumor or cancer to other sites or the formation or establishment of metastatic tumors or cancer at other sites distal to the primary tumor or cancer.

[0493] In further embodiments of the present disclosure, provided herein are combination therapies for treating cancer comprising a crystalline form or a crystalline salt form of Compound 1 and a checkpoint inhibitor, which may produce a potent and durable immune response with improved therapeutic benefit and more manageable toxicity.

[0494] In further embodiments of the present disclosure, provided herein is a combination therapy for treating cancer, the combination therapy comprising a crystalline form or a crystalline salt form of Compound 1 and an immune checkpoint inhibitor. In embodiments of the present disclosure, provided herein is a method for treating cancer and / or preventing the establishment of metastases by using a crystalline form or a crystalline salt form of Compound 1 of the present invention, which acts synergistically with a checkpoint inhibitor.

[0495] In further embodiments, the present disclosure provides methods for one or more of the following: 1) reducing or inhibiting the growth, proliferation, migration, or invasiveness of tumor or cancer cells that potentially or actually give rise to metastasis, 2) reducing or inhibiting the formation or establishment of metastases that arise from a primary tumor or cancer to one or more other sites, locations, or regions distinct from the primary tumor or cancer, 3) reducing or inhibiting the growth or amplification of metastases at one or more other sites, locations, or regions distinct from the primary tumor or cancer after metastases have formed or established, 4) reducing or inhibiting the formation or establishment of further metastases after metastases have formed or established, 5) prolonged overall survival, 6) prolonged progression-free survival, or 7) disease stabilization. The methods comprise 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 described herein.

[0496] In embodiments of the disclosure, administration of a crystalline form or crystalline salt form of Compound 1 in combination with an immunotherapeutic agent results in a detectable or measurable improvement in a given subject's condition, for example, a condition related to cell proliferation or a cell hyperproliferative disorder, a neoplasm, tumor or cancer, or the presence of metastasis. The objective of the present invention is to alleviate or ameliorate one or more adverse (physical) symptoms or consequences associated with the treatment of a disease, i.e., to provide a therapeutic benefit or beneficial effect.

[0497] A therapeutic benefit or beneficial effect is any objective or subjective, temporary, immediate, or long-term improvement in 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. A satisfactory clinical endpoint of a treatment 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 inhibition or reversal of one or more physiological, biochemical, or cellular manifestations or characteristics of a cell proliferation or cell hyperproliferative disorder, e.g., a neoplasm, tumor, or cancer, or metastasis. A therapeutic benefit or improvement may therefore be, but is not limited to, the destruction of a target proliferating cell (e.g., a neoplasm, tumor, or cancer, or metastasis), or the elimination of one or more, most, or all, pathologies, 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, therapeutic benefit or improvement does not require cure or complete destruction of all target proliferating cells (e.g., neoplasm, tumor or cancer, or metastasis), or elimination of all pathologies, adverse symptoms, or complications associated with or caused by a cell proliferation or hyperproliferative disorder, e.g., a 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, may reduce mortality and prolong survival, 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.

[0498] Specific non-limiting examples of therapeutic utility include reducing the volume (size or cell mass) or cell number of a neoplasm, tumor or cancer, or metastasis; inhibiting or preventing an increase in the volume of a neoplasm, tumor or cancer (e.g., stabilizing); delaying or inhibiting the progression, worsening, or metastasis of a neoplasm, tumor, or cancer; or inhibiting the proliferation, growth, or metastasis of a neoplasm, tumor, or cancer.

[0499] In embodiments of the present disclosure, administration of an immunotherapeutic agent in combination therapy with a crystalline form or crystalline salt form of Compound 1 confers a detectable or measurable improvement or overall response by 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, whether measurable or not, and no new lesions (confirmed by repeated serial assessments for at least 4 weeks from the date of initial documentation); (ii) irPR - a ≥ 50% reduction in tumor burden compared to baseline (confirmed by serial assessments for at least 4 weeks after initial documentation);

[0500] Optionally, any of the methods described herein may not produce an immediate effect. For example, following treatment, the number or mass of cells in a neoplasm, tumor, or cancer may increase, but may be followed by an eventual stabilization or reduction in tumor cell mass, size, or cell number over time in a given subject.

[0501] Additional adverse symptoms and complications associated with neoplasia, tumors, cancer, and metastasis that may be inhibited, reduced, diminished, slowed, or prevented include, for example, nausea, loss of appetite, fatigue, pain, and discomfort. Thus, partial or complete reduction or elimination of 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 well-being, e.g., increased energy, appetite, psychological well-being, are all specific, non-limiting examples of therapeutic benefits.

[0502] Therapeutic benefit or improvement can therefore also include a subjective improvement in the quality of life of the treated subject. In additional embodiments, the method prolongs or extends the subject's lifespan (survival). In further embodiments, the method improves the subject's quality of life.

[0503] In one embodiment, administration of the immunotherapeutic agent in combination therapy with a crystalline form or crystalline salt form of Compound 1 results in a clinically meaningful improvement in one or more markers of disease status 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) blood levels of tumor antigens, such as carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA), depending on the tumor, (vii) nutritional status (weight, appetite, serum albumin), (viii) pain control or analgesic use, and (ix) CRP / albumin ratio.

[0504] Treatment with the crystalline form or crystalline salt form of Compound 1 in combination with immunotherapeutic agents results in additional combined immunity, including the development of innate and type I immunity, as well as immune modulation that more efficiently restores proper immune function.

[0505] In various exemplary methods, a checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecific, or immune cell-engaging multivalent antibody / fusion protein / construct) against a checkpoint molecule of interest (e.g., PD-1) can be sequenced, and the polynucleotide sequence can then be cloned into a vector for expression or propagation. The sequence encoding the antibody of interest or its antigen-binding fragment can be maintained in the vector in a host cell, which can then be propagated and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g., Tiller et al., 2008, J. Immunol. Methods 329:112; U.S. Patent No. 7,314,622.

[0506] Pharmaceutical compositions comprising a crystalline form or crystalline salt form of Compound 1 according to the present disclosure typically contain an effective amount of a crystalline form or crystalline salt form of Compound 1, an immunotherapeutic agent, and / or both, dispersed in a pharmaceutically acceptable excipient. The phrase "pharmaceutically or pharmacologically acceptable" refers to molecular entities and compositions that do not produce harmful, allergic, or other adverse reactions when administered to an animal, such as a human, as appropriate. Preparation of pharmaceutical compositions comprising a crystalline form or crystalline salt form of Compound 1 is described in Remington's Pharmaceutical Sciences, 21 st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006), and will be known to those skilled in the art in light of the present disclosure. It is also understood that for animal (e.g., human) administration, preparations should meet sterility, pyrogenicity, general safety and purity standards. Specific examples of pharmaceutically acceptable excipients for combination compositions comprising a crystalline form or crystalline salt form of Compound 1 mixed with an immunotherapeutic agent as described herein are borate buffer or sterile saline solution (0.9% NaCl).

[0507] 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 using methods such as those described in Remington's Pharmaceutical Sciences 21. st and prepared for storage in the form of a lyophilized formulation or an aqueous solution and / or suspension by mixing with optional pharmaceutically acceptable excipients or stabilizers as fully described and explained in "Pharm. Pharmacology, 1999, 14:100-110, 1999," Ed., (Lippincott, Williams and Wilkins, Philadelphia, PA, 2006). Acceptable excipients, buffers, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include suitable aqueous and / or nonaqueous excipients that may be used in the pharmaceutical compositions of the present disclosure, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants, buffers, such as phosphates, citrates, and other organic acids. Antioxidants may be included, for example: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzylalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkylparabens, such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than about 10 residues).Other exemplary pharmaceutically acceptable excipients may 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, including 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).

[0508] In one illustrative embodiment, the pharmaceutical composition may optionally contain pharmaceutically acceptable auxiliary substances, such as pH adjusters and buffers and toxicity adjusters, as needed to approximate physiological conditions, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. In some embodiments, the checkpoint inhibitor antibodies or antigen-binding fragments thereof of the present disclosure may be formulated for this purpose and lyophilized for storage and reconstituted in a suitable excipient prior to use by lyophilization and reconstitution techniques known in the art. In one exemplary pharmaceutical composition comprising 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 disposable, prefilled pen, including, for example, an approximately 1 mL prefilled glass syringe, or as a disposable, prefilled vial. Preferably, pharmaceutical compositions containing a checkpoint inhibitor antibody or antigen-binding fragment thereof are clear and colorless, with a pH ranging from about 6.9 to 5.0, preferably from 6.5 to 5.0, and even more preferably from about 6.0 to about 5.0. In various embodiments, a formulation containing the pharmaceutical composition, when reconstituted and administered to a subject, 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 a checkpoint inhibitor antibody or antigen-binding fragment thereof per mL of solution. Exemplary injection or infusion excipients may include mannitol, citric acid monohydrate, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for parenteral administration, e.g., intravenous, intramuscular, intraperitoneal, or subcutaneous administration.

[0509] In another exemplary embodiment, one or more immunotherapeutic agents or antigen-binding fragments thereof are formulated for intravenous or subcutaneous administration as a sterile aqueous solution comprising 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 antibody, along with sodium acetate, polysorbate 80, and sodium chloride, at a pH ranging from about 5 to 6. Preferably, the intravenous or subcutaneous formulation is a sterile aqueous solution comprising 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, EDTA, methionine, and any combination thereof, as well as many other compounds known in the art.

[0510] In one embodiment, a pharmaceutical composition of the present disclosure comprises the following ingredients at pH 5.8: 5-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80, along with a crystalline form or crystalline salt form of Compound 1. This composition may be provided as a lyophilized powder. When the powder is reconstituted at its full volume, the composition retains the same formulation. Alternatively, the powder may be reconstituted at half the volume, in which case the composition comprises 10-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80 at pH 5.8.

[0511] In one embodiment, a portion of the dose is administered by intravenous bolus, and the remainder 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 may be administered by intravenous injection. A predetermined dose of the immunotherapeutic agent or antigen-binding fragment thereof may be administered over, for example, 1 to 2 to 5 hours.

[0512] In further embodiments, a portion of the dose is administered by subcutaneous injection and / or infusion in the form of a bolus, and the remainder by infusion of the immunotherapeutic formulation. In some exemplary doses, the immunotherapeutic formulation may be administered subcutaneously at a dose 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 intravenous injection of the immunotherapeutic agent or antigen-binding fragment thereof. In some embodiments, the dose may be given as a bolus, with the remaining immunotherapeutic dose administered subcutaneously or intravenously. A predetermined dose of the immunotherapeutic agent or antigen-binding fragment thereof may be administered, for example, over a period of 1 to 2 to 5 hours.

[0513] The formulations herein may contain more than one active compound, as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide one or more immunotherapeutic agents with different specificities. Alternatively, or in addition, the composition may include an anti-inflammatory agent, a chemotherapeutic agent, a cytotoxic agent, a cytokine, a growth inhibitory agent, and / or a small molecule antagonist. Such molecules are suitably present in the combination in amounts that are useful for the intended purpose.

[0514] Formulations to be used for in vivo administration should be sterile or nearly sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0515] In various embodiments, formulations of the illustrative pharmaceutical compositions described herein can be prepared using methods well known in the art of pharmaceutical formulation. In general, such preparation methods may include bringing into association an active ingredient with an excipient or one or more other accessory ingredients, and then, if desired, packaging the product into a desired single- or multi-dosage unit.

[0516] In some embodiments, compositions comprising the crystalline form or 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 crystalline salt form of Compound 1. In some instances, liposomes comprising 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, enhance targeted drug delivery by selectively transporting the drug to specific cells or organs.

[0517] In another embodiment, the crystalline form or crystalline salt form of Compound 1 can be delivered in a vesicle, particularly a liposome (Langer, Science 249:1527-1533 (1990); Treat et al., in LIPOSOMES IN See THE THERAPY OF INFECTIOUS DISEASE AND CANCER, Lopez-Berestein and Fidler (eds.), Liss, NY, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally supra).

[0518] In yet another embodiment, a composition comprising a crystalline form or crystalline salt form of Compound 1, or a combination, or a composition comprising 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 a crystalline form or crystalline salt form of Compound 1 may include polymeric materials that impart sustained, intermediate, pulsed, or alternating 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); Levy et al. (See also, During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989). Other controlled-release systems discussed in the review by Langer (Science 249:1527-1533 (1990)) can be used.

[0519] The optimum 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.

[0520] The present disclosure also provides crystalline forms or crystalline compositions of Compound 1, as described herein. Also provided is 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, including at least a salt form and one or more checkpoint inhibitor antibodies or antigen-binding fragments thereof. In other embodiments, the kit may include one or more additional containers providing a pharmaceutically acceptable excipient, e.g., a diluent. In one embodiment, the kit may include at least one container, which may contain the crystalline form or crystalline salt form of Compound 1 of the present disclosure, a checkpoint inhibitor antibody or antigen-binding fragment thereof. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to a subject in need thereof for the treatment of a checkpoint molecule-mediated disease or disorder.

[0521] In some embodiments of the present disclosure, the immunotherapeutic agent is a population of immune cells and can be administered in combination with a crystalline form 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, e.g., leukocytes (nucleated white blood cells), that contain (e.g., express) a receptor that binds to an antigen of interest. Leukocytes of the present disclosure can be, for example, neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the leukocytes 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, γδ T cells, or regulatory (suppressor) T cells. In some embodiments, the immune cells are dendritic cells.

[0522] In some embodiments, the immune cells of the present disclosure are genetically engineered to express an antigen-binding receptor. Cells are said to be "genetically engineered" when they contain an engineered (exogenous) nucleic acid. The genetically engineered nucleic acid of the present disclosure may be introduced into cells by any known (e.g., conventional) method. For example, the genetically engineered nucleic acid can be introduced into cells by electroporation (see, e.g., Heiser W. C., "Transscription Factor Protocols: Methods in Molecular Biology. TM. 2000; 130:117-134"), chemical (e.g., calcium phosphate or lipid) transfection (see, e.g., Lewis W. H., et al., "Somatic 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 a 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 cells (see, e.g., Capecchi MR Cell. 1980 November;22(2 Pt 2):479-88), or may be introduced into cells by retroviral transduction.

[0523] Some aspects of the present disclosure provide an "adoptive immune 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, e.g., a chimeric antigen receptor), expanding the cells ex vivo, and then reintroducing the immune cells into the subject. This method results in a larger number of genetically engineered immune cells in the subject than could be achieved by conventional 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.

[0524] The immune cells of the present disclosure comprise a receptor that binds to an antigen, e.g., an antigen encoded by an exogenously delivered nucleic acid, as provided herein. In some embodiments, the leukocytes have been modified (e.g., , genetically modified). In some embodiments, the receptor may be a naturally occurring antigen receptor (normally expressed in immune cells), a recombinant antigen receptor (not normally expressed in 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. A "chimeric antigen receptor" refers to an artificial immune cell receptor that is genetically engineered to recognize and bind to an antigen expressed by a tumor cell. Generally, CARs are designed 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) (Enblad et al., Human Gene Therapy. 2015;26(8):498-505), the disclosure of which is incorporated herein by reference in its entirety.

[0525] In some embodiments, the antigen-binding receptor is a chimeric antigen receptor (CAR). T cells expressing a CAR are referred to as "CAR T cells." CAR T cell receptors, in some embodiments, comprise the signaling domain of a T cell receptor (TcR) complex and an antigen recognition domain (e.g., a single-chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015;26(8):498-505), the disclosure of which is incorporated herein by reference in its entirety.

[0526] There are four generations of CARs, each containing 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 through 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 TcR CD3-zeta chain. Third-generation costimulatory domains may include, for example, a combination of CD3z, CD27, CD28, 4-1BB, ICOS, or OX40. A CAR, in some embodiments, may comprise an ectodomain (e.g., CD3), hinge, transmembrane domain, and endodomain typically derived from a single-chain variable fragment (scFv), along with one (first generation), two (second generation), or three (third generation) signaling domains derived from CD3Z and / or costimulatory molecules (Maude et al., Blood. 2015; 125(26):4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2):151-155), the disclosures of which are incorporated herein by reference in their entireties.

[0527] In some embodiments, the chimeric antigen receptor (CAR) is a universal cytokine-killing redirected T cell (TRUCK), also known as a 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 CAR engagement with the target. TRUCK cells can deposit various therapeutic cytokines in the target, resulting in therapeutic concentrations at the target site and avoiding systemic toxicity.

[0528] These CARs typically differ in their functional properties. The CD3 zeta signaling domain of the T cell receptor, when engaged, activates and induces T cell proliferation but can lead to anergy (a 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 modified T cells. While similar antitumor effects are observed in vitro with CD28 or 4-1BB CARs, preclinical in vivo studies have shown that 4-1 These findings suggest that 4-1BB CARs may result in superior proliferation and / or persistence. Clinical trials suggest that while both of these second-generation CARs can induce substantial T cell proliferation in vivo, CARs containing the 4-1BB costimulatory domain appear to be more durable. Third-generation CARs combine multiple signaling domains (costimulatory) to increase efficacy. Fourth-generation CARs are additionally modified by constitutive or inducible expression of transgenic cytokines that are released by CAR T cells to regulate T cell responses. See, for example, 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.

[0529] In some embodiments, illustrative immunotherapeutic agents are first-generation chimeric antigen receptor CARs. 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 universal cytokine killing redirected T cell (TRUCK).

[0530] In some embodiments, a chimeric antigen receptor (CAR) comprises an extracellular domain comprising 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" 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 and transmembrane domains of the CAR. A "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. A "hinge domain" refers to any oligopeptide or polypeptide that functions to confer flexibility to a CAR, or a domain thereof, or to prevent steric hindrance of a CAR, or a domain thereof. In some embodiments, a spacer or hinge domain can 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) can be included in other regions of a CAR.

[0531] In some embodiments, a CAR of the present disclosure comprises an antigen-binding domain, e.g., a single-chain Fv (scFv) specific for a tumor antigen. The selection of the binding domain depends on the type and number of ligands that define the surface of the target cell. For example, the antigen-binding domain can be selected to recognize a ligand that acts as a cell surface marker on target cells associated with a specific disease state, e.g., cancer or autoimmune disease. Thus, examples of cell surface markers that can act as ligands for the antigen-binding domain in a CAR of the present disclosure include those associated with cancer cells and / or other forms of diseased cells. In some embodiments, a CAR is 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.

[0532] An antigen-binding domain (e.g., scFv) that "specifically binds" to a target or epitope is an art-recognized term, and methods for determining such specific binding are also known in the art. A molecule is said to exhibit "specific binding" when it reacts or associates more frequently, more rapidly, with a longer duration and / or with higher affinity with a particular target antigen than 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.

[0533] In some embodiments, immune cells expressing CARs are genetically modified 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 to multiple targets include "split-signal CARs," which limit complete immune cell activation to tumors expressing multiple antigens; "tandem CARs" (TanCARs), which contain an ectodomain with two scFvs; and "universal ectodomain CARs," which incorporate avidin- or fluorescein isothiocyanate (FITC)-specific scFvs to recognize tumor cells incubated with tagged monoclonal antibodies (Mabs).

[0534] A CAR is said to be "bispecific" when it recognizes two different antigens (having two different antigen recognition domains). In some embodiments, a bispecific CAR consists of two different antigen recognition domains in tandem in a single transgenic receptor (referred to as a TanCAR; see, e.g., Grada Z et al. Molecular Therapy Nucleic Acids 2013;2:e105, incorporated herein by reference in its entirety). Thus, in some embodiments, the method includes delivering to a tumor a combination comprising a crystalline form or crystalline salt form of Compound 1 and an immunotherapeutic agent, where the immunotherapeutic agent is an engineered nucleic acid encoding an antigen or an engineered nucleic acid that induces expression of an autoantigen, and delivering to the tumor immune cells expressing a bispecific CAR that binds to two antigens, one of which is encoded by the engineered nucleic acid.

[0535] In some embodiments, the CAR is an antigen-specific inhibitory CAR (iCAR), which can be used, for example, to avoid off-tumor 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 to block nonspecific immune suppression that can result, for example, from target expression outside the tumor. iCARs can be based on the inhibitory molecules CTLA-4 or PD-1, for example. In some embodiments, these iCARs block T cell responses from T cells activated by either endogenous T cell receptors or activating CARs. In some embodiments, this inhibitory effect is temporary.

[0536] In some embodiments, CARs may be used in adoptive cell transfer, in which immune cells are removed from a subject and modified to express a receptor specific for an antigen, e.g., a tumor-specific antigen. The modified immune cells can then recognize and kill cancer cells and are 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).

[0537] According to another embodiment of the present disclosure, the tumor antigen 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, glycoproteins, or glycopeptides. In yet another embodiment, the antigen component may be patient-specific or may be common to many or most patients with a particular type of cancer. According to one embodiment, the antigen component consists of a cell lysate derived from tumor tissue removed from the patient to be treated. In another embodiment, the lysate may be engineered or synthetic from exosomes derived from tumor tissue. In yet another embodiment, the antigen component consists of a cell lysate derived from tumor tissue extracted from one or more unrelated individuals or from tumor cell lines.

[0538] In various embodiments, exemplary immunotherapeutic agents include one or more cancer vaccines for use in combination with the crystalline or crystalline salt form of Compound 1. The tumor-associated antigen component of the vaccine may be prepared by a variety of well-known techniques. For individual protein components, the antigen protein is isolated from tumor tissue or tumor cell lines by standard chromatographic means, such as high-performance liquid chromatography or affinity chromatography, or alternatively, synthesized by standard recombinant DNA techniques in a suitable expression system, such as E. coli, yeast, or plants. The tumor-associated antigen protein is then purified from the expression system by standard chromatographic means. In the case of peptide antigen 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 (e.g., multilamellar liposomes). For tumor-associated antigen components derived from a patient's own tumor or a tumor from another individual, or cell lines, tumor tissue or a single-cell suspension derived from such tumor tissue is typically homogenized in a suitable buffer. The homogenate can also be fractionated, for example, by centrifugation, to isolate specific cellular components, such as cell membranes or soluble materials. The tumor material can be used directly, or tumor-associated antigens can be extracted for incorporation into a vaccine using a buffer containing a low concentration of a suitable agent, such as a detergent. An example of a detergent suitable for extracting antigenic proteins from tumor tissue, tumor cells, and tumor cell membranes is diheptanoylphosphatidylcholine. Exosomes derived from tumor tissue or tumor cells, whether autologous or xenogeneic to the patient, can be used as starting materials for antigen components for incorporation into vaccines or for the extraction of tumor-associated antigens.

[0539] In some embodiments of the present disclosure, the combination therapy comprises a crystalline form or a crystalline salt form of Compound 1 in combination with a cancer vaccine immunotherapeutic. In various examples, the cancer vaccine comprises 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 agent component in the cancer vaccine of the present disclosure is any biological response modifier (BRM) capable of eliciting humoral and cellular immune responses against cancer cells in a patient, improving the efficacy of a therapeutic cancer vaccine. According to one aspect, the immunostimulatory agent is a cytokine or a combination of cytokines. Examples of such cytokines include interferons, such as IFN-gamma, interleukins, such as IL-2, IL-15, and IL-23, colony-stimulating factors, such as M-CSF and GM-CSF, and tumor necrosis factor. According to another embodiment, the immunostimulatory component of the disclosed cancer vaccines includes one or more adjuvant-type immunostimulators, with or without immunostimulatory cytokines, such as APC Toll-like receptor agonists or costimulatory / cell adhesion membrane proteins. Examples of Toll-like receptor agonists include lipid A and CpG, and costimulatory / adhesion proteins, such as CD80, CD86, and ICAM-1.

[0540] In some embodiments, the immunostimulatory 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 to 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 is one or more cytokines, e.g., interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ), one or more Toll-like receptor agonists and / or adjuvants, e.g., monophosphoryl lipid A, lipid A, muramyl dipeptide (MDP) lipid conjugates, and double-stranded RNA, or one or more costimulatory membrane proteins and / or cell adhesion proteins, such as CD80, CD86, and ICAM-1, or or any combination of the above. In one embodiment, the cancer vaccine comprises 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 comprises an immunostimulatory agent 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 conjugates and double-stranded RNA. In yet another embodiment, the cancer vaccine comprises an immunostimulatory agent that is a costimulatory membrane protein and / or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[0541] In various embodiments, the immunotherapeutic agent may include a cancer vaccine incorporating any tumor antigen that may potentially be used to construct a fusion protein according to the present invention, and in particular: (a) NY-ESO-1, SSX2, SCP1, and RAGE, BAGE, GAGE, and MAGE family polypeptides, e.g., GAGE-1, GAGE-2, MAGE-1, which may be used to combat melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumors. (b) mutated antigens including p53 associated with various solid tumors, e.g., colon, lung, and head and neck cancer; p21 / R associated with melanoma, pancreatic cancer, and colon cancer; CDK4 associated with melanoma; MUM1 associated with melanoma; caspase-8 associated with head and neck cancer; CIA0205 associated with bladder cancer; HLA-A2-R1701, beta-catenin associated with melanoma; TCR associated with T-cell non-Hodgkin's lymphoma; BCR-abl associated with chronic myeloid leukemia; triosephosphate isomerase; KIA0205; CDC-27, and LDLR-FUT; (c) overexpressed antigens including galectin 4 associated with colon cancer; (d) shared antigens, such as melanoma-melanocyte differentiation antigens, e.g., MART-1 / Melan A; gpl00; MC1R; melanocyte-stimulating hormone receptor; tyrosine kinase A; and tyrosine kinase B.For example, tyrosinase-related protein-1 / TRP1 and tyrosinase-related protein-2 / TRP2, which are associated with melanoma; (e) prostate-related antigens, including PAP, PSA, PSMA, PSH-P1, PSM-P1, PSM-P2, which are associated with prostate cancer; (f) immunoglobulin idiotypes, which are 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 including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, pl85erbB2, pl80erbB-3, c-met, mn-23H1, TAG-72-4, CA19-9, CA72-4, CAM17.1, NuMa, K-ras, pi6 , TAGE, PSCA, CT7, 43-9F, 5T4, 791Tgp72, beta-HCG, BCA225, BTAA, CA125, CA15-3 (CA27.29\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 binding protein / cyclophilin C-associated protein), TAAL6,; It may be selected from TAG72, TLP, TPS or any combination thereof.

[0542] 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.

[0543] In various embodiments, illustrative immunotherapeutic agents may include mRNA operable to encode any one or more of the above cancer antigens useful in formulating cancer vaccines. In some illustrative 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 preference 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 via a single nucleotide linker; d) each cancer antigen comprises 20-40 amino acids and includes a centrally located SNP variant; e) at least 40% of the cancer antigens have the highest affinity for class I MHC molecules from the subject; f) at least 40% of the cancer antigens have the 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. have binding affinity for MHC; and / or j) the mRNA encoding the cancer antigen is arranged such that the cancer antigen is ordered to minimize spurious epitopes.

[0544] In various embodiments, the combinations disclosed herein, comprising a crystalline form or crystalline salt form of Compound 1 and a cancer vaccine immunotherapeutic agent, can be used to elicit an immune response in a subject against a cancer antigen. The method includes administering to the subject an RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigen polypeptide or immunogenic fragment thereof, thereby eliciting an immune response in the subject specific to the antigen polypeptide or immunogenic fragment thereof, in combination with administering a crystalline form or crystalline salt form of Compound 1, either in the same composition or in a separate composition administered simultaneously or sequentially, wherein the anti-antigen polypeptide antibody titer in the subject is increased after vaccination compared to the anti-antigen polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer. An "anti-antigen polypeptide antibody" is a serum antibody that specifically binds to an antigen polypeptide.

[0545] 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 listed in the package insert for the vaccine. As used herein, a conventional vaccine refers to a vaccine other than the mRNA vaccine of the present invention. For example, conventional vaccines include, but are not limited to, live microbial vaccines, killed microbial vaccines, subunit vaccines, protein antigen vaccines, DNA vaccines, etc. In exemplary embodiments, a conventional vaccine is one that has received regulatory approval and / or is registered with a national drug enforcement agency, e.g., the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA).

[0546] In some embodiments, the anti-antigen polypeptide antibody titer in the subject increases by 1 log to 10 log after vaccination compared to the anti-antigen polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer. In some embodiments, the anti-antigen polypeptide antibody titer in the subject increases by 1 log after vaccination compared to the anti-antigen polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer. In some embodiments, the anti-antigen polypeptide antibody titer in the subject increases by 2 logs after vaccination compared to the anti-antigen polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a conventional vaccine against cancer.

[0547] An aspect of the present invention provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide, wherein the RNA polynucleotides are present in a formulation for in vivo administration to a host that confers antibody titers superior to the standard of seroprotection against the first antigen in an acceptable percentage of human subjects. In some embodiments, the antibody titers produced by the mRNA vaccines of the present invention are neutralizing antibody titers. In some embodiments, the neutralizing antibody titers exceed those of protein vaccines. In other embodiments, the neutralizing antibody titers produced by the mRNA vaccines of the present invention exceed those of adjuvanted protein vaccines. In still other embodiments, the neutralizing antibody titer produced by the mRNA vaccine of the present invention is 1,000 to 10,000, 1,200 to 10,000, 1,400 to 10,000, 1,500 to 10,000, 1,000 to 5,000, 1,000 to 4,000, 1,800 to 10,000, 2,000 to 10,000, 2,000 to 5,000, 2,000 to 3,000, 2,000 to 4,000, 3,000 to 5,000, 3,000 to 4,000, or 2,000 to 2,500. Neutralizing titers are typically expressed as the highest serum dilution required to achieve a 50% reduction in plaque counts.

[0548] In preferred embodiments, 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, antibody titers are expressed as the reciprocal of the highest dilution (in a serial dilution assay) that still gives a positive result. In exemplary embodiments, antibody titers are determined or measured by enzyme-linked immunosorbent assay (ELISA). In exemplary embodiments, antibody titers are determined or measured by a neutralization assay, e.g., a microneutralization assay. In certain embodiments, antibody titers are expressed as a ratio, e.g., 1:40, 1:100, etc.

[0549] In exemplary embodiments of the 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, or greater than 1:10000. In exemplary embodiments, antibody titers are produced or achieved 10 days post-vaccination, 20 days post-vaccination, 30 days post-vaccination, 40 days post-vaccination, or 50 days post-vaccination or more. In exemplary embodiments, titers are produced or achieved after a single dose of vaccine is administered to a subject. In other embodiments, titers are produced or achieved after multiple doses, for example, after a first and second dose (e.g., a booster dose). In exemplary aspects of the invention, antigen-specific antibodies are measured in units of g / ml, or in units of IU / L (International Units per Liter) or mIU / ml (milliliter). In exemplary embodiments of the invention, an effective vaccine produces >0.5 μg / mL, >0.1 μg / mL, >0.2 μg / mL, >0.35 μg / mL, >0.5 μg / mL, >1 μg / mL, >2 μg / mL, >5 μg / mL, or >10 μg / mL. In exemplary embodiments of the invention, an effective vaccine produces >10 mIU / mL, >20 mIU / mL, >50 mIU / mL, >100 mIU / mL, >200 mIU / mL, >500 mIU / mL, or >1000 mIU / mL. ml. In exemplary embodiments, the antibody level or concentration is produced or achieved 10 days post-vaccination, 20 days post-vaccination, 30 days post-vaccination, 40 days post-vaccination, or 50 days post-vaccination or more. In exemplary embodiments, the level or concentration is produced or achieved after a single dose of the vaccine is administered to a subject. In other embodiments, the level or concentration is produced or achieved after multiple doses, e.g., after a first and a second dose (e.g., a booster dose). 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, e.g., a microneutralization assay. Also provided is a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide or linear polypeptide, wherein the RNA polynucleotides are in a formulation for in vivo administration to a host to elicit higher, longer-lasting antibody titers than those generated by an mRNA vaccine encoding the first antigen polypeptide, the RNA polynucleotides having a stabilizing element or formulated with an adjuvant. In some embodiments, the RNA polynucleotide is formulated to produce neutralizing antibodies within one week of 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.

[0550] An immunotherapeutic agent comprising a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification or, optionally, no nucleotide modification, wherein the open reading frame encodes a first antigen polypeptide or linear polypeptide, and the RNA polynucleotides are present in a 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 antigen polypeptide, the mRNA vaccine having a stabilizing element or formulated with an adjuvant.

[0551] Another aspect provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame containing at least one chemical modification or, optionally, no nucleotide modification, wherein the open reading frame encodes a first antigen polypeptide or linear polypeptide, the vaccine comprising at least 10-fold less RNA polynucleotide than required for an unmodified mRNA vaccine to generate an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present in a dosage of 25-100 micrograms.

[0552] Aspects of the invention also provide vaccine dosage units comprising 10 μg to 400 μg of one or more RNA polynucleotides having an open reading frame encoding a first antigen polypeptide or linear polypeptide, with at least one chemical modification, or optionally no nucleotide modification, formulated for delivery to a human subject, and a pharmaceutically acceptable excipient. In some embodiments, the vaccine further comprises cationic lipid nanoparticles.

[0553] Aspects of the present invention provide methods of creating, maintaining, or restoring antigenic memory against a tumor in an individual or population of individuals, comprising administering to the individual or population an antigenic memory booster nucleic acid vaccine, the vaccine comprising: (a) at least one RNA polynucleotide, the polynucleotide comprising at least one chemical modification or optionally no nucleotide modification, and comprising two or more codon-optimized open reading frames encoding a set of reference antigenic polypeptides; and (b) optionally a pharmaceutically acceptable excipient. In some embodiments, the vaccine is administered intramuscularly, intradermally, or intradermally. The composition is administered to the individual via a route selected from the group consisting of intramuscular administration and subcutaneous administration. In some embodiments, the administering step comprises contacting the subject's muscle tissue with a device suitable for injection of the composition. In some embodiments, the administering step comprises contacting the subject's muscle tissue with a device suitable for injection of the composition in combination with electroporation.

[0554] An embodiment of the present invention provides a method of vaccinating a subject, the method comprising administering to the subject a single dosage 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 antigen polypeptide or a linear polypeptide, in an amount useful for vaccinating the subject.

[0555] Another aspect provides a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigen polypeptide or linear polypeptide, the vaccine comprising at least 10-fold less RNA polynucleotide than required for an unmodified mRNA vaccine to generate an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present in a dosage of 25-100 micrograms.

[0556] In some embodiments, the crystalline form or crystalline salt form of Compound 1 may be used in combination with a bispecific antibody immunotherapeutic agent. The bispecific antibody may comprise a protein construct having a first antigen-binding site and a second antigen-binding site that binds to cytotoxic immune cells. The first antigen-binding site may bind to a tumor antigen specifically treated by the combination of the present invention. For example, the first antigen-binding site may bind to a tumor antigen selected from the following non-limiting examples: 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, among others. In some embodiments, the first antigen-binding site has specificity for a protein or peptide that is overexpressed in tumor cells compared to corresponding non-tumor cells. In some embodiments, the first antigen-binding site has specificity for a protein that is overexpressed in 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 tumor cells' origin. Note that such proteins are not necessarily different from tumor antigens.Non-limiting examples include carcinoembryonic antigen (CEA), which is mostly overexpressed in colon, breast, lung, pancreatic, and gastrointestinal cancers; heregulin receptors (HER-2, neu, or c-erbB-2), which are frequently overexpressed in breast, ovarian, colon, lung, prostate, and cervical cancers; epidermal growth factor receptors (EGFR), which are highly expressed in a wide range of solid tumors, including those of the breast, head and neck, non-small cell lung, and prostate; asialoglycoprotein receptors; transferrin receptors; serpin enzyme complex receptors expressed in hepatocytes; fibroblast growth factor receptors (FGFR), which are overexpressed in pancreatic ductal adenocarcinoma cells; vascular endothelial growth factor receptors (VEGFR) for anti-angiogenic gene therapy; folate receptors, which are selectively overexpressed in 90% of non-mucinous ovarian cancers; cell surface glycocalyx; carbohydrate receptors; and polymeric immunoglobulin receptors.

[0557] The second antigen-binding site 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 a cytotoxic immune cell suitable for use according to the present disclosure include CD2, CD3, CD4, CD5, CD8, CD11a, CD11b, CD14, CD1 Examples of antigen-binding sites include CD3, 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 site binds to CD3 of cytotoxic immune cells, e.g., CIK cells. In some embodiments, the second antigen-binding site binds to CD56 of cytotoxic immune cells. In some embodiments, the second antigen-binding site binds to an Fc receptor of cytotoxic immune cells. In some embodiments, the Fc region of the bispecific antibody binds to an Fc receptor of a cytotoxic immune cell. In some embodiments, the second antigen-binding site 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 site is specific for an antigen on the 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 site specifically binds to an antigen expressed on the surface of the cytotoxic immune cell.Exemplary, non-limiting antigens expressed on the surface of cytotoxic immune cells suitable for modulation according to the present disclosure 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 modulating agent is an activator of a costimulatory molecule (e.g., an OX40 agonist). In one embodiment, the OX40 agonist is a bispecific antibody molecule directed 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 to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3, and / or -5), TIM-3, or LAG-3. In one exemplary embodiment, the OX40 antibody molecule is administered in combination with an anti-PD-1 antibody molecule (e.g., an anti-PD-1 molecule 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 site binds to an Fc receptor on cytotoxic immune cells, such as CIK cells.

[0558] In some embodiments, the bispecific antibody immunotherapeutic agent has specificity for a tumor antigen and CIK cells, and brings tumor antigens expressed by tumor cells into close proximity with CIK cells, leading to the elimination of the tumor cells through the anti-tumor cytotoxicity of CIK cells. In some embodiments, the bispecific antibody has specificity for a tumor antigen but not for CIK cells. In some embodiments, the bispecific antibody has specificity for CIK cells but not for tumor cells, but the Fc region of the bispecific antibody can bind to the Fc receptor of the tumor cell, which then brings the tumor cells into close proximity with the CIK cells, leading to elimination of the tumor cells through the anti-tumor cytotoxicity of the CIK cells. In some embodiments, the bispecific antibody has specificity for CIK cells but not for tumor cells, but the Fc region of the bispecific antibody can bind to the Fc receptor of the tumor cell, which then brings the tumor cells into close proximity with the CIK cells, leading to elimination of the tumor cells through the anti-tumor cytotoxicity of the CIK cells.

[0559] In some embodiments, crystalline or crystalline salt forms of Compound 1 may be used in combination with immune cell-engaging multivalent antibody / fusion protein / construct immunotherapeutics. In various embodiments, exemplary immunotherapeutics include immune cell-engaging multivalent antibody / fusion protein / constructs, which may include recombinant structures, such as all genetically engineered antibodies that do not mimic the original IgG structure. Here, different strategies for multimerizing antibody fragments are utilized. For example, shortening the peptide linker between the V domains forces scFvs to self-associate into dimers (diabodies; 55 kDa). Bispecific diabodies are formed by the noncovalent association of two VHA-VLB and VHB-VLA fragments expressed in the same cell. This leads to the formation of heterodimers with two distinct 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.

[0560] Also included are di-diabodies, known in the art. This 130 kDa molecule is formed by fusing a 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 trimers and trimeric fragments by shortening the linker to <5 or 0-2 residues. Also exemplified is the (scFv)2 construct known as a "bispecific T cell engager" (BITE). BITE is a bispecific single-chain antibody consisting of two scFv antibody fragments linked via a flexible linker against a surface antigen on target cells and CD3 on T cells. Bivalent (Fab)2 and trivalent (Fab)3 antibody formats are also exemplified. Minibodies and trimeric bodies generated from scFvs are also exemplified. Exemplary constructs useful for targeting tumor antigens can include one or more of: diabodies, single-chain (sc)-diabodies (scFv)2, miniantibodies, minibodies, barnase barstar, scFv-Fc, sc(Fab)2, trimeric antibody constructs, triabody antibody constructs, trimeric body antibody constructs, tribody antibody constructs, collabody antibody constructs, (scFv-TNFα)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.

[0561] In some embodiments, a crystalline form or crystalline salt form of Compound 1 may be used in combination with a radioconjugated immunotherapeutic agent.

[0562] In various embodiments, the radioconjugate is a small or large molecule (referred to herein as a "cellular targeting agent"), such as a polypeptide, antibody, or antibody fragment thereof, that is coupled or otherwise immobilized to a radionuclide, or multiple radionuclides, such that binding of the radioconjugate to its target (a protein or molecule on or within a cancer cell) leads to death or pathology of said cancer cell. In various embodiments, the radioconjugate can be a radionuclide-labeled cellular targeting agent, or the cellular targeting agent can be coupled or otherwise immobilized to a particle, or microparticle, or nanoparticle that contains multiple radionuclides. Methods for synthesizing radioconjugates are known in the art and may include any class of immunoglobulin or antigen-binding portion thereof conjugated to a toxic radionuclide.

[0563] In some embodiments, molecules that bind to cancer cells may be known as "cell targeting agents." As used herein, exemplary cell targeting agents enable drug-containing nanoparticles or radionuclides to target specific types of target cells. Examples of cell targeting agents include, but are not limited to, small molecules (e.g., folic acid, adenosine, purines) and large molecules (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 receptors, alpha v beta 3, aminopeptidase P, alpha fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-1, chemokine receptors, clusterin, carcinoembryonic antigen, CD20, epithelial tumor antigens, melanoma-associated antigens, Ras, p53, Her2 / Neu, ErbB2, ErbB3, ErbB4, folate receptors, prostate-specific membrane antigen, prostate-specific antigen, purinergic receptors, radiation-induced cell surface receptors, serpin B3, serpin B4, squamous cell carcinoma antigen, thrombospondin, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, 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 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, among others.

[0564] The use of folic acid as a targeting agent in radioconjugates also allows both tumor cells and regulatory T (Treg) cells to be targeted and destroyed. It is widely accepted that large numbers of Treg cells suppress tumor immunity. Specifically, Treg cells suppress (allergic and auto-)reactive T cells without killing them through contact-dependent or cytokine (e.g., IL-10, TGF-beta, etc.) secretion. FR4 is selectively upregulated in Treg cells. Antibody blockade of FR4 has been shown to deplete Treg cells and induce tumor immunity in tumor-bearing mice. Therefore, folic acid-coated PBM nanoparticles carrying cytotoxic agents can target FR4-expressing cells for their destruction, inhibiting tumor progression both directly (i.e., BrCa cells) and indirectly (i.e., associated breast tumor and surrounding Treg cells).

[0565] In another further embodiment, the targeting agent is an antibody or peptide or immune cell engaging multivalent antibody / fusion protein / construct capable of binding to a tumor associated antigen 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, etc.

[0566] In some embodiments, a crystalline form of Compound 1 described herein or The crystalline salt form can be used in combination with vaccination protocols for cancer treatment. In some embodiments, the crystalline form or crystalline salt form 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 to cancer antigens.

[0567] The amounts of both the crystalline form or crystalline salt form of Compound 1 disclosed herein and one or more additional therapeutic agents (in those compositions containing additional therapeutic agents described above) that may be combined with excipient materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. In certain embodiments, the compositions of the invention are formulated so that they can be administered at a dosage of 0.01 to 100 mg / kg body weight / day.

[0568] The additional therapeutic agent and the crystalline form or crystalline salt form of Compound 1 disclosed herein may act synergistically. Therefore, 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 may cause fewer side effects in the patient, assuming a lower dose is used. In certain embodiments, the additional therapeutic agent may be administered in such compositions at a dosage of 0.01 to 10,000 μg / kg body weight / day.

[0569] In some embodiments, the crystalline form or crystalline salt form of Compound 1 disclosed herein is used to inhibit the activity of the following kinases: 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, PDGFβ / R, CSFIR, KIT, F 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.

[0570] 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®), rucaparib (Rubraca®), niraparib (Zejula®), talazoparib (Talzenna®), and TPST-1120.

[0571] In some embodiments, the crystalline forms 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, e.g., cancer. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, zanubrutinib, upadacitinib, fedratinib, entrectinib, alpelisib, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, and palvosic. These include ribociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, glitter, 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 CK1-a inhibitor, a Wnt pathway inhibitor (e.g., SST-215), or an electrocorticoid receptor inhibitor (e.g., esaxerenone or XL-550) for the treatment of a disease disclosed herein, e.g., cancer.

[0572] 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 a disease disclosed herein, e.g., cancer.

[0573] Labeled Compounds and Assay Methods Another aspect relates to labeled crystalline forms or crystalline salt forms (radiolabeled, fluorescently labeled, etc.) of the invention that are useful in assays, as well as imaging techniques, for localizing and quantifying TAM kinase in tissue samples, including humans, both in vitro and in vivo, and for identifying TAM kinase ligands by inhibiting the binding of labeled compounds. Accordingly, the present invention includes TAM kinase assays comprising such labeled compounds.

[0574] The present invention further includes isotopically labeled crystalline forms or crystalline salt forms of the present invention. An "isotopically" or "radiolabeled" compound is a crystalline form or crystalline salt form of the present invention in which one or more atoms have been replaced or substituted by an atom having an atomic mass or mass number that is different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the crystalline forms or crystalline salt forms of the present invention include, but are not limited to: 2 H (also written as D for 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 I. The radionuclide incorporated into the ready-to-use radiolabeled compound will depend on the particular application of the radiolabeled compound. For example, in in vitro metalloprotease labeling and competition assays, 3 H, 14 C. 82 Br, 125 I, 131 I, or 35Compounds 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 is generally most useful. In some embodiments, in the crystalline forms or crystalline salt forms described herein, one or more hydrogens are replaced by deuterium, e.g., the hydrogen is attached to a carbon atom. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound when administered to mammals, particularly humans.

[0575] 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.

[0576] 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.

[0577] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds.For example, labeled newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to bind to TAM by monitoring their concentration change when contacted with TAM kinase through label tracking.For example, a test compound (labeled) can be evaluated for its ability to reduce the binding of another compound known to bind to TAM kinase (i.e., reference compound).Therefore, the ability of a test compound to compete with a reference compound for binding to TAM kinase is directly correlated to binding affinity.On the other hand, in some other screening assays, the reference compound is labeled, and the test compound is not labeled.Therefore, the concentration of the labeled reference compound is monitored to evaluate the competition between the reference compound and the test compound, thereby revealing the relative binding affinity of the test compound.

[0578] Preparation and Examples

[0579] General Experimental Procedures

[0580] Aqueous Slurry Experiments: A salt of Compound 1 whose aqueous solubility was determined to be less than 1 mg / mL was slurried in 20 mL of water at ambient temperature for 1 day. The solid was then collected by vacuum filtration and analyzed by XRPD.

[0581] Crush-cool (CC): Concentrated solutions of compound 1 and various counterions were prepared in MeOH with stirring at elevated temperatures. The capped vial containing the hot solution was transferred to a freezer (approximately -20°C) and rapidly cooled. The solid that formed was collected. If no solid was present, further crystallization techniques were used.

[0582] Crush Precipitation (CP): Clear solutions of Compound 1 and coformer were prepared in various solvents at room temperature. Aliquots of various antisolvents were slowly added to the solutions with gentle stirring until the solids were crushed into solution. The mixtures were allowed to stir for a specified period of time. The formed solids were collected by positive pressure filtration.

[0583] Fast Cool (FC): Concentrated solutions of compound 1 and various counterions were prepared in acetone or MeOH at elevated temperatures with stirring. The capped vial containing the hot solution was transferred to the benchtop at ambient temperature. The solid that formed was collected. If no solid was present, further crystallization techniques were used.

[0584] Fast Evaporation (FE): Clear solutions of Compound 1 and coformer were prepared in various solvents. The vials were left uncapped and the solvent was allowed to evaporate at ambient conditions.

[0585] Interconversion Slurry: A slurry of Compound 1 Form A was prepared by adding enough solid to a given solvent system at ambient conditions to ensure undissolved solids were present. The mixture was then stirred for an extended period of time to ensure saturation. The desired form of solid was then added to an aliquot of the saturated solution (filtered through a 0.2 μm nylon filter) to ensure undissolved solids were present. The mixture was then stirred at ambient temperature for an extended period of time to isolate the solid.

[0586] Isolation Technique: Generally, prior to isolation of the solids, each non-ambient sample was removed from the temperature control device to minimize equilibration to ambient temperature, followed by rapid solid isolation.

[0587] Decanting the liquid phase: Decant some of the solids isolated from solution-based crystallization techniques to a suspension (if necessary). The wet solids were collected by centrifugation (as appropriate), discarding the liquid phase, and allowing the wet solids to settle. The solids were briefly dried (e.g., air-dried or dried under nitrogen) unless otherwise specified herein as "analysis wet."

[0588] Positive pressure filtration: Solids were collected on 0.2 μm nylon or PTFE filters by pressing the slurry through a syringe and Swinnex filter holder assembly. Generally, solids were briefly dried by blowing a 20 mL syringe of air onto the filter. When referred to herein as "analysis wet," the solids were left moist with the mother liquor. Some samples were briefly dried under a gentle stream of nitrogen gas prior to analysis.

[0589] Vacuum filtration: Solids were collected on a paper or nylon filter by vacuum filtration and air-dried on the filter under reduced pressure before being transferred to a vial.

[0590] Reaction crystallization (RC): Compound 1 and various coformers were combined in a hot acetone slurry, with the coformer concentration being 2-fold greater than the API molar concentration. The solution was stirred for a period of time. When a clear solution was observed, further crystallization techniques were used.

[0591] Stability study: Various Compound 1 salts 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 the period.

[0592] Slow Cooling (SC): Concentrated solutions of Compound 1 and various coformers were prepared in various solvents at elevated temperatures with stirring. The vials were capped in a heated sample block, the hot plate was turned off, and the vials were allowed to slowly cool to ambient temperature in the heated vial block. The clear solutions were further cooled in a refrigerator (5-7°C) and / or freezer (approximately -20°C) upon cooling to ambient temperature. If no solids were present, further crystallization techniques were used.

[0593] Slow evaporation: Solutions were prepared in various solvents with stirring and typically filtered through 0.2 μm nylon or PTFE filters. Each solution was evaporated from a covered vial (e.g., loosely capped or wrapped in perforated aluminum foil) at ambient conditions unless otherwise noted. Solutions were evaporated to dryness unless noted as partially evaporated (solids present with small amounts of solvent remaining), in which case the solids were isolated as described herein.

[0594] Solubility Estimation: Aliquots of various solvents were added to a measured amount of Compound 1 with stirring (typically sonication) at the stated temperature until complete dissolution was achieved, as judged by visual observation. If dissolution occurred after the addition of the first aliquot, the value is reported as ">". If dissolution did not occur, the value is reported as '<'.

[0595] Aqueous solubility estimation: Aliquots of water were added to measured amounts of various Compounds 1 with sonication.

[0596] Slurry experiments: Saturated solutions of Compound 1 and various coformers were prepared in various solvents and solvent mixtures. The mixtures were stirred at ambient and elevated temperatures for the durations described. Solids were collected by the techniques described and, where appropriate, further crystallization techniques were used.

[0597] Desolvation in a vacuum oven: Desolvation determined by various analytical methods Desolvation was attempted on the salt of Compound 1. 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 successful desolvation.

[0598] Vapor diffusion: Concentrated solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. The filtered solutions were dispensed into small vials, which were then placed into larger vials containing antisolvent. The smaller vials were left uncapped, while the larger vials were capped to allow vapor diffusion to occur. Any solids present were isolated as described herein.

[0599] Steam stress: Selected solids were transferred to a small vial, which was then placed in a larger vial containing solvent. The smaller vial was left uncapped, while the larger vial was capped and subjected to steam stress at the stated temperature.

[0600] Coformer means one or more pharmaceutically acceptable bases and / or pharmaceutically acceptable acids disclosed herein that are associated with Compound 1. Exemplary coformers, as used herein, include fumaric acid, HCl, and phosphoric acid.

[0601] equipment measurement technology

[0602] Differential Scanning Calorimetry (DSC): 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 sealed or open aluminum DSC pans, and the weight was accurately recorded. A weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. Samples were analyzed from -30 to 250°C at a ramp rate of 10°C / min. Thermograms were plotted by reference temperature (x-axis), but results are reported by sample temperature.

[0603] Dynamic Vapor Sorption (DVS)

[0604] a. VTI: Automated 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 range of 5% to 95% RH in 10% RH increments under a nitrogen purge. The equilibration criteria used for analysis was less than 0.0100% weight change in 5 minutes, with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0605] b. Intrinsic: Automated 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 range of 5% to 95% RH in 10% RH increments under a nitrogen purge. The equilibrium criteria used for analysis was less than 0.0100% weight change in 5 minutes, with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[0606] Hot Stage Microscopy (HSM): Hot stage microscopy was performed using a Linkam hot stage (FTIR600) attached to 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. As the stage heated, each sample was visually observed using a 20x objective with crossed polarizers and a primary red corrector. Images were recorded on a SPOT Insight™ color digital camera. Capture was performed using OT software (version 4.5.9).

[0607] Optical microscopy: Samples were viewed under a Motic or Wolfe optical microscope with crossed polarizers or under a Leica stereomicroscope with a first order red corrector with crossed polarizers.

[0608] pKa and logP Determinations: pKa and logP determinations were carried out by Pion Inc. / Sirius Analytical Instruments Ltd., East Sussex, UK.

[0609] Proton nuclear magnetic resonance spectroscopy of solutions ( 1 HNMR): Solution 1 H NMR spectra were acquired by Spectral Data Services of Champaign, IL. Samples were prepared by dissolving approximately 5-10 mg of sample in DMSO-d. Data acquisition parameters are listed on the first page of each spectrum in the data section of this report.

[0610] 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. The open pans were inserted into a TG furnace. The furnace was heated under nitrogen. Each sample was heated from ambient temperature to 350°C at a ramp rate of 2, 5, or 10°C / min. Thermograms were plotted by reference temperature (x-axis), while results were reported by sample temperature.

[0611] X-ray powder diffraction (XRPD)

[0612] a. Reflectance: XRPD patterns were collected at room temperature (298 Kelvin) on a PANalytical X'Pert PRO MPD diffractometer using incident beam Cu Kα radiation generated using a long fine-focus source and a nickel filter. The diffractometer was configured with a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position. Samples were loaded into wells. An anti-scatter slit (SS) was used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize spread from the axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software version 2.2b. Data acquisition parameters for each pattern are displayed above the image in the data section of this report, including the divergence slit (DS) and incident beam SS.

[0613] b. Transmission: XRPD patterns were collected at room temperature (298 Kelvin) on a PANalytical X'Pert PRO MPD diffractometer using incident beam Cu radiation generated using an Optix long fine focus source. An elliptical tilted multilayer mirror was used to focus the Cu Kα X-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed position of the Si111 peak matched the NIST-certified position. Samples were sandwiched between 3 μm-thick thin films and analyzed in transmission geometry. A beam stop, short anti-scatter extension, and an anti-scatter knife edge were used to minimize background caused by air. Soller slits for the incident and diffracted beams were used to minimize spread from the axial divergence. Diffraction patterns were captured using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software version 2. 2b. The data acquisition parameters for each pattern are listed above the images in the data section of this report, including a divergence slit (DS) in front of the mirror.

[0614] XRPD Indexing

[0615] Indexing and structure refinement are computationally tested. Agreement between the observed peaks and accepted peak positions, marked by bars in the figures referencing a given indexed XRPD pattern, 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 corresponding to the assigned annihilation symbols, unit cell parameters, and derived quantities is tabulated. [Example]

[0616] Preparation Example 1: Synthesis of Compound 1

[0617] Step 1: N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (4): [ka]

[0618] 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 vigorously stirred at 20 °C until the reaction was complete. The mixture was poured into saturated aqueous NaHCO (400 mL) and extracted with EtOAc (4 × 100 mL). The combined organic phase was washed with saturated aqueous NaCl (100 mL), dried over anhydrous NaSO, and concentrated to give compound 4 (21 g, crude) (50% purity). 1C 17 H 15 MS(EI) for FN2O3, actual value 314.9 (MH+).

[0619] Step 2: Methyl 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylate (6): [ka]

[0620] Compound 4 (5.99g, 9.5mmol, 1.2eq), Compound 5 (2g, 8.0mm A mixture of Pd(OAc) (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 KPO (2.53 g, 11.9 mmol, 1.5 equiv.) in anisole (50 mL) was stirred at 110 °C for 2 hours (h) under a 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(400MHz,CDCl3)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 MS (EI) for FN3O6, actual value 530.0 (MH+).

[0621] Step 3: 4-[4-[[1-[(4-fluorophenyl)carbamoyl]cyclopropane-carbonyl]amino]phenoxy]-7-methoxyquinoline-6-carboxylic acid (7) [ka]

[0622] 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 a pH of approximately 8 with 1 M aqueous HCl and concentrated to remove the solvent. Water (50 mL) was added, and the mixture was adjusted to a pH of approximately 6 with 1 M aqueous HCl. The resulting precipitate was filtered, washed with water (2 × 10 mL), and dried under vacuum to give compound 7 (1.7 g, 97.0% yield). 1 H NMR(400MHz,DMSO-d6)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 MS (EI) for FN3O6, actual value 516.1 (MH+).

[0623] Step 4: 1-N'-(4-fluorophenyl)-1-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4-yl]oxyphenyl]cyclopropane-1,1-dicarboxamide (1) [ka]

[0624] Compound 7 (300 mg, 582.0 μmol, 1 equivalent), HATU (332 mg, 87 A solution of 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 resulting filtrate was purified by preparative HPLC (column: Waters Xbridge 150 mm). * 25mm * 5 μm, gradient: 33–63% acetonitrile in 10 mM aqueous NH4HCO3, flow rate: 25 mL / min). Compound 1 was obtained (105.4 mg, 34.3% yield). 1 H NMR(400MHz,DMSO-d6)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),2.84d,3H)1.47(s,4H);C 29 H 25 MS (EI) for FN4O5, actual value 529.1 (MH+).

[0625] Example 1: Preparation of Compound 1 Fumarate Salt Form A

[0626] Fumaric acid (1 equivalent) in acetone was added to the free base of Compound 1 (1 equivalent), and the resulting reddish slurry was stirred at about 50° C. for 4 days. The slurry was then cooled to RT and stirred for an additional day to give a pink slurry. The solids were then removed by positive pressure filtration to give a mixture of fumarate salt Form A and free base Form A.

[0627] Example 2: Preparation of Compound 1 Hemi-Fumarate Salt Form B

[0628] Fumaric acid (2 equivalents) in acetone was added to the free base of Compound 1 (1 equivalent) and the resulting reddish slurry was stirred at about 50° C. for 6 days, resulting in an off-white slurry. The solids were then removed by positive pressure filtration of the hot solution to yield hemifumarate salt Form B.

[0629] Example 3: Preparation of Compound 1HCl Form A

[0630] One equivalent of HCl was added to the free base of Compound 1 in THF, and the resulting dark reddish slurry was stirred at RT for 3 days, resulting in a thick, off-white slurry. The solids were then removed by positive pressure filtration to yield HCl Form A.

[0631] Example 4: Preparation of Compound 1HCl Form B

[0632] One equivalent of HCl was added to the free base of Compound 1 in chloroform, and the resulting reddish slurry was stirred at about 50° C. for 3 days, resulting in a pale pink slurry. The solids were then removed by positive pressure filtration to obtain HCl Form B.

[0633] Example 5: Preparation of Compound 1HCl Form C

[0634] One equivalent of HCl was added to the free base of Compound 1 in methanol at a temperature of about 60° C., resulting in a yellowish slurry. The solution was then subjected to CC to about −20° C. and kept cold for about 2 days to give a clear orange solution. Partial FE gave a clear red solution, then 4 volumes of the anti-solvent MTBE was added and the solution was stirred at RT for 1 day to give an off-white solid, Compound 1HCl Form C, which was isolated by positive pressure filtration.

[0635] Example 6: Preparation of Compound 1HCl Form D

[0636] Two equivalents of HCl were added to the free base of Compound 1 at about 50° C., and the resulting pink slurry was stirred for 5 days at 50° C. Solid Compound 1 HCl Form D was isolated by positive pressure filtration.

[0637] Example 7: Preparation of Compound 1 Form A

[0638] Compound 1 Form A is likely the most thermodynamically stable crystalline form of the free base of Compound 1. Therefore, multiple procedures lead to the formation of this form. A list of some of the possible procedures for obtaining Compound 1 Form A is listed in Table 17. This list in Table 17 is not exhaustive, and in fact, there are likely many additional procedures that produce this form.

[0639] Table 17: Selected procedures for preparing Compound 1 Form A [Table 17]

[0640] Example 8: Preparation of Compound 1 Form B

[0641] Compound 1 was dissolved in AcOH and crystallized by VD using diethyl ether as an antisolvent.

[0642] Example 9: Preparation of Compound 1 Form C

[0643] Compound 1 was dissolved in HFIPA and crystallized by CP using MTBE as a poor solvent. Ta.

[0644] Example 10: Preparation of Compound 1 Form D

[0645] Compound 1 was dissolved in methanol and crystallized by CC. The mixture was then slurried at 2-8°C to obtain Form D.

[0646] Example 11: Preparation of Compound 1 Form E

[0647] Method A: Compound 1 was dissolved in THF and crystallized by CC.

[0648] Method B: Compound 1 was dissolved in 90:10 THF:water and precipitated by CP.

[0649] Example 12: Preparation of Compound 1 Form F

[0650] Method A: Compound 1 was dissolved in chloroform and crystallized by SE.

[0651] Method B: Compound 1 was slurried in chloroform.

[0652] Example 13: Preparation of Compound 1 Form G

[0653] Compound 1 was crystallized by dissolving it in chloroform and placing the mixture in a refrigerator.

[0654] Example 14: Preparation of Compound 1 Form H

[0655] Form H was obtained by VS of amorphous Compound 1 with DCM.

[0656] Example 15: Preparation of Compound 1 Form K

[0657] Compound 1 Form K was prepared by desolvation of Form F or Form G, which are chloroform solvates.

[0658] Example 16: Preparation of Compound 1 Form O

[0659] Compound 1 Form O was found in salts with various counterions in TFE-containing solvent systems, likely as TFE solvates.

[0660] Example 17: Preparation of Compound 1 Phosphate Form A

[0661] One molar equivalent of phosphoric acid was added to a slurry of compound 1 in chloroform, and the resulting mixture was then stirred for 3 days at about 50° C. The product was isolated by positive pressure filtration.

[0662] Example 18: Preparation of Compound 1 Form I

[0663] Compound 1 in a 90:10 THF / water mixture was triturated with heptane and then stirred at freezing temperatures for 7 days.

[0664] Example 19: Preparation of Compound 1 Form J

[0665] Compound 1 was stirred in acetone for 14 days.

[0666] Example 20: Preparation of Compound 1 Form L

[0667] Compound 1 was slurried in chloroform for 14 days.

[0668] Example 21: Preparation of Compound 1 Form M

[0669] Dehydration of Compound 1 Form E in vacuum at about 77°C for 1 day.

[0670] Example 22: Preparation of Compound 1 Form N

[0671] Compound 1 was stirred in a 70:30 mixture of TFE / MTBE at room temperature for 7 days.

[0672] Other embodiments The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can 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. Therefore, it should be understood that the foregoing detailed description is intended to be illustrative and not restrictive.

[0673] The scope of the present invention should, therefore, be determined not with reference to the above detailed description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. In one embodiment, for example, the following items are provided: (Item 1) compound 1 [ka] or a crystalline solid form of a hydrate or solvate thereof. (Item 2) 2. The crystalline solid form of Compound 1 according to item 1, wherein the crystalline solid form of Compound 1 is characterized as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form K, Form O, or Form Q. (Item 3) Item 3. The crystalline solid form according to item 2, characterized as Compound 1 Form A. (Item 4) The Compound 1 Form A is characterized by one or more peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the one or more peaks are 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.00, 20.46, 20.85, 21.4 4. The crystalline solid form of any one of items 2-3, wherein the crystalline solid form is selected from: 21.5, 21.55, 21.76, 22.16, 22.35, 22.58, 22.87, 23.79, 24.11, 24.29, 24.35, 24.87, 25.42, 25.81, 26.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56. (Item 5) 5. The crystalline solid form of any one of items 2 to 4, wherein Compound 1 Form A is characterized by one or more peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the one or more peaks are selected from 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19. (Item 6) 6. The crystalline solid form of any one of items 2 to 5, wherein Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the peaks are 10.83, 10.98, 11.36, 11.79, 12.04, 14.33, 18.07, 19.09, 20.00, 22.58, 24.87, and 28.19. (Item 7) Compound 1 Form A is characterized by all of the following peaks in an XRPD pattern at ±0.20 2-theta scale, wherein the peaks are: 5.48, 9.93, 10.83, 10.98, 11.36, 11.79, 12.04, 12.25, 12.62, 14.33, 14.67, 15.33, 16.02, 16.51, 16.77, 18.07, 19.09, 19.34, 19.60, 20.07, 21.09, 22.09, 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, 68.0 7.09, 26.72, 27.04, 27.44, 27.77, 27.98, 28.19, and 28.56. (Item 8) 8. The crystalline solid form of any one of items 2 to 7, wherein Compound 1 Form A is characterized by an endotherm with an onset temperature greater than 200° C. in a DSC thermogram. (Item 9) 9. The crystalline solid form of any one of items 2 to 8, wherein Compound 1 Form A is characterized by weight loss at temperatures above 200° C. in a TGA thermogram. (Item 10) 10. The crystalline solid form of any one of items 2 to 9, wherein Compound 1 Form A is characterized by a weight gain of about 0.8 to about 1.0 wt % as determined by DVS analysis when collected in a 5% relative humidity environment to a 95% relative humidity environment. (Item 11) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form B. (Item 12) 12. The crystalline solid form of item 11, wherein Compound 1 Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.58, 10.49, 11.27, 12.10, 13.26, 13.52, 15.15, and 16.69. (Item 13) 13. The crystalline solid form according to any one of items 11 to 12, wherein Compound 1 Form B is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 10.49, 12.10, 13.26, and 13.52. (Item 14) Item 15: The crystalline solid form of any one of items 11 to 13, wherein Compound 1 Form B is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, the peaks being 10.49, 12.10, 13.26, and 13.52. 15. The crystalline solid form of any one of items 11 to 14, wherein Compound 1 Form B is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 9.58, 10.49, 11.27, 12.10, 13.26, 13.52, 15.15, and 16.69. (Item 16) 16. The crystalline solid form of any one of items 11 to 15, wherein Compound 1 Form B is characterized by a first weight loss of about 0.3 wt % between temperatures of 38 and 92°C and a second weight loss of about 11.2 wt % between temperatures of 92 and 188°C in a TGA thermogram. (Item 17) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form C. (Item 18) 18. The crystalline solid form of item 17, wherein Compound 1 Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 3.89, 7.95, 9.31, 10.54, 12.96, 16.61, 17.64, and 20.47. (Item 19) 19. The crystalline solid form according to any one of items 17-18, wherein Compound 1 Form C is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 3.89, 7.95, 9.31, and 17.64. (Item 20) 20. The crystalline solid form of any one of items 17 to 19, wherein Compound 1 Form C is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 3.89, 7.95, 9.31, and 17.64. (Item 21) 21. The crystalline solid form of any one of items 17 to 20, wherein Compound 1 Form C is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 3.89, 7.95, 9.31, 10.54, 12.96, 16.61, 17.64, and 20.47. (Item 22) 22. The crystalline solid form of any one of items 17-21, wherein Compound 1 Form C is characterized by a first weight loss of about 0.4 wt% between temperatures of 40 and 75°C, a second weight loss of about 13.8 wt% between temperatures of 75 and 154°C, and a third weight loss of about 1.9 wt% between temperatures of 190 and 220°C in a TGA thermogram. (Item 23) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form D. (Item 24) 24. The crystalline solid form of item 23, wherein Compound 1 Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 5.43, 7.00, 10.21, 18.96, 23.62, 24.99, 26.62, 27.10, and 29.64. (Item 25) 25. The crystalline solid according to any one of items 23 to 24, wherein Compound 1 Form D is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 5.43, 7.00, 10.21, and 29.64. Body form. (Item 26) 26. The crystalline solid form of any one of items 23 to 25, wherein Compound 1 Form D is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 5.43, 7.00, 10.21, and 29.64. (Item 27) 27. The crystalline solid form of any one of items 23 to 26, wherein Compound 1 Form D is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 5.43, 7.00, 10.21, 18.96, 23.62, 24.99, 26.62, 27.10, and 29.64. (Item 28) 28. The crystalline solid form of any one of items 23 to 27, wherein Compound 1 Form D is characterized by a weight loss of about 13.5 wt% between temperatures of 38 and 130°C in a TGA thermogram. (Item 29) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form E. (Item 30) 30. The crystalline solid form of item 29, wherein Compound 1 Form E is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.13, 9.77, 10.37, 13.73, 14.79, 26.37, 29.12, and 29.95. (Item 31) 31. The crystalline solid form of any one of items 29-30, wherein Compound 1 Form E is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 10.37, 14.79, 26.37, and 29.95. (Item 32) 33. The crystalline solid form of any one of claims 29 to 31, wherein Compound 1 Form E is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, the peaks being 10.37, 14.79, 26.37, and 29.95. 33. The crystalline solid form of any one of items 29 to 32, wherein Compound 1 Form E is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.13, 9.77, 10.37, 13.73, 14.79, 26.37, 29.12, and 29.95. (Item 34) 34. The crystalline solid form of any one of items 29 to 33, wherein Compound 1 Form E is characterized by a weight loss of about 8.2 wt% between temperatures of 60 and 130°C in a TGA thermogram. (Item 35) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form F. (Item 36) 36. The crystalline solid form of item 35, wherein Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 7.44, 8.56, 13.65, 16.27, 19.25, 25.93, 29.2, and 29.9. (Item 37) 37. The crystalline solid according to any one of items 35 to 36, wherein Compound 1 Form F is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 7.44, 8.56, 13.65, and 29.9. form. (Item 38) 38. The crystalline solid form of any one of items 35 to 37, wherein Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 7.44, 8.56, 13.65, and 29.9. (Item 39) 39. The crystalline solid form of any one of items 35 to 38, wherein Compound 1 Form F is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 7.44, 8.56, 13.65, 16.27, 19.25, 25.93, 29.2, and 29.9. (Item 40) 40. The crystalline solid form of any one of items 35-39, wherein Compound 1 Form F is characterized by a first weight loss of about 0.1 wt % between temperatures of 38 and 77° C. and a second weight loss of about 14.4 wt % between temperatures of 77 and 178° C. in a TGA thermogram. (Item 41) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form G. (Item 42) 42. The crystalline solid form of item 41, wherein Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.71, 9.47, 14.40, 17.04, 17.85, 21.10, 30.3, and 30.7. (Item 43) 43. The crystalline solid form of any one of items 41 to 42, wherein Compound 1 Form G is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 6.71, 9.47, 30.3, and 30.7. (Item 44) 44. The crystalline solid form of any one of items 41 to 43, wherein Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.71, 9.47, 30.3, and 30.7. (Item 45) 45. The crystalline solid form of any one of items 41 to 44, wherein Compound 1 Form G is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.71, 9.47, 14.40, 17.04, 17.85, 21.10, 30.3, and 30.7. (Item 46) 46. ​​The crystalline solid form of any one of items 41 to 45, wherein Compound 1 Form G is characterized by a weight loss of about 20.8 wt% between temperatures of 40 and 165°C in a TGA thermogram. (Item 47) Item 2. The crystalline solid form according to item 2, characterized as Compound 1 Form H. (Item 48) 48. The crystalline solid form of item 47, wherein Compound 1 Form H is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.30, 11.42, 11.73, 17.52, 18.01, 18.56, 21.95, and 25.69. (Item 49) The Compound 1 Form H is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, the one or more peaks being 6.30, 17.52, 18. 49. The crystalline solid form according to any one of items 47 to 48, wherein the crystalline solid form is selected from the group consisting of 25.56, 25.69, and 25.70. (Item 50) 50. The crystalline solid form of any one of items 47 to 49, wherein Compound 1 Form H is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.30, 17.52, 18.56, and 25.69. (Item 51) 51. The crystalline solid form of any one of items 47 to 50, wherein Compound 1 Form H is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 6.30, 11.42, 11.73, 17.52, 18.01, 18.56, 21.95, and 25.69. (Item 52) Item 2. The crystalline solid form of Compound 1, characterized as Compound 1 Form K. (Item 53) 53. The crystalline solid form of item 52, wherein Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42. (Item 54) 54. The crystalline solid form of any one of items 52-53, wherein Compound 1 Form K is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.39, 8.10, 22.34, and 24.50. (Item 55) 55. The crystalline solid form of any one of items 52 to 54, wherein Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.39, 8.10, 22.34, and 24.50. (Item 56) 56. The crystalline solid form of any one of items 52 to 55, wherein Compound 1 Form K is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 6.39, 8.10, 11.53, 19.89, 21.11, 22.34, 24.50, and 26.42. (Item 57) 58. The crystalline solid form of any one of claims 52 to 56, wherein Compound 1 Form K is characterized by an endotherm having an onset temperature of about 226°C in a DSC thermogram. 58. The crystalline solid form of any one of items 52 to 57, wherein Compound 1 Form K is characterized by a weight loss of about 0.2 wt% between temperatures of 40 and 180°C in a TGA thermogram. (Item 59) Item 2. The crystalline solid form of Compound 1 characterized as Form O. (Item 60) 60. The crystalline solid form of item 59, wherein Compound 1 Form O is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.10, 9.01, 14.92, 17.14, 17.58, 23.96, 25.62, and 27.96. (Item 61) 61. The crystalline compound of any one of items 59 to 60, wherein Compound 1 Form O is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 6.10, 14.92, 17.14, and 23.96. Solid form. (Item 62) 62. The crystalline solid form of any one of items 59 to 61, wherein Compound 1 Form O is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.10, 14.92, 17.14, and 23.96. (Item 63) 63. The crystalline solid form of any one of items 59 to 62, wherein Compound 1 Form O is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 6.10, 9.01, 14.92, 17.14, 17.58, 23.96, 25.62, and 27.96. (Item 64) Item 3. The crystalline solid form according to item 2, characterized as Compound 1 Form Q. (Item 65) 65. The crystalline solid form of item 64, wherein Compound 1 Form Q is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01. (Item 66) 66. The crystalline solid form of any one of items 64-65, wherein Compound 1 Form Q is characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, wherein the one or more peaks are selected from 8.61, 9.74, 16.07, and 20.04. (Item 67) 67. The crystalline solid form of any one of items 64 to 66, wherein Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 8.61, 9.74, 16.07, and 20.04. (Item 68) 68. The crystalline solid form of any one of items 64 to 67, wherein Compound 1 Form Q is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 6.11, 8.61, 9.06, 9.74, 15.69, 16.07, 20.04, and 24.01. (Item 69) 69. The crystalline solid form of any one of items 64-68, wherein Compound 1 Form Q is characterized by an endotherm having an onset temperature of about 194-195° C. in a DSC thermogram. (Item 70) 70. The crystalline solid form of any one of items 64-69, wherein Compound 1 Form Q is characterized by a weight loss of about 11-12 wt% between temperatures of 120-160°C in a TGA thermogram. (Item 71) structure [ka] 1. A crystalline hydrochloride salt of Compound 1, or a hydrate or solvate thereof, having the formula: (Item 72) 72. The crystalline hydrochloride salt according to item 71, characterized as Compound 1 HCl Form A, Compound 1 HCl Form B, Compound 1 HCl Form C, or Compound 1 HCl Form D. (Item 73) 73. The crystalline hydrochloride salt form of item 72, wherein Compound 1 HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, 28.07, 28.4, and 30.0. (Item 74) 74. The crystalline hydrochloride salt form of any one of items 72-73, wherein Compound 1HCl Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 13.49, 17.47, 18.49, and 30.0. (Item 75) 75. The crystalline hydrochloride salt form of any one of items 72 to 74, wherein Compound 1HCl Form A is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 13.49, 17.47, 18.49, and 30.0. (Item 76) 76. The crystalline hydrochloride salt form of any one of items 72 to 75, wherein Compound 1 HCl Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the peaks are 5.19, 13.49, 13.69, 13.89, 14.84, 15.12, 16.34, 16.68, 17.47, 18.49, 20.31, 23.18, 24.39, 25.87, 26.34, 27.06, 28.07, 28.4, and 30.0. (Item 77) 73. The crystalline hydrochloride salt form according to item 71 or 72, characterized as Compound 1 HCl Form B. (Item 78) 78. The crystalline hydrochloride salt form of item 77, wherein Compound 1 HCl Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.72, 15.89, 16.63, 17.37, 18.32, 19.51, 21.04, 21.30, 21.81, 23.40, 24.76, 26.20, and 27.71. (Item 79) 79. The crystalline hydrochloride salt form of any one of items 77-78, wherein the Compound 1HCl Form B is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 9.72, 17.37, 18.32, and 19.51. (Item 80) 80. The crystalline hydrochloride salt form of any one of items 77 to 79, wherein Compound 1HCl Form B is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are 9.72, 17.37, 18.32, and 19.51. (Item 81) The Compound 1HCl Form B is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, wherein the peaks are: 9.72, 15.89, 1 6.63, 17.37, 18.32, 19.51, 21.04, 21.30, 21.81, 23.40, 24.76, 26.20, and 27.71. (Item 82) 73. The crystalline hydrochloride salt form according to item 71 or 72, characterized as Compound 1 HCl Form C. (Item 83) 83. The crystalline hydrochloride salt form of item 82, wherein the Compound 1 HCl Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, and 29.5. (Item 84) 84. The crystalline hydrochloride salt form of any one of items 82-83, wherein the Compound 1HCl Form C is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 2.5, 3.0, 4.3, 11.6, 17.1, 19.0, 20.5, 26.8, and 29.5. (Item 85) 85. The crystalline hydrochloride salt form of any one of items 82 to 84, wherein Compound 1HCl Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, and 29.5. (Item 86) 86. The crystalline hydrochloride salt form of any one of items 82 to 85, wherein the Compound 1 HCl Form C is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are 2.5, 3.0, 4.3, 6.2, 7.3, 7.8, 8.8, 11.6, 17.1, 19.0, 20.5, 26.8, and 29.5. (Item 87) 73. The crystalline hydrochloride salt form according to item 71 or 72, characterized as Compound 1 HCl Form D. (Item 88) The Compound 1HCl Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are: 3.47, 5.27, 6.93, 8.21, 8.97, 9.86, 10.16, 10.44, 10.69, 11.28, 12.26, 12.75, 13.27, 13.92, 14.23, 14.54, 14.95, 15.44, 15.69, 16.28, 17.26, 17.75, 18.27, 18.92, 19.23, 20.24, 20.54, 21.24, 22.24, 23.24, 25.24, 26.24, 27.24, 28.24, 29.24, 30.24, 31.24, 32.24, 33.24, 34.24, 35.24, 36.24, 37.24, 38.24, 39.24, 40.24, 41.24, 42.24, 43.24, 44.24, 45.24, 46.24, 47.24, 48.24, 49.24, 50.24, 51.24, 52.24, 53.24, 54.24, 55.24, 56.24, 57.24, 58.24, 59.24, 60.24, 61.24, 62.24, 88. The crystalline hydrochloride salt form of item 87, selected from: 0.58, 15.80, 16.08, 16.25, 17.84, 18.44, 18.65, 19.34, 19.75, 20.13, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.15, 24.39, 24.60, 24.91, 25.16, 26.27, 27.03, 27.61, and 28.37. (Item 89) 90. The crystalline hydrochloride salt form of any one of claims 87-88, wherein Compound 1 HCl Form D is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 3.47, 5.27, 10.16, 10.69, 12.26, 14.54, 14.95, 17.84, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.91, and 25.16. The Compound 1HCl Form D is characterized by all of the following peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the peaks are: 3.47, 5.27, 10.16, 10.69, 12.26, 14.54, 14.95, 17.84, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.91, and 25. 89. The crystalline hydrochloride salt form of any one of items 87 to 89, wherein the crystalline hydrochloride salt form is .16. (Item 91) The Compound 1HCl Form D is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale, wherein the peaks are: 3.47, 5.27, 6.93, 8.21, 8.97, 9.86, 10.16, 10.44, 10.69, 11.28, 12.26, 12.75, 13.27, 13.92, 14.23, 14.54, 14.95, 15.44, 15.58, 15.80, 16.08, 16.25, 17.84, 18.44, 18.65, 19.34, 19.75, 20.13, 20.93, 21.29, 22.05, 22.69, 22.90, 23.69, 24.15, 24.39, 24.60, 24.91, 25.16, 26.27, 27.03, 27.61, and 28.37. (Item 92) structure [ka] 1. A crystalline fumarate salt of Compound 1, or a hydrate or solvate thereof, having the formula: (Item 93) Item 93. The crystalline fumarate salt according to item 92, characterized as Compound 1 hemifumarate Form B. (Item 94) 94. Compound 1 hemifumarate Form B according to item 93, characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, said one or more peaks being selected from 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.88. (Item 95) 95. Compound 1 hemifumarate Form B according to any one of items 93 to 94, characterized by one or more peaks in an XRPD pattern at 2θ scale ±0.2, said one or more peaks being selected from 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05. (Item 96) 96. Compound 1 hemifumarate Form B according to any one of items 93 to 95, characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 9.08, 10.81, 16.95, 17.44, 22.29, 22.48, 23.82, 24.37, 26.34, and 27.05. (Item 97) and characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, said peaks being 7.55, 9.08, 10.81, 13.24, 15.89, 16.95, 17.14, 17.29, 17.44, 18.24, 19.16, 19.91, 20.19, 20.42, 20.70, 21.16, 21.74, 22.29, 22.48, 22.75, 23.82, 24.37, 26.34, 27.05, and 27.06. Item 98. Compound 1 hemifumarate Form B according to any one of Items 93 to 96, wherein the mol / L of the compound is 0.88. 98. Compound 1 hemifumarate Form B according to any one of paragraphs 93 to 97, characterized by an endotherm with an onset temperature of about 226° C. in a DSC thermogram. (Item 99) 99. Compound 1 hemifumarate Form B according to any one of items 93 to 98, characterized by negligible weight loss at a temperature of about 220°C in a TGA thermogram. (Item 100) 99. Compound 1 hemifumarate Form B according to any one of items 93 to 99, characterized by a weight gain of about 0.2 wt% as measured by DVS in an environment of 5% relative humidity to 95% relative humidity. (Item 101) structure [ka] 1. A crystalline phosphate salt of Compound 1, or a hydrate or solvate thereof, having the formula: (Item 102) Item 103. The crystalline phosphate salt according to Item 101, characterized as Compound 1 Phosphate Form A. 103. The crystalline phosphate form of item 102, wherein the Compound 1 phosphate Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2-theta scale, wherein the one or more peaks are selected from 6.3, 6.8, 10.5, 12.7, 13.8, 16.1, 17.3, 18.1, 18.8, 19.4, 20.3, 20.9, 21.2, 22.1, 23.2, 24.7, 27.4, 27.8, and 28.5. (Item 104) 104. The crystalline phosphate form of any one of items 102-103, wherein the Compound 1 Phosphate Form A is characterized by one or more peaks in an XRPD pattern at ±0.2 2θ scale, wherein the one or more peaks are selected from 6.3, 6.8, 13.8, 16.1, 19.4, 20.3, 23.2, and 24.7. (Item 105) 105. The crystalline phosphate form of any one of items 102 to 104, wherein the Compound 1 Phosphate Form A is characterized by all of the following peaks in an XRPD pattern at 2θ scale ±0.2, the peaks being 6.3, 6.8, 13.8, 16.1, 19.4, 20.3, 23.2, and 24.7. (Item 106) 106. The crystalline phosphate form of any one of items 102 to 105, wherein the Compound 1 Phosphate Form A is characterized by all of the following peaks in an XRPD pattern at ±0.2 2θ scale,...

Claims

[Claim 1] Chronic myeloid leukemia.

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