Solid forms of FGFR inhibitors and methods of making same

Abstract

The present disclosure relates to solid forms and polymorphs of Compound (1): 3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1, 3, 4, 7-tetrahydro-2H-pyrrolo [3 ', 2': 5, 6] pyrido [4, 3-d] pyrimidin-2-one, methods for their preparation, and intermediates in their preparation, which are useful in the treatment of FGFR-related or mediated diseases, such as cancer. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201980042915.X (application date: May 3, 2019, invention name: Solid form of FGFR inhibitor and preparation method thereof). Field of the Invention

[0002] The present application relates to solid forms of fibroblast growth factor receptor (FGFR) inhibitors, including methods for their preparation and intermediates in their preparation, which can be used to treat FGFR-mediated diseases, such as cancer. Background of the Invention

[0003] Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase, which is bound to fibroblast growth factor (FGF) ligands. There are four kinds of FGFR proteins (FGFR1-4), which can bind ligands and participate in the regulation of many physiological processes including tissue development, angiogenesis, wound healing and metabolic regulation. When ligands are bound, receptors undergo dimerization and phosphorylation, thereby causing the activity of stimulating protein kinases and recruiting many intracellular docking proteins. These interactions promote the activation of a series of intracellular signal transduction pathways, including Ras-MAPK, AKT-PI3K and phospholipase C, and the intracellular signal transduction pathways are important (reviewed in Cytokine & Growth Factor Reviews, 2005, etc., Eswarakumar, etc.) for cell growth, proliferation and survival. This path is abnormally activated by the overexpression of FGF ligands or FGFR or the activating mutation of FGFR and can cause tumor development, progress and resistance to conventional cancer therapy. In human cancer, the gene changes that cause non-ligand-dependent receptor activation have been described, including gene amplification, chromosomal translocation and somatic mutation. Large-scale DNA sequencing of thousands of tumor samples has shown that the components of FGFR pathways are among the most frequently mutated in human cancer. Many of these activating mutations are identical to germline mutations that cause skeletal dysplasia syndrome. The mechanism that causes abnormal ligand-dependent signal transduction in human disease includes the overexpression of FGF and the variation of FGFR splicing, so that the receptor has more promiscuous ligand binding ability (in Knights and Cook Pharmacology & Therapeutics, 2010; Turner and Grose, Nature Reviews Cancer, reviewed in 2010). Therefore, the inhibitor of research and development targeting FGFR can be used for the clinical treatment of the disease with elevated FGF or FGFR activity.

[0004] Cancer types in which FGF / FGFRs are implicated include, but are not limited to, carcinomas (e.g., bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer); hematopoietic malignancies (e.g., multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenstrom's macroglubulinemia); and other neoplasms (e.g., glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in oncogenic neoplasms, FGFR activation has also been implicated in skeletal and cartilage cell disorders, including, but not limited to, achondroplasia and craniosynostosis syndrome.

[0005] In particular, FGFR4-FGF19 signaling axis is involved in the pathogenesis of many cancers including hepatocellular carcinoma (Heinzle et al., Cur. Pharm. Des. 2014, 20: 2881). Ectopic expression of FGF19 in transgenic mice has been shown to cause tumor formation in the liver and it has been found that neutralizing antibodies to FGF19 inhibits tumor growth in mice. In addition, overexpression of FGFR4 has been observed in a variety of tumor types including hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, lung cancer and thyroid cancer. In addition, activating mutations in FGFR4 have been reported in rhabdomyosarcoma (Taylor et al. JCI 2009, 119: 3395).

[0006] FGFR inhibitors are currently under development for the treatment of cancer. For example, the molecule 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one and other small molecule inhibitors of FGFR are reported in, for example, U.S. Publication Nos. 2012 / 0165305; 2014-0045814; 2013-0338134; 2014 / 0171405; 2014 / 0315902; 2016 / 0115164; 2016 / 0244448; 2016 / 0244449; and 2016-0244450. Therefore, there is a need for new solid forms of FGFR inhibitory molecules for preparing pharmaceutically usable formulations and dosage forms having suitable properties relevant to, for example, facilitating the manufacture of safe, effective, and high-quality drug products. Summary of the Invention

[0007] Provided herein are solid forms of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one ("Compound 1").

[0008] Also provided herein are pharmaceutical compositions comprising a solid form as described herein and one or more pharmaceutically acceptable carriers or excipients.

[0009] The present disclosure also provides methods of inhibiting FGFR enzymes using the solid forms as described herein.

[0010] The present disclosure also provides methods of treating using a solid form as described herein. The present disclosure also provides the use of a solid form as described herein in the manufacture of a medicament for use in therapy. The present disclosure also provides a solid form as described herein for use in therapy.

[0011] Also provided herein are methods of preparing 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one and solid forms thereof as described herein.

[0012] Also provided herein are intermediates useful for preparing 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-ones and solid forms thereof described herein.

[0013] Also provided herein is a method of treating cholangiocarcinoma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1. Also provided herein is a method of treating a spinal cord / lymphoid neoplasm (e.g., 8p11 myeloproliferative syndrome) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of Compound 1. Additionally, provided herein is a method of increasing the survival or progression-free survival of a patient with cholangiocarcinoma characterized by an FGFR2 fusion, comprising administering to the patient Compound 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown is the X-ray powder diffraction (XRPD) pattern of Compound 1, Form I.

[0015] Figure 2 Shown is a differential scanning calorimetry (DSC) thermogram of Compound 1, Form I.

[0016] Figure 3 Shown is a thermogravimetric analysis (TGA) thermogram of Compound 1, Form I.

[0017] Figure 4 Shown is the XRPD pattern of Compound 1, Form II.

[0018] Figure 5 Shown is the DSC thermogram of Compound 1, Form II.

[0019] Figure 6 Shown is the TGA thermogram of Compound 1, Form II.

[0020] Figure 7 Shown is the XRPD pattern of Compound 1, Form IIa.

[0021] Figure 8 Shown is the DSC thermogram of Compound 1, Form Ha.

[0022] Figure 9 Shown is the TGA thermogram of Compound 1, Form Ha.

[0023] Figure 10 Shown is the XRPD pattern of Compound 1, Form III.

[0024] Figure 11 Shown is the DSC thermogram of Compound 1, Form III.

[0025] Figure 12 Shown is the TGA thermogram of Compound 1, Form III.

[0026] Figure 13 Shown is the XRPD pattern of Compound 1, Form IV.

[0027] Figure 14 Shown is the DSC thermogram of Compound 1, Form IV.

[0028] Figure 15 Shown is the TGA thermogram of Compound 1, Form IV.

[0029] Figure 16 The XRPD pattern of Compound 1, Form V is shown.

[0030] Figure 17 The DSC thermogram of Compound 1, Form V is shown.

[0031] Figure 18 Shown is the XRPD pattern of Compound 1, Form VI.

[0032] Figure 19 Shown is the DSC thermogram of Compound 1, Form VI.

[0033] Figure 20 Shown is the TGA thermogram of Compound 1, Form VI.

[0034] Figure 21 Shown is the XRPD pattern of Compound 1, Form VII.

[0035] Figure 22 Shown is the DSC thermogram of Compound 1, Form VII.

[0036] Figure 23 Shown is the TGA thermogram of Compound 1, Form VII.

[0037] Figure 24 Shown is the XRPD pattern of Compound 1, Form VIII.

[0038] Figure 25 Shown is the DSC thermogram of Compound 1, Form VIII.

[0039] Figure 26 Shown is the TGA thermogram of Compound 1, Form VIII.

[0040] Figure 27 Shown is the XRPD pattern of Compound 1, Form VIIIa.

[0041] Figure 28 Shown is the XRPD pattern of Compound 1, Form IX.

[0042] Figure 29 Shown is the DSC thermogram of Compound 1, Form IX.

[0043] Figure 30 Shown is the TGA thermogram of Compound 1, Form IX.

[0044] Figure 31 The XRPD pattern of Compound 1, Form X is shown.

[0045] Figure 32 The DSC thermogram of Compound 1, Form X is shown.

[0046] Figure 33 The TGA thermogram of Compound 1, Form X is shown.

[0047] Figure 34 Shown is the XRPD pattern of Compound 1, Form XI.

[0048] Figure 35 Shown is the DSC thermogram of Compound 1, Form XI.

[0049] Figure 36Shown is the TGA thermogram of Compound 1, Form XI.

[0050] Figure 37 Shown is the XRPD pattern of Compound 1, Form XII.

[0051] Figure 38 Shown is the DSC thermogram of Compound 1, Form XII.

[0052] Figure 39 Shown is the TGA thermogram of Compound 1, Form XII.

[0053] Figure 40 Shown is the XRPD pattern of Compound 1, Form XIII.

[0054] Figure 41 Shown is the DSC thermogram of Compound 1, Form XIII.

[0055] Figure 42 Shown is the TGA thermogram of Compound 1, Form XIII.

[0056] Figure 43 Shown is the XRPD pattern of Compound 1, Form XIIIa.

[0057] Figure 44 Shown is the DSC thermogram of Compound 1, Form XIIIa.

[0058] Figure 45 Shown is the XRPD pattern of Compound 1, Form XIV.

[0059] Figure 46 Shown is the DSC thermogram of Compound 1, Form XIV.

[0060] Figure 47 Shown is the TGA thermogram of Compound 1, Form XIV.

[0061] Figure 48 Shown is the XRPD pattern of Compound 1, Form XV.

[0062] Figure 49 Shown is the DSC thermogram of Compound 1, Form XV.

[0063] Figure 50 Shown is the TGA thermogram of Compound 1, Form XV.

[0064] Figure 51 Shown is the XRPD pattern of Compound 1, Form XVI.

[0065] Figure 52 Shown is the DSC thermogram of Compound 1, Form XVI.

[0066] Figure 53 Shown is the TGA thermogram of Compound 1, Form XVI.

[0067] Figure 54 Shown is the XRPD pattern of Compound 1, Form XVII.

[0068] Figure 55 Shown is the DSC thermogram of Compound 1, Form XVII.

[0069] Figure 56 Shown is the TGA thermogram of Compound 1, Form XVII.

[0070] Figure 57 Shown is the XRPD pattern of Compound 1, Form XVIII.

[0071] Figure 58 Shown is the DSC thermogram of Compound 1, Form XVIII.

[0072] Figure 59 Shown is the TGA thermogram of Compound 1, Form XVIII.

[0073] Figure 60 Shown is the XRPD pattern of Compound 1, Form XIX.

[0074] Figure 61 Shown is the DSC thermogram of Compound 1, Form XIX.

[0075] Figure 62 Shown is the TGA thermogram of Compound 1, Form XIX.

[0076] Figure 63 Shown is the XRPD pattern of Compound 1, Form XX.

[0077] Figure 64 Shown is the DSC thermogram of Compound 1, Form XX.

[0078] Figure 65 Shown is the TGA thermogram of Compound 1, Form XX.

[0079] Figure 66 Shown is the XRPD pattern of Compound 1, Form XXI.

[0080] Figure 67 Shown is the DSC thermogram of Compound 1, Form XXI.

[0081] Figure 68 Shown is the XRPD pattern of Compound 1, Form XXII.

[0082] Figure 69Shown is the DSC thermogram of Compound 1, Form XXII.

[0083] Figure 70 Shown is the XRPD pattern of Compound 1, Form XXIII.

[0084] Figure 71 Shown is the DSC thermogram of Compound 1, Form XXIII.

[0085] Figure 72 Shown is the TGA thermogram of Compound 1, Form XXIII.

[0086] Figure 73 Shown is the XRPD pattern of Compound 1, Form XXIV.

[0087] Figure 74 Shown is the DSC thermogram of Compound 1, Form XXIV.

[0088] Figure 75 Shown is the TGA thermogram of Compound 1, Form XXIV.

[0089] Figure 76 Shown is the XRPD pattern of Compound 1, Form XXV.

[0090] Figure 77 Shown is the DSC thermogram of Compound 1, Form XXV.

[0091] Figure 78 Shown is the XRPD pattern of Compound 1, Form XXVI.

[0092] Figure 79 Shown are the best percent change in target lesion size from baseline according to the independent observer in patients with CCA and FGFR2 translocation (cohort A).

[0093] Figure 80 Shown are the duration of treatment and responses confirmed by an independent observer in patients with CCA and FGFR2 translocation (cohort A).

[0094] Figure 81 Kaplan-Meier estimates of progression-free survival (PFS; estimated by an independent observer) in cohorts A, B, and C are shown.

[0095] Figure 82 Shown is an overview of clinical and cytogenetic responses in patients with spinal cord / lymphoid neoplasms harboring FGFR1 rearrangements.

[0096] Figure 83Shown is a baseline PET scan of a patient with myeloproliferative and T-lymphoblastic lymphoma (TLL) before treatment with Compound 1.

[0097] Figure 84 Shown is a baseline PET scan of a patient with myeloproliferative and T-lymphoblastic lymphoma (TLL) following treatment with Compound 1. DETAILED DESCRIPTION

[0098] The present disclosure is particularly directed to solid forms of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (Compound 1), including crystalline and amorphous forms, as well as methods and intermediates for preparing the compound. The structure of Compound 1 is shown below.

[0099]

[0100] Compound 1 is described in US Patent No. 9,611,267, which is incorporated herein by reference in its entirety.

[0101] Compound 1 can be isolated into one or more solid forms. The solid forms described herein (e.g., crystalline forms) can have certain advantages, for example, they can have desirable properties such as ease of handling, ease of processing, storage stability, and ease of purification. In addition, crystalline forms can be used to improve the performance characteristics of drug products, such as dissolution profile, shelf life, and bioavailability.

[0102] As used herein, and unless otherwise indicated, the term "about" should be used in conjunction with a value or range of values ​​provided to describe a particular solid form (e.g., a particular temperature or temperature range, such as that describing melting, dehydration, or glass transition; a change in mass, such as that with temperature or humidity; solvent or water content, e.g., by mass or percentage; or a peak position, such as that measured by, e.g., 13 C NMR, DSC, TGA, and XRPD) indicates that the value or range of values ​​may vary to an extent that one of ordinary skill in the art would consider reasonable while still describing the specific solid form. Specifically, the term "about" when used in this context indicates that a value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the recited value or range of values ​​while still describing the specific solid form. The term "about" when used in reference to a degree 2-theta value refers to + / - 0.2 degrees 2-theta.

[0103] As used herein, the phrase "solid form" refers to a compound provided herein in an amorphous state or a crystalline state ("crystalline form" or "crystalline solid" or "crystalline solid form"), wherein the compound provided herein in a crystalline state may optionally include a solvent or water within the crystal lattice, for example, to form a solvated or hydrated crystalline form. In some embodiments, the compound provided herein is in a crystalline state as described herein.

[0104] As used herein, the term "peak" or "characteristic peak" refers to an XRPD reflection having a relative height / intensity that is at least about 3% of the maximum peak height / intensity.

[0105] As used herein, the term "crystalline" or "crystalline form" refers to a crystalline solid form of a compound, including but not limited to single-component or multi-component crystal forms, such as solvates, hydrates, inclusion compounds, and co-crystals. For example, crystalline means having a regular repetition and / or orderly arrangement of molecules and having a distinguishable crystal lattice. The term "crystalline form" is intended to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells), typically have different physical properties due to their different crystal lattices, and in some cases, have different water or solvent contents. Different crystal lattices can be identified by solid-state characterization methods, such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS) further help identify the crystalline form and help determine stability and solvent / water content.

[0106] Different crystalline forms of a particular substance, such as Compound 1 as described herein, may include both an anhydrous form of the substance and a solvated / hydrated form of the substance, wherein each of the anhydrous form and the solvated / hydrated form differs from the other according to different XRPD patterns or other solid-state characterization methods, thereby meaning that the crystal lattices are different. In some cases, a single crystalline form (e.g., identified by a unique XRPD pattern) may have a variable water or solvent content, wherein the crystal lattice remains substantially unchanged (as does the XRPD pattern) despite compositional changes with respect to water and / or solvent.

[0107] The reflections (peaks) of an XRPD pattern are typically considered to be the fingerprints of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely, particularly depending on sample preparation techniques, crystal size distribution, the filters used, the sample installation procedure, and the specific instrument employed. In some cases, depending on the machine type or settings (e.g., whether a Ni filter is used), new peaks may be observed or existing peaks may disappear. As used herein, the term "peak" refers to a reflection whose relative height / intensity is at least about 3% or at least about 4% of the maximum peak height / intensity. In addition, instrument deviations and other factors may affect 2-θ values. Therefore, peak assignments such as those reported herein may vary by plus or minus about 0.2 ° (2-θ) and the term "substantially" as used herein in the context of XRPD is intended to encompass such variations.

[0108] In the same manner, temperature readings associated with DSC, TGA, or other thermal experiments can vary by about ±3°C depending on the instrument, specific settings, sample preparation, etc. Thus, reference to a crystalline form reported herein having a DSC thermogram "substantially" as shown in any of the Figures should be understood to encompass such variations.

[0109] As is known in the art, crystalline forms of substances can be obtained by many methods. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in a confined space (such as in a nanopore or capillary), recrystallization on a surface or template (such as on a polymer), recrystallization in the presence of an additive (such as a co-crystal counter-molecule), desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, exposure to moisture, grinding, and solvent drop grinding.

[0110] As used herein, the term "amorphous" or "amorphous form" is intended to mean that the substance, component, or product in question is not crystalline, for example, as determined by XRPD, or that the substance, component, or product in question is not birefringent, for example, when viewed under a microscope. For example, amorphous means that there is substantially no regularly repeating arrangement of molecules or a lack of long-range ordered crystals, that is, the amorphous form is non-crystalline. An amorphous form does not exhibit a determined x-ray diffraction pattern with sharp maxima. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous forms and / or crystalline forms. For example, an amorphous substance can be identified by the absence of reflections in an XRPD spectrum.

[0111] As used herein, the term "substantially amorphous" means that the majority of the weight of a sample or preparation of Compound 1 is amorphous and the remainder of the sample is a crystalline form of the same compound. In some embodiments, a substantially amorphous sample has less than about 5% crystallinity (e.g., about 95% of the same compound in amorphous form), less than about 4% crystallinity (e.g., about 96% of the same compound in amorphous form), less than about 3% crystallinity (e.g., about 97% of the same compound in amorphous form), less than about 2% crystallinity (e.g., about 98% of the same compound in amorphous form), less than about 1% crystallinity (e.g., about 99% of the same compound in amorphous form), or about 0% crystallinity (e.g., about 100% of the same compound in amorphous form). In some embodiments, the term "completely amorphous" means less than about 99% or about 0% crystallinity.

[0112] Compound 1 can be prepared in batches, referred to as batches, samples, or preparations. A batch, sample, or preparation can include Compound 1 in any of the crystalline or non-crystalline forms described herein, including hydrated and non-hydrated forms and mixtures thereof.

[0113] The compounds provided herein (e.g., Compound 1) may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds provided herein may be replaced or substituted with atomic isotopes of natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0114] In some embodiments, compound 1 is substantially separated.Term " substantially separated " means that compound is at least partially or substantially separated from the environment in which it is formed or detected.Partial separation can include, for example, a composition rich in compound, salt, hydrate, solvate or solid form provided herein.Substantially separating can include containing by weight at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97% or at least about 99% of the compound, salt, hydrate, solvate or solid form provided herein.

[0115] As used herein, the term "hydrate" is intended to refer to a solid form of Compound 1 that includes water. The water in the hydrate may be present in a stoichiometric amount relative to the amount of salt in the solid, or may be present in varying amounts, such as may be present in conjunction with a channel hydrate.

[0116] As used herein, the term "substantially" when referring to a characteristic pattern of a crystalline form, such as an XRPD pattern, DSC thermogram, TGA thermogram, or the like, means that the patterns of the present invention may not be consistent with the reference presented herein, but are within the limits of experimental error and therefore can be considered to be derived from the same crystalline form as disclosed herein as judged by one of ordinary skill in the art.

[0117] As used herein, the term "substantially crystalline" means that the majority of the weight of a sample or preparation of Compound 1 is crystalline and the remainder of the sample is a non-crystalline form of the same compound (e.g., an amorphous form). In some embodiments, a substantially crystalline sample has at least about 95% crystallinity (e.g., about 5% of the same compound in a non-crystalline form), at least about 96% crystallinity (e.g., about 4% of the same compound in a non-crystalline form), at least about 97% crystallinity (e.g., about 3% of the same compound in a non-crystalline form), at least about 98% crystallinity (e.g., about 2% of the same compound in a non-crystalline form), at least about 99% crystallinity (e.g., about 1% of the same compound in a non-crystalline form), or about 100% crystallinity (e.g., about 0% of the same compound in a non-crystalline form). In some embodiments, the term "completely crystalline" means at least about 99% or about 100% crystallinity.

[0118] As used herein, the term "% crystallinity" or "crystalline purity" refers to the percentage of a crystalline form in a preparation or sample, which may contain other forms, such as an amorphous form of the same compound, or at least one other crystalline form of a compound, or a mixture thereof. In some embodiments, the crystalline form can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, the crystalline form can be isolated to have a purity greater than about 99%.

[0119] As used herein, the term "reaction" is used as known in the art and generally refers to bringing together chemical reagents in such a manner so that they interact at the molecular level to achieve a chemical or physical conversion. In some embodiments, the reaction involves at least two reagents, wherein a second reagent is used in a molar equivalent or more molar equivalent relative to the first reagent. In some embodiments, the reaction steps of the synthesis process may also involve one or more substances, such as solvents and / or catalysts, in addition to the reagents. The reaction steps of the methods described herein may be carried out for a time suitable for preparing the identified product and under conditions suitable for preparing the identified product.

[0120] As used herein, the term "converting" in reference to altering an intermediate or starting reagent or material in a chemical reaction means subjecting the intermediate or starting reagent or material to appropriate reagents and conditions (e.g., temperature, time, solvent, etc.) to effect some change (e.g., breaking or forming a chemical bond) to produce the desired product.

[0121] Compound 1 can be prepared into various crystalline forms, including, for example, Form I, Form II, Form II-a, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form VIIIa, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIII-a, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX, Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV or Form XXVI. In some embodiments, the solid form of Compound 1 is amorphous.

[0122] Compound 1 Form I

[0123] Provided herein is a crystalline, solid form of Compound 1, designated Form I, described below in the Examples.

[0124] In some embodiments, Form I has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 12.9, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0125] In some embodiments, Form I has at least two characteristic XRPD peaks selected from about 6.8, about 12.9, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0126] In some embodiments, Form I has at least three characteristic XRPD peaks selected from about 6.8, about 12.9, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0127] In some embodiments, Form I has at least one characteristic XRPD peak selected from about 6.8, about 9.6, about 12.9, about 18.6, about 19.4, about 22.6, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0128] In some embodiments, Form I has at least two characteristic XRPD peaks selected from about 6.8, about 9.6, about 12.9, about 18.6, about 19.4, about 22.6, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0129] In some embodiments, Form I has at least three characteristic XRPD peaks selected from about 6.8, about 9.6, about 12.9, about 18.6, about 19.4, about 22.6, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

[0130] In some embodiments, Form I has characteristic peaks substantially as follows Figure 1 The XRPD pattern shown in .

[0131] In some embodiments, Form I exhibits a DSC thermogram having endothermic peaks at temperatures of about 201°C and 276°C. In some embodiments, Form I exhibits a DSC thermogram having an endothermic peak at a temperature of about 201°C. In some embodiments, Form I exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form I has substantially Figure 2 In some embodiments, Form I has substantially Figure 3 The TGA thermogram shown in .

[0132] In some embodiments, Form I has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 12.9, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta; and Form I exhibits a DSC thermogram with endothermic peaks at temperatures of about 201°C and 276°C.

[0133] Also provided herein is a method for preparing Form I of Compound 1, comprising recrystallizing Compound 1 in a solvent. In some embodiments, the solvent is a mixture of dichloromethane and methyl tert-butyl ether. In some embodiments, the method for preparing Form I of Compound 1 comprises recrystallizing Compound 1 from a mixture of dichloromethane and methyl tert-butyl ether. In some embodiments, recrystallization comprises a) heating a solution of Compound 1 in a mixture of dichloromethane and methyl tert-butyl ether to an elevated temperature for a first period of time, and b) cooling to a lower temperature for a second period of time. In some embodiments, the elevated temperature is ≥30°C, ≥35°C, ≥36°C, ≥39°C, or ≥40°C. In certain embodiments, the first period of time is between 5 and 6 hours. In some embodiments, the first period of time is greater than 5 hours. In some embodiments, the lower temperature is ambient temperature. In some embodiments, the lower temperature is approximately 23°C. In some embodiments, the second period of time is between 10 and 11 hours. In some embodiments, the second period of time is longer than 5, 8, or 10 hours. In some embodiments, the second period of time is 10.5 hours.

[0134] In some embodiments, Form I can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity of greater than about 99%.

[0135] Compound 1 Form II

[0136] Provided herein is a solid form of Compound 1 having Form II described below in the Examples.

[0137] In some embodiments, Form II has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.5, about 12.8, about 13.3, and about 25.8 degrees 2-theta.

[0138] In some embodiments, Form II has at least two characteristic XRPD peaks selected from the group consisting of: about 6.8, about 9.5, about 12.8, about 13.3, and about 25.8 degrees 2-theta.

[0139] In some embodiments, Form II has at least three characteristic XRPD peaks selected from the group consisting of: about 6.8, about 9.5, about 12.8, about 13.3, and about 25.8 degrees 2-theta.

[0140] In some embodiments, Form II has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.5, about 12.8, about 13.3, about 19.0, about 20.5, about 22.6, about 25.8, about 26.2, and about 27.4 degrees 2-theta.

[0141] In some embodiments, Form II has at least two characteristic XRPD peaks selected from about 6.8, about 9.5, about 12.8, about 13.3, about 19.0, about 20.5, about 22.6, about 25.8, about 26.2, and about 27.4 degrees 2-theta.

[0142] In some embodiments, Form II has at least three characteristic XRPD peaks selected from about 6.8, about 9.5, about 12.8, about 13.3, about 19.0, about 20.5, about 22.6, about 25.8, about 26.2, and about 27.4 degrees 2-theta.

[0143] In some embodiments, Form II has characteristic peaks substantially as Figure 4 The XRPD pattern shown in .

[0144] In some embodiments, Form II exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form II has substantially Figure 5 In some embodiments, Form II has substantially Figure 6 The TGA thermogram shown in .

[0145] In some embodiments, Form II has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.5, about 12.8, about 13.3, and about 25.8 degrees 2-theta; and Form II exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C.

[0146] Also provided herein is a method for preparing Form II of Compound 1, comprising evaporating a saturated solution of Compound 1, Form I in dichloromethane at 50±1°C.

[0147] In some embodiments, Form II can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0148] Compound 1 Form II-a

[0149] Provided herein is a solid form of Compound 1 having Form II-a described below in the Examples.

[0150] In some embodiments, Form II-a has at least one characteristic XRPD peak selected from the group consisting of: about 6.9, about 9.4, about 13.3, about 16.3, and about 19.9 degrees 2-theta.

[0151] In some embodiments, Form II-a has at least two characteristic XRPD peaks selected from the group consisting of: about 6.9, about 9.4, about 13.3, about 16.3, and about 19.9 degrees 2-theta.

[0152] In some embodiments, Form II-a has at least three characteristic XRPD peaks selected from the group consisting of: about 6.9, about 9.4, about 13.3, about 16.3, and about 19.9 degrees 2-theta.

[0153] In some embodiments, Form II-a has at least one characteristic XRPD peak selected from about 6.9, about 9.4, about 12.9, about 13.3, about 16.3, about 17.5, about 19.0, about 19.9, about 22.5, and about 26.1 degrees 2-theta.

[0154] In some embodiments, Form II-a has at least two characteristic XRPD peaks selected from about 6.9, about 9.4, about 12.9, about 13.3, about 16.3, about 17.5, about 19.0, about 19.9, about 22.5, and about 26.1 degrees 2-theta.

[0155] In some embodiments, Form II-a has at least three characteristic XRPD peaks selected from about 6.9, about 9.4, about 12.9, about 13.3, about 16.3, about 17.5, about 19.0, about 19.9, about 22.5, and about 26.1 degrees 2-theta.

[0156] In some embodiments, Form II-a has characteristic peaks substantially as follows Figure 7 The XRPD pattern shown in .

[0157] In some embodiments, Form II-a exhibits a DSC thermogram having an endothermic peak at a temperature of about 275° C. In some embodiments, Form II-a has substantially Figure 8 In some embodiments, Form II-a has substantially Figure 9 The TGA thermogram shown in .

[0158] In some embodiments, Form II-a has at least one characteristic XRPD peak selected from the group consisting of: about 6.9, about 9.4, about 13.3, about 16.3, and about 19.9 degrees 2-theta; and Form II-a exhibits a DSC thermogram having an endothermic peak at a temperature of about 275°C.

[0159] Also provided herein is a method for preparing Form II-a of Compound 1, comprising evaporating a solution of Compound 1, Form I in dichloromethane at 25±1°C.

[0160] In some embodiments, Form II-a can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0161] Compound 1 Form III

[0162] Provided herein is a solid form of Compound 1 having Form III described below in the Examples.

[0163] In some embodiments, Form III has at least one characteristic XRPD peak selected from the group consisting of: about 3.5, about 13.9, about 15.0, about 15.3, about 16.8, and about 18.6.

[0164] In some embodiments, Form III has at least two characteristic XRPD peaks selected from about 3.5, about 13.9, about 15.0, about 15.3, about 16.8, and about 18.6.

[0165] In some embodiments, Form III has at least three characteristic XRPD peaks selected from the group consisting of: about 3.5, about 13.9, about 15.0, about 15.3, about 16.8, and about 18.6.

[0166] In some embodiments, Form III has at least one characteristic XRPD peak selected from about 3.5, about 6.7, about 8.5, about 13.9, about 15.0, about 15.3, about 16.8, about 18.6, about 19.3, about 21.5, about 22.9, about 24.2, and about 25.9 degrees 2-theta.

[0167] In some embodiments, Form III has at least two characteristic XRPD peaks selected from about 3.5, about 6.7, about 8.5, about 13.9, about 15.0, about 15.3, about 16.8, about 18.6, about 19.3, about 21.5, about 22.9, about 24.2, and about 25.9 degrees 2-theta.

[0168] In some embodiments, Form III has at least three characteristic XRPD peaks selected from about 3.5, about 6.7, about 8.5, about 13.9, about 15.0, about 15.3, about 16.8, about 18.6, about 19.3, about 21.5, about 22.9, about 24.2, and about 25.9 degrees 2-theta.

[0169] In some embodiments, Form III has characteristic peaks substantially as follows Figure 10 The XRPD pattern shown in .

[0170] In some embodiments, Form III exhibits a DSC thermogram having endothermic peaks at temperatures of about 101°C, 204°C, and 276°C. In some embodiments, Form III exhibits a DSC thermogram having an endothermic peak at a temperature of about 101°C. In some embodiments, Form III exhibits a DSC thermogram having an endothermic peak at a temperature of about 204°C. In some embodiments, Form III exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form III has substantially Figure 11 In some embodiments, Form III has substantially Figure 12 The TGA thermogram shown in .

[0171] In some embodiments, Form III has at least one characteristic XRPD peak selected from the group consisting of: about 3.5, about 13.9, about 15.0, about 15.3, about 16.8, and about 18.6; and Form III exhibits a DSC thermogram having endothermic peaks at temperatures of about 101°C, 204°C, and 276°C.

[0172] Also provided herein is a method for preparing Form III of Compound 1, comprising adding Compound 1, Form I to a solution of Compound 1, Form I in 1,4-dioxane, stirring at 25±1° C. for 2 days, and removing the supernatant by centrifugation.

[0173] In some embodiments, Form III can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0174] Compound 1 Form IV

[0175] Provided herein is a solid form of Compound 1 having Form IV described below in the Examples.

[0176] In some embodiments, Form IV has at least one characteristic XRPD peak selected from the group consisting of: about 10.1, about 13.0, about 14.0, about 18.4, about 22.2, about 24.3, and about 26.4 degrees 2-theta.

[0177] In some embodiments, Form IV has at least two characteristic XRPD peaks selected from the group consisting of: about 10.1, about 13.0, about 14.0, about 18.4, about 22.2, about 24.3, and about 26.4 degrees 2-theta.

[0178] In some embodiments, Form IV has at least three characteristic XRPD peaks selected from the group consisting of: about 10.1, about 13.0, about 14.0, about 18.4, about 22.2, about 24.3, and about 26.4 degrees 2-theta.

[0179] In some embodiments, Form IV has at least one characteristic XRPD peak selected from about 10.1, about 13.0, about 14.0, about 15.6, about 17.3, about 18.4, about 20.2, about 21.4, about 22.2, about 22.7, about 24.3, about 26.4, and about 26.8 degrees 2-theta.

[0180] In some embodiments, Form IV has at least two characteristic XRPD peaks selected from about 10.1, about 13.0, about 14.0, about 15.6, about 17.3, about 18.4, about 20.2, about 21.4, about 22.2, about 22.7, about 24.3, about 26.4, and about 26.8 degrees 2-theta.

[0181] In some embodiments, Form IV has at least three characteristic XRPD peaks selected from about 10.1, about 13.0, about 14.0, about 15.6, about 17.3, about 18.4, about 20.2, about 21.4, about 22.2, about 22.7, about 24.3, about 26.4, and about 26.8 degrees 2-theta.

[0182] In some embodiments, Form IV has characteristic peaks substantially as Figure 13 The XRPD pattern shown in .

[0183] In some embodiments, Form IV exhibits a DSC thermogram having endothermic peaks at temperatures of about 109°C, 203°C, and 278°C. In some embodiments, Form IV exhibits a DSC thermogram having an endothermic peak at a temperature of about 109°C. In some embodiments, Form IV exhibits a DSC thermogram having an endothermic peak at a temperature of about 203°C. In some embodiments, Form IV exhibits a DSC thermogram having an endothermic peak at a temperature of about 278°C. In some embodiments, Form IV has substantially Figure 14 In some embodiments, Form IV has substantially Figure 15 The TGA thermogram shown in .

[0184] In some embodiments, Form IV has at least one characteristic XRPD peak selected from the group consisting of: about 10.1, about 13.0, about 14.0, about 18.4, about 22.2, about 24.3, and about 26.4 degrees 2-theta; and Form IV exhibits a DSC thermogram having endothermic peaks at temperatures of about 109°C, 203°C, and 278°C.

[0185] Also provided herein is a method of preparing Form IV of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1, Form I in 1,4-dioxane and stirring at 25±1°C for 6 days.

[0186] In some embodiments, Form IV can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0187] Compound 1 Form V

[0188] Provided herein is a solid form of Compound 1 having Form V described below in the Examples.

[0189] In some embodiments, Form V has at least one characteristic XRPD peak selected from the group consisting of: about 7.4, about 14.8, about 21.3, about 22.0, and about 22.3 degrees 2-theta.

[0190] In some embodiments, Form V has at least two characteristic XRPD peaks selected from the group consisting of: about 7.4, about 14.8, about 21.3, about 22.0, and about 22.3 degrees 2-theta.

[0191] In some embodiments, Form V has at least three characteristic XRPD peaks selected from the group consisting of: about 7.4, about 14.8, about 21.3, about 22.0, and about 22.3 degrees 2-theta.

[0192] In some embodiments, Form V has characteristic peaks substantially as follows Figure 16 The XRPD pattern shown in .

[0193] In some embodiments, Form V exhibits a DSC thermogram having endothermic peaks at temperatures of about 91°C, 203°C, and 276°C. In some embodiments, Form V exhibits a DSC thermogram having an endothermic peak at a temperature of about 91°C. In some embodiments, Form V exhibits a DSC thermogram having an endothermic peak at a temperature of about 203°C. In some embodiments, Form V exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form V has substantially Figure 17 DSC thermogram shown in .

[0194] In some embodiments, Form V has at least one characteristic XRPD peak selected from the group consisting of: about 7.4, about 14.8, about 21.3, about 22.0, and about 22.3 degrees 2-theta; and Form V exhibits a DSC thermogram with endothermic peaks at temperatures of about 91 °C, 203 °C, and 276 °C.

[0195] Also provided herein is a method of preparing Form V of Compound 1, comprising allowing a saturated solution of Compound 1, Form I in 1,4-dioxane to stand for greater than 30 days.

[0196] In some embodiments, Form V can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0197] Compound 1 Form VI

[0198] Provided herein is a solid form of Compound 1 having Form VI described below in the Examples.

[0199] In some embodiments, Form VI has at least one characteristic XRPD peak selected from the group consisting of: about 9.1, about 9.5, about 14.4, about 17.6, about 18.6, about 19.9, and about 22.3 degrees 2-theta.

[0200] In some embodiments, Form VI has at least two characteristic XRPD peaks selected from about 9.1, about 9.5, about 14.4, about 17.6, about 18.6, about 19.9, and about 22.3 degrees 2-theta.

[0201] In some embodiments, Form VI has at least three characteristic XRPD peaks selected from the group consisting of about 9.1, about 9.5, about 14.4, about 17.6, about 18.6, about 19.9, and about 22.3 degrees 2-theta.

[0202] In some embodiments, Form VI has at least one characteristic XRPD peak selected from about 7.8, about 9.1, about 9.5, about 10.2, about 11.4, about 12.1, about 13.4, about 14.4, about 15.9, about 17.6, about 18.6, about 19.2, about 19.9, about 22.3, about 22.7, about 25.4, and about 26.2 degrees 2-theta.

[0203] In some embodiments, Form VI has at least two characteristic XRPD peaks selected from about 7.8, about 9.1, about 9.5, about 10.2, about 11.4, about 12.1, about 13.4, about 14.4, about 15.9, about 17.6, about 18.6, about 19.2, about 19.9, about 22.3, about 22.7, about 25.4, and about 26.2 degrees 2-theta.

[0204] In some embodiments, Form VI has at least three characteristic XRPD peaks selected from about 7.8, about 9.1, about 9.5, about 10.2, about 11.4, about 12.1, about 13.4, about 14.4, about 15.9, about 17.6, about 18.6, about 19.2, about 19.9, about 22.3, about 22.7, about 25.4, and about 26.2 degrees 2-theta.

[0205] In some embodiments, Form VI has characteristic peaks substantially as Figure 18 The XRPD pattern shown in .

[0206] In some embodiments, Form VI exhibits a DSC thermogram having an endothermic peak at a temperature of about 275° C. In some embodiments, Form VI has substantially Figure 19 In some embodiments, Form VI has substantially Figure 20 The TGA thermogram shown in .

[0207] In some embodiments, Form VI has at least one characteristic XRPD peak selected from the group consisting of: about 9.1, about 9.5, about 14.4, about 17.6, about 18.6, about 19.9, and about 22.3 degrees 2-theta; and Form VI exhibits a DSC thermogram having an endothermic peak at a temperature of about 275°C.

[0208] Also provided herein is a method for preparing Form VI of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1 prepared in methanol and stirring at 25 ± 1 °C for 3 days.

[0209] In some embodiments, Form VI can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0210] Compound 1 Form VII

[0211] Provided herein is a solid form of Compound 1 having Form VII described below in the Examples.

[0212] In some embodiments, Form VII has at least one characteristic XRPD peak selected from the group consisting of: about 9.8, about 15.4, about 18.8, about 19.6, and about 20.1 degrees 2-theta.

[0213] In some embodiments, Form VII has at least two characteristic XRPD peaks selected from the group consisting of: about 9.8, about 15.4, about 18.8, about 19.6, and about 20.1 degrees 2-theta.

[0214] In some embodiments, Form VII has at least three characteristic XRPD peaks selected from the group consisting of: about 9.8, about 15.4, about 18.8, about 19.6, and about 20.1 degrees 2-theta.

[0215] In some embodiments, Form VII has at least one characteristic XRPD peak selected from about 8.2, about 9.8, about 15.4, about 17.9, about 18.8, about 19.6, about 20.1, about 21.1, about 22.3, and about 24.3 degrees 2-theta.

[0216] In some embodiments, Form VII has at least two characteristic XRPD peaks selected from about 8.2, about 9.8, about 15.4, about 17.9, about 18.8, about 19.6, about 20.1, about 21.1, about 22.3, and about 24.3 degrees 2-theta.

[0217] In some embodiments, Form VII has at least three characteristic XRPD peaks selected from about 8.2, about 9.8, about 15.4, about 17.9, about 18.8, about 19.6, about 20.1, about 21.1, about 22.3, and about 24.3 degrees 2-theta.

[0218] In some embodiments, Form VII has characteristic peaks substantially as follows Figure 21 The XRPD pattern shown in .

[0219] In some embodiments, Form VII exhibits a DSC thermogram having endothermic peaks at temperatures of about 88°C, 201°C, and 276°C. In some embodiments, Form VII exhibits a DSC thermogram having an endothermic peak at a temperature of about 88°C. In some embodiments, Form VII exhibits a DSC thermogram having an endothermic peak at a temperature of about 201°C. In some embodiments, Form VII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form VII has substantially Figure 22 In some embodiments, Form VII has substantially Figure 23 The TGA thermogram shown in .

[0220] In some embodiments, Form VII has at least one characteristic XRPD peak selected from the group consisting of: about 9.8, about 15.4, about 18.8, about 19.6, and about 20.1 degrees 2-theta; and Form VII exhibits a DSC thermogram having endothermic peaks at temperatures of about 88°C, 201°C, and 276°C.

[0221] Also provided herein is a method for preparing Form VII of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1, Form I prepared in methyl isobutyl ketone and stirring at 25 ± 1 °C for 3 days.

[0222] In some embodiments, Form VII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0223] Compound 1 Form VIII

[0224] Provided herein is a solid form of Compound 1 having Form VIII described below in the Examples.

[0225] In some embodiments, Form VIII has at least one characteristic XRPD peak selected from the group consisting of: about 9.1, about 16.7, about 18.2, about 18.6, and about 20.2 degrees 2-theta.

[0226] In some embodiments, Form VIII has at least two characteristic XRPD peaks selected from the group consisting of: about 9.1, about 16.7, about 18.2, about 18.6, and about 20.2 degrees 2-theta.

[0227] In some embodiments, Form VIII has at least three characteristic XRPD peaks selected from the group consisting of: about 9.1, about 16.7, about 18.2, about 18.6, and about 20.2 degrees 2-theta.

[0228] In some embodiments, Form VIII has at least one characteristic XRPD peak selected from about 9.1, about 15.2, about 16.7, about 18.2, about 18.6, about 20.2, about 22.5, about 24.6, about 26.8, and about 29.8 degrees 2-theta.

[0229] In some embodiments, Form VIII has at least two characteristic XRPD peaks selected from about 9.1, about 15.2, about 16.7, about 18.2, about 18.6, about 20.2, about 22.5, about 24.6, about 26.8, and about 29.8 degrees 2-theta.

[0230] In some embodiments, Form VIII has at least three characteristic XRPD peaks selected from about 9.1, about 15.2, about 16.7, about 18.2, about 18.6, about 20.2, about 22.5, about 24.6, about 26.8, and about 29.8 degrees 2-theta.

[0231] In some embodiments, Form VIII has characteristic peaks substantially as follows Figure 24 The XRPD pattern shown in .

[0232] In some embodiments, Form VIII exhibits a DSC thermogram having endothermic peaks at temperatures of about 201°C and 277°C. In some embodiments, Form VIII exhibits a DSC thermogram having an endothermic peak at a temperature of about 201°C. In some embodiments, Form VIII exhibits a DSC thermogram having an endothermic peak at a temperature of about 277°C. In some embodiments, Form VIII has substantially Figure 25 In some embodiments, Form VIII has substantially Figure 26 The TGA thermogram shown in .

[0233] In some embodiments, Form VIII has at least one characteristic XRPD peak selected from the group consisting of: about 9.1, about 16.7, about 18.2, about 18.6, and about 20.2 degrees 2-theta; and Form VIII exhibits a DSC thermogram with endothermic peaks at temperatures of about 201°C and 277°C.

[0234] Also provided herein is a method of preparing Form VIII of Compound 1, comprising adding Compound 1, Form I to a solution of Compound 1 in acetone and stirring at 25 ± 1 °C for 3 days.

[0235] In some embodiments, Form VIII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0236] Compound 1 Form VIII-a

[0237] Provided herein is a solid form of Compound 1 having Form VIII-a described below in the Examples.

[0238] In some embodiments, Form VIII-a has at least one characteristic XRPD peak selected from the group consisting of: about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, and about 21.1 degrees 2-theta.

[0239] In some embodiments, Form VIII-a has at least two characteristic XRPD peaks selected from the group consisting of: about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, and about 21.1 degrees 2-theta.

[0240] In some embodiments, Form VIII-a has at least three characteristic XRPD peaks selected from the group consisting of: about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, and about 21.1 degrees 2-theta.

[0241] In some embodiments, Form VIII-a has at least one characteristic XRPD peak selected from about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, about 21.1, about 22.0, about 23.5, about 24.1, about 24.3, and about 29.5 degrees 2-theta.

[0242] In some embodiments, Form VIII-a has at least two characteristic XRPD peaks selected from about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, about 21.1, about 22.0, about 23.5, about 24.1, about 24.3, and about 29.5 degrees 2-theta.

[0243] In some embodiments, Form VIII-a has at least three characteristic XRPD peaks selected from about 8.9, about 16.2, about 18.0, about 18.4, about 19.9, about 21.1, about 22.0, about 23.5, about 24.1, about 24.3, and about 29.5 degrees 2-theta.

[0244] In some embodiments, Form VIII-a has characteristic peaks substantially as follows Figure 27 The XRPD pattern shown in .

[0245] Also provided herein is a method of preparing Form VIII-a of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1 in methyl ethyl ketone and stirring at 50±1°C for 3 days.

[0246] In some embodiments, Form VIII-a can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0247] Compound 1 Form IX

[0248] Provided herein is a solid form of Compound 1 having Form IX described below in the Examples.

[0249] In some embodiments, Form IX has at least one characteristic XRPD peak selected from the group consisting of: about 8.5, about 9.2, about 12.1, about 14.6, about 15.6, about 18.6, about 22.4, and about 22.9 degrees 2-theta.

[0250] In some embodiments, Form IX has at least two characteristic XRPD peaks selected from about 8.5, about 9.2, about 12.1, about 14.6, about 15.6, about 18.6, about 22.4, and about 22.9 degrees 2-theta.

[0251] In some embodiments, Form IX has at least three characteristic XRPD peaks selected from about 8.5, about 9.2, about 12.1, about 14.6, about 15.6, about 18.6, about 22.4, and about 22.9 degrees 2-theta.

[0252] In some embodiments, Form IX has at least one characteristic XRPD peak selected from about 8.5, about 9.2, about 12.1, about 13.9, about 14.6, about 15.6, about 16.8, about 18.6, about 19.3, about 22.4, about 22.9, about 24.6, and about 31.4 degrees 2-theta.

[0253] In some embodiments, Form IX has at least two characteristic XRPD peaks selected from about 8.5, about 9.2, about 12.1, about 13.9, about 14.6, about 15.6, about 16.8, about 18.6, about 19.3, about 22.4, about 22.9, about 24.6, and about 31.4 degrees 2-theta.

[0254] In some embodiments, Form IX has at least three characteristic XRPD peaks selected from about 8.5, about 9.2, about 12.1, about 13.9, about 14.6, about 15.6, about 16.8, about 18.6, about 19.3, about 22.4, about 22.9, about 24.6, and about 31.4 degrees 2-theta.

[0255] In some embodiments, Form IX has characteristic peaks substantially as follows Figure 28 The XRPD pattern shown in .

[0256] In some embodiments, Form IX exhibits a DSC thermogram having endothermic peaks at temperatures of about 201°C and 276°C. In some embodiments, Form IX exhibits a DSC thermogram having an endothermic peak at a temperature of about 201°C. In some embodiments, Form IX exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form IX has substantially Figure 29 In some embodiments, Form IX has substantially Figure 30 The TGA thermogram shown in .

[0257] In some embodiments, Form IX has at least one characteristic XRPD peak selected from the group consisting of: about 8.5, about 9.2, about 12.1, about 14.6, about 15.6, about 18.6, about 22.4, and about 22.9 degrees 2-theta; and Form IX exhibits a DSC thermogram with endothermic peaks at temperatures of about 201°C and 276°C.

[0258] Also provided herein is a method of preparing Form IX of Compound 1 comprising adding Compound 1, Form I to a cloudy solution of Compound 1, Form I in methyl tert-butyl ether and stirring at 25±1° C. for 3 days.

[0259] In some embodiments, Form IX can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0260] Compound 1 Form X

[0261] Provided herein is a solid form of Compound 1 having Form X described below in the Examples.

[0262] In some embodiments, Form X has at least one characteristic XRPD peak selected from the group consisting of: about 10.1, about 14.6, about 15.4, about 15.7, about 18.1, and about 22.3 degrees 2-theta.

[0263] In some embodiments, Form X has at least two characteristic XRPD peaks selected from the group consisting of: about 10.1, about 14.6, about 15.4, about 15.7, about 18.1, and about 22.3 degrees 2-theta.

[0264] In some embodiments, Form X has at least three characteristic XRPD peaks selected from the group consisting of: about 10.1, about 14.6, about 15.4, about 15.7, about 18.1, and about 22.3 degrees 2-theta. In some embodiments, Form X has at least one characteristic XRPD peak selected from the group consisting of: about 4.9, about 10.1, about 11.3, about 14.6, about 15.4, about 15.7, about 17.2, about 18.1, about 19.5, about 20.0, about 22.3, about 23.8, about 25.3, about 25.7, and about 26.3 degrees 2-theta.

[0265] In some embodiments, Form X has at least two characteristic XRPD peaks selected from about 4.9, about 10.1, about 11.3, about 14.6, about 15.4, about 15.7, about 17.2, about 18.1, about 19.5, about 20.0, about 22.3, about 23.8, about 25.3, about 25.7, and about 26.3 degrees 2-theta.

[0266] In some embodiments, Form X has at least three characteristic XRPD peaks selected from about 4.9, about 10.1, about 11.3, about 14.6, about 15.4, about 15.7, about 17.2, about 18.1, about 19.5, about 20.0, about 22.3, about 23.8, about 25.3, about 25.7, and about 26.3 degrees 2-theta.

[0267] In some embodiments, Form X has characteristic peaks substantially as follows Figure 31 The XRPD pattern shown in .

[0268] In some embodiments, Form X exhibits a DSC thermogram having endothermic peaks at temperatures of about 202°C and 276°C. In some embodiments, Form X exhibits a DSC thermogram having an endothermic peak at a temperature of about 202°C. In some embodiments, Form X exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form X has substantially Figure 32 In some embodiments, Form X has substantially the following: Figure 33 The TGA thermogram shown in .

[0269] In some embodiments, Form X has at least one characteristic XRPD peak selected from the group consisting of: about 10.1, about 14.6, about 15.4, about 15.7, about 18.1, and about 22.3 degrees 2-theta; and Form X exhibits a DSC thermogram with endothermic peaks at temperatures of about 202°C and 276°C.

[0270] Also provided herein is a method of preparing Form X of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1, Form I in ethyl acetate and stirring at 25±1°C for 3 days.

[0271] In some embodiments, Form X can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0272] Compound 1 Form XI

[0273] Provided herein is a solid form of Compound 1 having Form XI described below in the Examples.

[0274] In some embodiments, Form XI has at least one characteristic XRPD peak selected from the group consisting of: about 3.9, about 7.5, about 13.0, about 17.3, about 21.4, and about 22.8 degrees 2-theta.

[0275] In some embodiments, Form XI has at least two characteristic XRPD peaks selected from the group consisting of: about 3.9, about 7.5, about 13.0, about 17.3, about 21.4, and about 22.8 degrees 2-theta.

[0276] In some embodiments, Form XI has at least three characteristic XRPD peaks selected from the group consisting of: about 3.9, about 7.5, about 13.0, about 17.3, about 21.4, and about 22.8 degrees 2-theta.

[0277] In some embodiments, Form XI has at least one characteristic XRPD peak selected from about 3.9, about 4.3, about 7.5, about 13.0, about 13.7, about 15.0, about 16.5, about 17.3, about 19.1, about 19.9, about 21.4, about 22.2, about 22.8, about 25.2, and about 26.9 degrees 2-theta.

[0278] In some embodiments, Form XI has at least two characteristic XRPD peaks selected from about 3.9, about 4.3, about 7.5, about 13.0, about 13.7, about 15.0, about 16.5, about 17.3, about 19.1, about 19.9, about 21.4, about 22.2, about 22.8, about 25.2, and about 26.9 degrees 2-theta.

[0279] In some embodiments, Form XI has at least three characteristic XRPD peaks selected from about 3.9, about 4.3, about 7.5, about 13.0, about 13.7, about 15.0, about 16.5, about 17.3, about 19.1, about 19.9, about 21.4, about 22.2, about 22.8, about 25.2, and about 26.9 degrees 2-theta.

[0280] In some embodiments, Form XI has characteristic peaks substantially as follows Figure 34 The XRPD pattern shown in .

[0281] In some embodiments, Form XI exhibits a DSC thermogram having endothermic peaks at temperatures of about 141°C and 279°C. In some embodiments, Form XI exhibits a DSC thermogram having an endothermic peak at a temperature of about 141°C. In some embodiments, Form XI exhibits a DSC thermogram having an endothermic peak at a temperature of about 279°C. In some embodiments, Form XI has substantially Figure 35 In some embodiments, Form XI has substantially Figure 36 The TGA thermogram shown in .

[0282] In some embodiments, Form XI has at least one characteristic XRPD peak selected from the group consisting of: about 3.9, about 7.5, about 13.0, about 17.3, about 21.4, and about 22.8 degrees 2-theta; and Form XI exhibits a DSC thermogram with endothermic peaks at temperatures of about 141 °C and 279 °C.

[0283] Also provided herein is a method of preparing Form XI of Compound 1, comprising adding Compound 1, Form I to 5 mL of a cloudy solution of Compound 1, Form I in ethyl formate and stirring at 25±1°C for 3 days.

[0284] In some embodiments, Form XI can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0285] Compound 1 Form XII

[0286] Provided herein is a solid form of Compound 1 having Form XII described below in the Examples.

[0287] In some embodiments, Form XII has at least one characteristic XRPD peak selected from the group consisting of: about 7.5, about 14.1, about 17.3, about 18.3, about 22.1, and about 22.7 degrees 2-theta.

[0288] In some embodiments, Form XII has at least two characteristic XRPD peaks selected from about 7.5, about 14.1, about 17.3, about 18.3, about 22.1, and about 22.7 degrees 2-theta.

[0289] In some embodiments, Form XII has at least three characteristic XRPD peaks selected from about 7.5, about 14.1, about 17.3, about 18.3, about 22.1, and about 22.7 degrees 2-theta.

[0290] In some embodiments, Form XII has at least one characteristic XRPD peak selected from about 3.9, about 7.5, about 9.8, about 11.5, about 12.9, about 14.1, about 17.3, about 18.3, about 22.1, about 22.7, about 24.3, about 26.3, and about 26.9 degrees 2-theta.

[0291] In some embodiments, Form XII has at least two characteristic XRPD peaks selected from about 3.9, about 7.5, about 9.8, about 11.5, about 12.9, about 14.1, about 17.3, about 18.3, about 22.1, about 22.7, about 24.3, about 26.3, and about 26.9 degrees 2-theta.

[0292] In some embodiments, Form XII has at least three characteristic XRPD peaks selected from about 3.9, about 7.5, about 9.8, about 11.5, about 12.9, about 14.1, about 17.3, about 18.3, about 22.1, about 22.7, about 24.3, about 26.3, and about 26.9 degrees 2-theta.

[0293] In some embodiments, Form XII has characteristic peaks substantially as follows Figure 37 The XRPD pattern shown in .

[0294] In some embodiments, Form XII exhibits a DSC thermogram having endothermic peaks at temperatures of about 105°C and 276°C. In some embodiments, Form XII exhibits a DSC thermogram having an endothermic peak at a temperature of about 105°C. In some embodiments, Form XII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form XII has substantially Figure 38 In some embodiments, Form XII has substantially the following: Figure 39 The TGA thermogram shown in .

[0295] In some embodiments, Form XII has at least one characteristic XRPD peak selected from the group consisting of: about 7.5, about 14.1, about 17.3, about 18.3, about 22.1, and about 22.7 degrees 2-theta; and Form XII exhibits a DSC thermogram with endothermic peaks at temperatures of about 105°C and 276°C.

[0296] Also provided herein is a method for preparing Form XII of Compound 1, comprising adding Compound 1, Form I to a cloudy solution of Compound 1, Form I prepared in 1,4-dioxane and stirring at 50±1°C for 2 days.

[0297] In some embodiments, Form XII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0298] Compound 1 Form XIII

[0299] Provided herein is a solid form of Compound 1 having Form XIII described below in the Examples.

[0300] In some embodiments, Form XIII has at least one characteristic XRPD peak selected from the group consisting of: about 7.7, about 15.2, about 15.7, about 21.9, about 23.1, and about 26.1 degrees 2-theta.

[0301] In some embodiments, Form XIII has at least two characteristic XRPD peaks selected from about 7.7, about 15.2, about 15.7, about 21.9, about 23.1, and about 26.1 degrees 2-theta.

[0302] In some embodiments, Form XIII has at least three characteristic XRPD peaks selected from about 7.7, about 15.2, about 15.7, about 21.9, about 23.1, and about 26.1 degrees 2-theta.

[0303] In some embodiments, Form XIII has at least one characteristic XRPD peak selected from about 4.0, about 7.7, about 10.9, about 11.6, about 14.2, about 15.2, about 15.7, about 17.8, about 19.0, about 21.9, about 22.2, about 23.1, about 25.6, and about 26.1 degrees 2-theta.

[0304] In some embodiments, Form XIII has at least two characteristic XRPD peaks selected from about 4.0, about 7.7, about 10.9, about 11.6, about 14.2, about 15.2, about 15.7, about 17.8, about 19.0, about 21.9, about 22.2, about 23.1, about 25.6, and about 26.1 degrees 2-theta.

[0305] In some embodiments, Form XIII has at least three characteristic XRPD peaks selected from about 4.0, about 7.7, about 10.9, about 11.6, about 14.2, about 15.2, about 15.7, about 17.8, about 19.0, about 21.9, about 22.2, about 23.1, about 25.6, and about 26.1 degrees 2-theta.

[0306] In some embodiments, Form XIII has characteristic peaks substantially as follows Figure 40The XRPD pattern shown in .

[0307] In some embodiments, Form XIII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form XIII has substantially Figure 41 In some embodiments, Form XIII has substantially Figure 42 The TGA thermogram shown in .

[0308] In some embodiments, Form XIII has at least two characteristic XRPD peaks selected from: about 7.7, about 15.2, about 15.7, about 21.9, about 23.1, and about 26.1 degrees 2-theta; and Form XIII exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C.

[0309] Also provided herein is a method of preparing Form XIII of Compound 1, Form I, comprising adding Compound 1, Form I to a cloudy solution of Compound 1 in THF and stirring at 50±1°C for 2 days.

[0310] In some embodiments, Form XIII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0311] Compound 1 Form XIII-a

[0312] Provided herein is a solid form of Compound 1 having Form XIII-a described below in the Examples.

[0313] In some embodiments, Form XIII-a has at least one characteristic XRPD peak selected from the group consisting of: about 6.9, about 7.7, about 10.4, about 15.2, about 21.5, and about 26.2 degrees 2-theta.

[0314] In some embodiments, Form XIII-a has at least two characteristic XRPD peaks selected from the group consisting of: about 6.9, about 7.7, about 10.4, about 15.2, about 21.5, and about 26.2 degrees 2-theta.

[0315] In some embodiments, Form XIII-a has at least three characteristic XRPD peaks selected from the group consisting of: about 6.9, about 7.7, about 10.4, about 15.2, about 21.5, and about 26.2 degrees 2-theta.

[0316] In some embodiments, Form XIII-a has at least one characteristic XRPD peak selected from about 6.9, about 7.7, about 8.3, about 10.4, about 10.9, about 12.1, about 14.4, about 15.2, about 18.6, about 19.7, about 21.5, about 22.3, about 22.6, and about 26.2 degrees 2-theta.

[0317] In some embodiments, Form XIII-a has at least two characteristic XRPD peaks selected from about 6.9, about 7.7, about 8.3, about 10.4, about 10.9, about 12.1, about 14.4, about 15.2, about 18.6, about 19.7, about 21.5, about 22.3, about 22.6, and about 26.2 degrees 2-theta.

[0318] In some embodiments, Form XIII-a has at least three characteristic XRPD peaks selected from about 6.9, about 7.7, about 8.3, about 10.4, about 10.9, about 12.1, about 14.4, about 15.2, about 18.6, about 19.7, about 21.5, about 22.3, about 22.6, and about 26.2 degrees 2-theta.

[0319] In some embodiments, Form XIII-a has characteristic peaks substantially as follows Figure 43 The XRPD pattern shown in .

[0320] In some embodiments, Form XIII-a exhibits a DSC thermogram having endothermic peaks at temperatures of about 75°C and 276°C. In some embodiments, Form XIII-a exhibits a DSC thermogram having an endothermic peak at a temperature of about 75°C. In some embodiments, Form XIII-a exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form XIII-a has substantially Figure 44 DSC thermogram shown in .

[0321] In some embodiments, Form XIII-a has at least one characteristic XRPD peak selected from the group consisting of: about 6.9, about 7.7, about 10.4, about 15.2, about 21.5, and about 26.2 degrees 2-theta; and Form XIII-a exhibits a DSC thermogram with endothermic peaks at temperatures of about 75°C and 276°C.

[0322] Also provided herein is a method for preparing Form XIII-a of Compound 1, comprising cooling a saturated solution of Compound 1, Form I in THF to -20°C and maintaining the temperature at -20°C for a period of time (eg, 3 h).

[0323] In some embodiments, Form XIII-a can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0324] Compound 1 Form XIV

[0325] Provided herein is a solid form of Compound 1 having Form XIV described below in the Examples.

[0326] In some embodiments, Form XIV has at least one characteristic XRPD peak selected from the group consisting of: about 7.0, about 14.1, about 16.1, about 20.0, about 22.0, and about 25.8 degrees 2-theta.

[0327] In some embodiments, Form XIV has at least two characteristic XRPD peaks selected from the group consisting of: about 7.0, about 14.1, about 16.1, about 20.0, about 22.0, and about 25.8 degrees 2-theta.

[0328] In some embodiments, Form XIV has at least three characteristic XRPD peaks selected from the group consisting of: about 7.0, about 14.1, about 16.1, about 20.0, about 22.0, and about 25.8 degrees 2-theta.

[0329] In some embodiments, Form XIV has at least one characteristic XRPD peak selected from about 7.0, about 8.6, about 9.2, about 9.6, about 10.3, about 11.5, about 12.2, about 14.1, about 14.5, about 16.1, about 17.6, about 18.3, about 18.7, about 19.3, about 20.0, about 22.0, about 22.3, about 22.9, and about 25.8 degrees 2-theta.

[0330] In some embodiments, Form XIV has at least two characteristic XRPD peaks selected from about 7.0, about 8.6, about 9.2, about 9.6, about 10.3, about 11.5, about 12.2, about 14.1, about 14.5, about 16.1, about 17.6, about 18.3, about 18.7, about 19.3, about 20.0, about 22.0, about 22.3, about 22.9, and about 25.8 degrees 2-theta.

[0331] In some embodiments, Form XIV has at least three characteristic XRPD peaks selected from about 7.0, about 8.6, about 9.2, about 9.6, about 10.3, about 11.5, about 12.2, about 14.1, about 14.5, about 16.1, about 17.6, about 18.3, about 18.7, about 19.3, about 20.0, about 22.0, about 22.3, about 22.9, and about 25.8 degrees 2-theta.

[0332] In some embodiments, Form XIV has characteristic peaks substantially as follows Figure 45 The XRPD pattern shown in .

[0333] In some embodiments, Form XIV exhibits a DSC thermogram having endothermic peaks at temperatures of about 78°C, 118°C, and 277°C. In some embodiments, Form XIV exhibits a DSC thermogram having an endothermic peak at a temperature of about 78°C. In some embodiments, Form XIV exhibits a DSC thermogram having an endothermic peak at a temperature of about 118°C. In some embodiments, Form XIV exhibits a DSC thermogram having an endothermic peak at a temperature of about 277°C. In some embodiments, Form XIV has substantially Figure 46 In some embodiments, Form XIV has substantially Figure 47 The TGA thermogram shown in .

[0334] In some embodiments, Form XIV has at least one characteristic XRPD peak selected from the group consisting of: about 7.0, about 14.1, about 16.1, about 20.0, about 22.0, and about 25.8 degrees 2-theta; and Form XIV exhibits a DSC thermogram with endothermic peaks at temperatures of about 78°C, 118°C, and 277°C.

[0335] Also provided herein is a method for preparing Form XIV of Compound 1, comprising evaporating a saturated solution of Compound 1, Form I in DMF at 25±1°C.

[0336] In some embodiments, Form XIV can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0337] Compound 1 Form XV

[0338] Provided herein is a solid form of Compound 1 having Form XV described below in the Examples.

[0339] In some embodiments, Form XV has at least one characteristic XRPD peak selected from the group consisting of: about 8.9, about 9.2, about 15.6, about 18.5, and about 22.4.

[0340] In some embodiments, Form XV has at least two characteristic XRPD peaks selected from about 8.9, about 9.2, about 15.6, about 18.5, and about 22.4.

[0341] In some embodiments, Form XV has at least three characteristic XRPD peaks selected from about 8.9, about 9.2, about 15.6, about 18.5, and about 22.4.

[0342] In some embodiments, Form XV has at least one characteristic XRPD peak selected from about 3.9, about 8.9, about 9.2, about 15.6, about 16.6, about 18.5, about 20.3, about 21.4, about 21.8, about 22.4, about 24.5, about 24.9, about 30.0, and about 31.1 degrees 2-theta.

[0343] In some embodiments, Form XV has at least two characteristic XRPD peaks selected from about 3.9, about 8.9, about 9.2, about 15.6, about 16.6, about 18.5, about 20.3, about 21.4, about 21.8, about 22.4, about 24.5, about 24.9, about 30.0, and about 31.1 degrees 2-theta.

[0344] In some embodiments, Form XV has at least three characteristic XRPD peaks selected from about 3.9, about 8.9, about 9.2, about 15.6, about 16.6, about 18.5, about 20.3, about 21.4, about 21.8, about 22.4, about 24.5, about 24.9, about 30.0, and about 31.1 degrees 2-theta.

[0345] In some embodiments, Form XV has characteristic peaks substantially as follows Figure 48 The XRPD pattern shown in .

[0346] In some embodiments, Form XV exhibits a DSC thermogram having endothermic peaks at temperatures of about 119°C and 276°C. In some embodiments, Form XV exhibits a DSC thermogram having an endothermic peak at a temperature of about 119°C. In some embodiments, Form XV exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form XV has substantially Figure 49 In some embodiments, Form XV has substantially the following: Figure 50 The TGA thermogram shown in .

[0347] In some embodiments, Form XV has at least one characteristic XRPD peak selected from: about 8.9, about 9.2, about 15.6, about 18.5, and about 22.4; and Form XV exhibits a DSC thermogram with endothermic peaks at temperatures of about 119°C and 276°C.

[0348] Also provided herein is a method of preparing Form XV of Compound 1, comprising evaporating a saturated solution of Compound 1, Form I in DMSO at 25±1°C.

[0349] In some embodiments, Form XV can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0350] Compound 1 Form XVI

[0351] Provided herein is a solid form of Compound 1 having Form XVI described below in the Examples.

[0352] In some embodiments, Form XVI has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 10.7, about 14.0, about 14.9, about 16.0, and about 19.9.

[0353] In some embodiments, Form XVI has at least two characteristic XRPD peaks selected from about 6.8, about 10.7, about 14.0, about 14.9, about 16.0, and about 19.9.

[0354] In some embodiments, Form XVI has at least three characteristic XRPD peaks selected from about 6.8, about 10.7, about 14.0, about 14.9, about 16.0, and about 19.9.

[0355] In some embodiments, Form XVI has at least one characteristic XRPD peak selected from about 6.8, about 9.4, about 10.7, about 14.0, about 14.9, about 16.0, about 17.5, about 18.5, about 19.2, about 19.9, about 22.2, about 23.5, about 24.5, about 25.4, about 25.7, about 26.1, and about 30.2 degrees 2-theta.

[0356] In some embodiments, Form XVI has at least two characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.7, about 14.0, about 14.9, about 16.0, about 17.5, about 18.5, about 19.2, about 19.9, about 22.2, about 23.5, about 24.5, about 25.4, about 25.7, about 26.1, and about 30.2 degrees 2-theta.

[0357] In some embodiments, Form XVI has at least three characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.7, about 14.0, about 14.9, about 16.0, about 17.5, about 18.5, about 19.2, about 19.9, about 22.2, about 23.5, about 24.5, about 25.4, about 25.7, about 26.1, and about 30.2 degrees 2-theta.

[0358] In some embodiments, Form XVI has characteristic peaks substantially as follows Figure 51 The XRPD pattern shown in .

[0359] In some embodiments, Form XVI exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form XVI has substantially Figure 52 In some embodiments, Form XVI has substantially the following: Figure 53 The TGA thermogram shown in .

[0360] In some embodiments, Form XVI has at least one characteristic XRPD peak selected from: about 6.8, about 10.7, about 14.0, about 14.9, about 16.0, and about 19.9; and Form XVI exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C.

[0361] Also provided herein is a method for preparing Form XVI of Compound 1, comprising evaporating a saturated solution of Compound 1, Form I in THF at 50±1°C.

[0362] In some embodiments, Form XVI can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0363] Compound 1 Form XVII

[0364] Provided herein is a solid form of Compound 1 having Form XVII described below in the Examples.

[0365] In some embodiments, Form XVII has at least one characteristic XRPD peak selected from the group consisting of: about 15.7, about 18.1, about 18.4, and about 32.2 degrees 2-theta.

[0366] In some embodiments, Form XVII has at least two characteristic XRPD peaks selected from the group consisting of: about 15.7, about 18.1, about 18.4, and about 32.2 degrees 2-theta.

[0367] In some embodiments, Form XVII has at least three characteristic XRPD peaks selected from the group consisting of: about 15.7, about 18.1, about 18.4, and about 32.2 degrees 2-theta.

[0368] In some embodiments, Form XVII has characteristic peaks substantially as follows Figure 54 The XRPD pattern shown in .

[0369] In some embodiments, Form XVII exhibits a DSC thermogram having endothermic peaks at temperatures of about 119°C and 276°C. In some embodiments, Form XVII exhibits a DSC thermogram having an endothermic peak at a temperature of about 119°C. In some embodiments, Form XVII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276°C. In some embodiments, Form XVII has substantially Figure 55 In some embodiments, Form XVII has substantially the following: Figure 56 The TGA thermogram shown in .

[0370] In some embodiments, Form XVII has at least one characteristic XRPD peak selected from: about 15.7, about 18.1, about 18.4, and about 32.2 degrees 2-theta; and Form XVII exhibits a DSC thermogram with endothermic peaks at temperatures of about 119°C and 276°C.

[0371] Also provided herein is a method of preparing Form XVII of Compound 1, comprising evaporating a saturated solution of Compound 1, Form I in DMSO at 50 ± 1 °C.

[0372] In some embodiments, Form XVII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0373] Compound 1 Form XVIII

[0374] Provided herein is a solid form of Compound 1 having Form XVIII described below in the Examples.

[0375] In some embodiments, Form XVIII has at least one characteristic XRPD peak selected from the group consisting of: about 9.4, about 14.6, about 16.2, about 17.5, about 18.8, about 22.3, and about 22.7 degrees 2-theta.

[0376] In some embodiments, Form XVIII has at least two characteristic XRPD peaks selected from about 9.4, about 14.6, about 16.2, about 17.5, about 18.8, about 22.3, and about 22.7 degrees 2-theta.

[0377] In some embodiments, Form XVIII has at least three characteristic XRPD peaks selected from about 9.4, about 14.6, about 16.2, about 17.5, about 18.8, about 22.3, and about 22.7 degrees 2-theta.

[0378] In some embodiments, Form XVIII has at least one characteristic XRPD peak selected from about 6.8, about 9.4, about 10.3, about 11.9, about 12.6, about 13.4, about 14.6, about 16.2, about 17.5, about 18.3, about 18.8, about 20.8, about 22.3, about 22.7, and about 25.4 degrees 2-theta.

[0379] In some embodiments, Form XVIII has at least two characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.3, about 11.9, about 12.6, about 13.4, about 14.6, about 16.2, about 17.5, about 18.3, about 18.8, about 20.8, about 22.3, about 22.7, and about 25.4 degrees 2-theta.

[0380] In some embodiments, Form XVIII has at least three characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.3, about 11.9, about 12.6, about 13.4, about 14.6, about 16.2, about 17.5, about 18.3, about 18.8, about 20.8, about 22.3, about 22.7, and about 25.4 degrees 2-theta.

[0381] In some embodiments, Form XVIII has characteristic peaks substantially as follows Figure 57 The XRPD pattern shown in .

[0382] In some embodiments, Form XVIII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form XVIII has substantially Figure 58 In some embodiments, Form XVIII has substantially Figure 59 The TGA thermogram shown in .

[0383] In some embodiments, Form XVIII has at least one characteristic XRPD peak selected from the group consisting of: about 9.4, about 14.6, about 16.2, about 17.5, about 18.8, about 22.3, and about 22.7 degrees 2-theta; and Form XVIII exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C.

[0384] Also provided herein are methods of preparing Form XVIII of Compound 1, comprising adding hexane to a saturated solution of Compound 1, Form I in chloroform.

[0385] In some embodiments, Form XVIII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0386] Compound 1 Form XIX

[0387] Provided herein is a solid form of Compound 1 having Form XIX described below in the Examples.

[0388] In some embodiments, Form XIX has at least one characteristic XRPD peak selected from the group consisting of: about 6.7, about 10.0, about 17.4, about 18.0, about 20.2, and about 21.4 degrees 2-theta.

[0389] In some embodiments, Form XIX has at least two characteristic XRPD peaks selected from the group consisting of: about 6.7, about 10.0, about 17.4, about 18.0, about 20.2, and about 21.4 degrees 2-theta.

[0390] In some embodiments, Form XIX has at least three characteristic XRPD peaks selected from the group consisting of: about 6.7, about 10.0, about 17.4, about 18.0, about 20.2, and about 21.4 degrees 2-theta.

[0391] In some embodiments, Form XIX has at least one characteristic XRPD peak selected from about 3.9, about 6.7, about 9.4, about 10.0, about 13.6, about 17.4, about 18.0, about 20.2, about 21.4, about 22.1, and about 25.0 degrees 2-theta.

[0392] In some embodiments, Form XIX has at least two characteristic XRPD peaks selected from about 3.9, about 6.7, about 9.4, about 10.0, about 13.6, about 17.4, about 18.0, about 20.2, about 21.4, about 22.1, and about 25.0 degrees 2-theta.

[0393] In some embodiments, Form XIX has at least three characteristic XRPD peaks selected from about 3.9, about 6.7, about 9.4, about 10.0, about 13.6, about 17.4, about 18.0, about 20.2, about 21.4, about 22.1, and about 25.0 degrees 2-theta.

[0394] In some embodiments, Form XIX has characteristic peaks substantially as follows Figure 60 The XRPD pattern shown in .

[0395] In some embodiments, Form XIX exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form XIX has substantially Figure 61 In some embodiments, Form XIX has substantially the following: Figure 62 The TGA thermogram shown in .

[0396] In some embodiments, Form XIX has at least one characteristic XRPD peak selected from the group consisting of: about 6.7, about 10.0, about 17.4, about 18.0, about 20.2, and about 21.4 degrees 2-theta; and Form XIX exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C.

[0397] Also provided herein is a method of preparing Form XIX of Compound 1, comprising adding methanol to a saturated solution of Compound 1, Form I in dichloromethane.

[0398] In some embodiments, Form XIX can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0399] Compound 1 Form XX

[0400] Provided herein is a solid form of Compound 1 having Form XX described below in the Examples.

[0401] In some embodiments, Form XX has at least one characteristic XRPD peak selected from the group consisting of: about 9.2, about 14.7, about 18.6, about 22.5, and about 23.0.

[0402] In some embodiments, Form XX has at least two characteristic XRPD peaks selected from the group consisting of: about 9.2, about 14.7, about 18.6, about 22.5, and about 23.0.

[0403] In some embodiments, Form XX has at least three characteristic XRPD peaks selected from the group consisting of: about 9.2, about 14.7, about 18.6, about 22.5, and about 23.0.

[0404] In some embodiments, Form XX has at least one characteristic XRPD peak selected from the group consisting of: about 9.2, about 14.7, about 15.6, about 18.6, about 22.3, about 22.5, about 23.0, about 24.7, and about 29.5 degrees 2-theta.

[0405] In some embodiments, Form XX has at least two characteristic XRPD peaks selected from about 9.2, about 14.7, about 15.6, about 18.6, about 22.3, about 22.5, about 23.0, about 24.7, and about 29.5 degrees 2-theta.

[0406] In some embodiments, Form XX has at least three characteristic XRPD peaks selected from about 9.2, about 14.7, about 15.6, about 18.6, about 22.3, about 22.5, about 23.0, about 24.7, and about 29.5 degrees 2-theta.

[0407] In some embodiments, Form XX has characteristic peaks substantially as follows Figure 63 The XRPD pattern shown in .

[0408] In some embodiments, Form XX exhibits a DSC thermogram having endothermic peaks at temperatures of about 108°C, 202°C, and 277°C. In some embodiments, Form XX exhibits a DSC thermogram having an endothermic peak at a temperature of about 108°C. In some embodiments, Form XX exhibits a DSC thermogram having an endothermic peak at a temperature of about 202°C. In some embodiments, Form XX exhibits a DSC thermogram having an endothermic peak at a temperature of about 277°C. In some embodiments, Form XX has substantially Figure 64 In some embodiments, Form XX has substantially the following: Figure 65 The TGA thermogram shown in .

[0409] In some embodiments, Form XX has at least one characteristic XRPD peak selected from the group consisting of: about 9.2, about 14.7, about 18.6, about 22.5, and about 23.0; and Form XX exhibits a DSC thermogram with endothermic peaks at temperatures of about 108°C, 202°C, and 277°C.

[0410] Also provided herein is a method for preparing Form XX of Compound 1, comprising adding a saturated solution of Compound 1, Form I in dichloromethane to methyl tert-butyl ether.

[0411] In some embodiments, Form XX can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0412] Compound 1 Form XXI

[0413] Provided herein is a solid form of Compound 1 having Form XXI described below in the Examples.

[0414] In some embodiments, Form XXI has at least one characteristic XRPD peak selected from the group consisting of: about 10.3, about 14.2, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0415] In some embodiments, Form XXI has at least two characteristic XRPD peaks selected from the group consisting of: about 10.3, about 14.2, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0416] In some embodiments, Form XXI has at least three characteristic XRPD peaks selected from the group consisting of: about 10.3, about 14.2, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0417] In some embodiments, Form XXI has at least one characteristic XRPD peak selected from about 3.9, about 6.5, about 10.3, about 13.2, about 14.2, about 17.5, about 19.4, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0418] In some embodiments, Form XXI has at least two characteristic XRPD peaks selected from about 3.9, about 6.5, about 10.3, about 13.2, about 14.2, about 17.5, about 19.4, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0419] In some embodiments, Form XXI has at least three characteristic XRPD peaks selected from about 3.9, about 6.5, about 10.3, about 13.2, about 14.2, about 17.5, about 19.4, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta.

[0420] In some embodiments, Form XXI has characteristic peaks substantially as follows Figure 66 The XRPD pattern shown in .

[0421] In some embodiments, Form XXI exhibits a DSC thermogram having endothermic peaks at temperatures of about 201°C and 277°C. In some embodiments, Form XXI exhibits a DSC thermogram having an endothermic peak at a temperature of about 201°C. In some embodiments, Form XXI exhibits a DSC thermogram having an endothermic peak at a temperature of about 277°C. In some embodiments, Form XXI has substantially Figure 67 DSC thermogram shown in .

[0422] In some embodiments, Form XXI has at least two characteristic XRPD peaks selected from the group consisting of: about 10.3, about 14.2, about 20.7, about 22.6, about 24.2, and about 27.1 degrees 2-theta; and Form XXI exhibits a DSC thermogram with endothermic peaks at temperatures of about 201°C and 277°C.

[0423] Also provided herein is a method for preparing Form XXI of Compound 1, comprising adding a saturated solution of Compound 1, Form I in dichloromethane to toluene.

[0424] In some embodiments, Form XXI can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0425] Compound 1 Form XXII

[0426] Provided herein is a solid form of Compound 1 having Form XXII described below in the Examples.

[0427] In some embodiments, Form XXII has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 14.3, about 17.5, about 18.5, and about 22.2 degrees 2-theta.

[0428] In some embodiments, Form XXII has at least two characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 14.3, about 17.5, about 18.5, and about 22.2 degrees 2-theta.

[0429] In some embodiments, Form XXII has at least three characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 14.3, about 17.5, about 18.5, and about 22.2 degrees 2-theta.

[0430] In some embodiments, Form XXII has at least one characteristic XRPD peak selected from about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 13.3, about 14.3, about 15.8, about 17.5, about 18.0, about 18.5, about 19.2, about 19.8, about 22.2, about 25.3, and about 26.1 degrees 2-theta.

[0431] In some embodiments, Form XXII has at least two characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 13.3, about 14.3, about 15.8, about 17.5, about 18.0, about 18.5, about 19.2, about 19.8, about 22.2, about 25.3, and about 26.1 degrees 2-theta.

[0432] In some embodiments, Form XXII has at least three characteristic XRPD peaks selected from about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 13.3, about 14.3, about 15.8, about 17.5, about 18.0, about 18.5, about 19.2, about 19.8, about 22.2, about 25.3, and about 26.1 degrees 2-theta.

[0433] In some embodiments, Form XXII has characteristic peaks substantially as follows Figure 68 The XRPD pattern shown in .

[0434] In some embodiments, Form XXII exhibits a DSC thermogram having an endothermic peak at a temperature of about 276° C. In some embodiments, Form XXII has substantially Figure 69 DSC thermogram shown in .

[0435] In some embodiments, Form XXII has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.4, about 10.1, about 11.4, about 12.1, about 14.3, about 17.5, about 18.5, and about 22.2 degrees 2-theta; and Form XXII exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C.

[0436] Also provided herein is a method for preparing Form XXII of Compound 1, comprising adding a saturated solution of Compound 1, Form I in dichloromethane to methanol.

[0437] In some embodiments, Form XXII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0438] Compound 1 Form XXIII

[0439] Provided herein is a solid form of Compound 1 having Form XXIII described below in the Examples.

[0440] In some embodiments, Form XXIII has at least one characteristic XRPD peak selected from the group consisting of: about 12.0, about 12.7, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0441] In some embodiments, Form XXIII has at least two characteristic XRPD peaks selected from the group consisting of: about 12.0, about 12.7, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0442] In some embodiments, Form XXIII has at least three characteristic XRPD peaks selected from the group consisting of: about 12.0, about 12.7, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0443] In some embodiments, Form XXIII has at least one characteristic XRPD peak selected from the group consisting of: about 12.0, about 12.7, about 13.2, about 14.3, about 18.9, about 19.6, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0444] In some embodiments, Form XXIII has at least two characteristic XRPD peaks selected from about 12.0, about 12.7, about 13.2, about 14.3, about 18.9, about 19.6, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0445] In some embodiments, Form XXIII has at least three characteristic XRPD peaks selected from about 12.0, about 12.7, about 13.2, about 14.3, about 18.9, about 19.6, about 21.0, about 24.9, and about 25.6 degrees 2-theta.

[0446] In some embodiments, Form XXIII has characteristic peaks substantially as follows Figure 70 The XRPD pattern shown in .

[0447] In some embodiments, Form XXIII exhibits a DSC thermogram having an endothermic peak at a temperature of about 277° C. In some embodiments, Form XXIII has substantially Figure 71 In some embodiments, Form XXIII has substantially Figure 72 The TGA thermogram shown in .

[0448] In some embodiments, Form XXIII has at least one characteristic XRPD peak selected from: about 12.0, about 12.7, about 21.0, about 24.9, and about 25.6 degrees 2-theta; and Form XXIII exhibits a DSC thermogram with an endothermic peak at a temperature of about 277°C.

[0449] Also provided herein is a method for preparing Form XXIII of Compound 1, comprising cooling 10 mL of a saturated solution of Compound 1, Form I in dichloromethane to -20°C and maintaining the temperature at -20°C for 3 h.

[0450] In some embodiments, Form XXIII can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0451] Compound 1 Form XXIV

[0452] Provided herein is a solid form of Compound 1 having Form XXIV described below in the Examples.

[0453] In some embodiments, Form XXIV has at least one characteristic XRPD peak selected from the group consisting of: about 8.6, about 15.6, about 18.1, about 20.4, about 22.2, about 22.9, about 24.2, and about 25.5 degrees 2-theta.

[0454] In some embodiments, Form XXIV has at least two characteristic XRPD peaks selected from about 8.6, about 15.6, about 18.1, about 20.4, about 22.2, about 22.9, about 24.2, and about 25.5 degrees 2-theta.

[0455] In some embodiments, Form XXIV has at least three characteristic XRPD peaks selected from about 8.6, about 15.6, about 18.1, about 20.4, about 22.2, about 22.9, about 24.2, and about 25.5 degrees 2-theta.

[0456] In some embodiments, Form XXIV has at least one characteristic XRPD peak selected from about 8.6, about 9.7, about 13.8, about 15.6, about 17.4, about 18.1, about 19.4, about 20.4, about 22.2, about 22.9, about 24.2, about 25.5, about 26.0, about 27.5, and about 27.9 degrees 2-theta.

[0457] In some embodiments, Form XXIV has at least two characteristic XRPD peaks selected from about 8.6, about 9.7, about 13.8, about 15.6, about 17.4, about 18.1, about 19.4, about 20.4, about 22.2, about 22.9, about 24.2, about 25.5, about 26.0, about 27.5, and about 27.9 degrees 2-theta.

[0458] In some embodiments, Form XXIV has at least three characteristic XRPD peaks selected from about 8.6, about 9.7, about 13.8, about 15.6, about 17.4, about 18.1, about 19.4, about 20.4, about 22.2, about 22.9, about 24.2, about 25.5, about 26.0, about 27.5, and about 27.9 degrees 2-theta.

[0459] In some embodiments, Form XXIV has characteristic peaks substantially as follows Figure 73 The XRPD pattern shown in .

[0460] In some embodiments, Form XXIV exhibits a DSC thermogram having an endothermic peak at a temperature of about 277° C. In some embodiments, Form XXIV has substantially Figure 74 In some embodiments, Form XXIV has substantially Figure 75 The TGA thermogram shown in .

[0461] In some embodiments, Form XXIV has at least one characteristic XRPD peak selected from the group consisting of: about 8.6, about 15.6, about 18.1, about 20.4, about 22.2, about 22.9, about 24.2, and about 25.5 degrees 2-theta; and Form XXIV exhibits a DSC thermogram with an endothermic peak at a temperature of about 277°C.

[0462] Also provided herein are methods of preparing Form XXIV of Compound 1, comprising circulating a saturated solution of Compound 1, Form I in DMF between 5-50°C for a period of time (e.g., at least three days or at least 72 hours).

[0463] In some embodiments, Form XXIV can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0464] Compound 1 Form XXV

[0465] Provided herein is a solid form of Compound 1 having Form XXV described below in the Examples.

[0466] In some embodiments, Form XXV has at least one characteristic XRPD peak selected from the group consisting of: about 16.6, about 18.4, about 20.4, about 22.4, about 24.4, about 24.9, and about 29.9 degrees 2-theta.

[0467] In some embodiments, Form XXV has at least two characteristic XRPD peaks selected from about 16.6, about 18.4, about 20.4, about 22.4, about 24.4, about 24.9, and about 29.9 degrees 2-theta.

[0468] In some embodiments, Form XXV has at least three characteristic XRPD peaks selected from about 16.6, about 18.4, about 20.4, about 22.4, about 24.4, about 24.9, and about 29.9 degrees 2-theta.

[0469] In some embodiments, Form XXV has at least one characteristic XRPD peak selected from about 16.6, about 18.4, about 20.4, about 21.7, about 22.4, about 24.4, about 24.9, about 25.7, about 29.9, about 31.9, about 35.8, and about 38.9 degrees 2-theta.

[0470] In some embodiments, Form XXV has at least two characteristic XRPD peaks selected from about 16.6, about 18.4, about 20.4, about 21.7, about 22.4, about 24.4, about 24.9, about 25.7, about 29.9, about 31.9, about 35.8, and about 38.9 degrees 2-theta.

[0471] In some embodiments, Form XXV has at least three characteristic XRPD peaks selected from about 16.6, about 18.4, about 20.4, about 21.7, about 22.4, about 24.4, about 24.9, about 25.7, about 29.9, about 31.9, about 35.8, and about 38.9 degrees 2-theta.

[0472] In some embodiments, Form XXV has characteristic peaks substantially as follows Figure 76 The XRPD pattern shown in .

[0473] In some embodiments, Form XXV exhibits a DSC thermogram with endothermic peaks at temperatures of about 113°C and 276°C. In some embodiments, Form XXV exhibits a DSC thermogram with an endothermic peak at a temperature of about 113°C. In some embodiments, Form XXV exhibits a DSC thermogram with an endothermic peak at a temperature of about 276°C. In some embodiments, Form XXIV has substantially Figure 77 DSC thermogram shown in .

[0474] In some embodiments, Form XXV has at least one characteristic XRPD peak selected from the group consisting of: about 16.6, about 18.4, about 20.4, about 22.4, about 24.4, about 24.9, and about 29.9 degrees 2-theta; and Form XXV exhibits a DSC thermogram with endothermic peaks at temperatures of about 113°C and 276°C.

[0475] Also provided herein are methods of preparing Form XXV of Compound 1, comprising cycling a saturated solution of Compound 1, Form I in DMSO between 5-50°C for a period of time (e.g., at least three days or at least 72 hours).

[0476] In some embodiments, Form XXV can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0477] Compound 1 Form XXVI

[0478] Provided herein is a solid form of Compound 1 having Form XXVI described below in the Examples.

[0479] In some embodiments, Form XXVI has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.9, about 19.9, and about 26.1 degrees 2-theta.

[0480] In some embodiments, Form XXVI has at least two characteristic XRPD peaks selected from the group consisting of: about 6.8, about 9.9, about 19.9, and about 26.1 degrees 2-theta.

[0481] In some embodiments, Form XXVI has at least three characteristic XRPD peaks selected from the group consisting of: about 6.8, about 9.9, about 19.9, and about 26.1 degrees 2-theta.

[0482] In some embodiments, Form XXVI has at least one characteristic XRPD peak selected from the group consisting of: about 6.8, about 9.4, about 9.9, about 10.6, about 19.9, about 25.7, about 26.1, and about 27.4 degrees 2-theta.

[0483] In some embodiments, Form XXVI has at least two characteristic XRPD peaks selected from about 6.8, about 9.4, about 9.9, about 10.6, about 19.9, about 25.7, about 26.1, and about 27.4 degrees 2-theta.

[0484] In some embodiments, Form XXVI has at least three characteristic XRPD peaks selected from about 6.8, about 9.4, about 9.9, about 10.6, about 19.9, about 25.7, about 26.1, and about 27.4 degrees 2-theta.

[0485] In some embodiments, Form XXVI has characteristic peaks substantially as follows Figure 78 The XRPD pattern shown in .

[0486] Also provided herein are methods of preparing Form XXVI of Compound 1, comprising drying Compound 1, Form V under vacuum at 50°C for a period of time (e.g., 3 days).

[0487] In some embodiments, Form XXVI can be isolated to have a purity of at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99%. In some embodiments, Form I can be isolated to have a purity greater than about 99%.

[0488] Method for preparing compound 1

[0489] The present application also provides a method for preparing Compound 1, wherein the method is suitable for scale-up. A method for preparing Compound 1 is described in US Pat. No. 9,611,267, the entire contents of which are incorporated herein by reference.

[0490] The present invention provides a method for preparing compound 1 having the following formula:

[0491]

[0492] or a salt thereof, the method comprising a) reacting a compound F8 having the formula:

[0493]

[0494] or its salts, wherein P 1 In some embodiments, P 1In some embodiments, P 1 is phenylsulfonyl or toluenesulfonyl.

[0495] In some embodiments, the deprotection in step a) comprises reacting compound F8 with a suitable deprotecting agent. In some embodiments, deprotection comprises treating with a base. In some embodiments, the base is sodium hydroxide or potassium hydroxide. In some embodiments, the base is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution. In some embodiments, the aqueous base solution is a 1M solution of a base. In some embodiments, deprotection is carried out at a temperature of 70-90°C (e.g., 80°C) in a suitable solvent. In some embodiments, the suitable solvent is 1,4-dioxane. In some embodiments, the base is present in an amount of ≥2, ≥3, or ≥4 molar equivalents relative to the compound of formula II.

[0496] In some embodiments, Compound 1 and Compound F8 are preferably in their non-salt form.

[0497] In some embodiments, Compound F8 or a salt thereof is prepared by a process comprising b) making Compound F7 having the formula:

[0498]

[0499] or its salt reacts with a base, wherein R 1 is Cl, Br or I.

[0500] In some embodiments, Compound F7 and Compound F8 are preferably in their non-salt form.

[0501] In some embodiments, the base in step b) is lithium hexamethyldisilazide ("LHMDS"), sodium hexamethyldisilazide ("NHMDS"), potassium hexamethyldisilazide ("KHMDS"), or lithium diisopropylamide ("LDA"). In some embodiments, the reaction of compound F7 with the base is carried out in THF at ambient temperature.

[0502] In some embodiments, Compound F7 or a salt thereof is prepared by a process comprising c) making Compound F6 having the formula:

[0503]

[0504] or its salt reacts with ethyl isocyanate.

[0505] In some embodiments, the method further comprises purifying Compound F7. In some embodiments, the purification comprises mixing Compound F7 with a first organic solvent at an elevated temperature to produce a first mixture; filtering the first mixture to produce a first solid; mixing the first solid with water to produce a second mixture; filtering the second mixture to produce a second solid; and mixing the second solid with a second organic solvent. In certain embodiments, the first organic solvent is acetonitrile and the second organic solvent is heptane.

[0506] In some embodiments, the reaction in step c) is carried out in the presence of an acid. In some embodiments, the acid is methanesulfonic acid, toluenesulfonic acid, or HCl.

[0507] In some embodiments, the reaction of Compound F6 with ethyl isocyanate is carried out in acetonitrile at ambient temperature.

[0508] In some embodiments, Compound F6 or a salt thereof is prepared by a process comprising d) making a Compound F4 having the formula:

[0509]

[0510] or a salt thereof and a compound F5 having the following formula:

[0511]

[0512] or its salt in the presence of a Lewis acid and a reducing agent, wherein P 1 is an amino protecting group and R 1 is Cl, Br or I.

[0513] In some embodiments, Compound F4 and Compound F5 are preferably in their non-salt form.

[0514] In some embodiments, the Lewis acid in step d) is chlorotrimethylsilane. In some embodiments, the reducing agent is a borane-THF complex ("BH3-THF").

[0515] In some embodiments, the reaction of Compound F4 and Compound F5 is carried out in DMF at room temperature.

[0516] In some embodiments, Compound F4 or a salt thereof is prepared by a process comprising e) making a Compound F3 having the formula:

[0517]

[0518] or a salt thereof and an acid. In some embodiments, P 1 In some embodiments, R 1is Cl, Br or I.

[0519] In some embodiments, Compound F3 and Compound F4 are preferably in their non-salt form.

[0520] In some embodiments, the acid in step e) is an aqueous acid. In some embodiments, the acid is HCl or sulfuric acid. In some embodiments, the acid is an aqueous HCl solution or an aqueous sulfuric acid solution.

[0521] In some embodiments, the reaction of Compound F3 is carried out in dichloromethane at room temperature.

[0522] In some embodiments, Compound F3 or a salt thereof is prepared by a process comprising f) making a Compound F2 having the formula:

[0523]

[0524] or a salt thereof with N-formylmorpholine in the presence of a base to form a mixture; and contacting the mixture with morpholine and an acid in the presence of a reducing agent.

[0525] In some embodiments, Compound F2 and Compound F3 are in their non-salt form.

[0526] In some embodiments, the base in step f) is lithium diisopropylamide or lithium hexamethyldisilazide. In some embodiments, the reaction of compound F2 with the base is carried out in THF at low temperature. In certain embodiments, the temperature is ≤-50°C, ≤-60°C, or ≤-70°C.

[0527] In some embodiments, the reducing agent in step f) is sodium triacetoxyborohydride, sodium borohydride, or sodium cyanoborohydride. In some embodiments, the acid in step f) is acetic acid. In some embodiments, the reaction in step f) is carried out at ambient temperature.

[0528] The present invention provides a method for preparing compound 1, comprising:

[0529] a) making a compound 2 having the following formula:

[0530]

[0531] Contact with N-formylmorpholine in the presence of a base to form compound 2a having the following formula:

[0532]

[0533] b) reacting compound 2a with morpholine in the presence of an acid and a reducing agent to form compound 3 having the following formula:

[0534]

[0535] c) converting compound 3 into compound 4 having the following formula:

[0536]

[0537] d) reacting compound 4 with compound 5 having the formula:

[0538]

[0539] In the presence of a Lewis acid and a reducing agent, the reaction forms a compound 6 having the following formula:

[0540]

[0541] e) reacting compound 6 with ethyl isocyanate to form compound 7 having the following formula:

[0542]

[0543] f) contacting compound 7 with a base to form compound 8 having the following formula:

[0544]

[0545] g) contacting Compound 8 with a base to produce Form I of Compound 1.

[0546] In some embodiments, the method further comprises recrystallizing Compound 1 in a solvent to produce Form I of Compound 1. In some embodiments, the solvent is a mixture of dichloromethane and methyl tert-butyl ether.

[0547] In some embodiments, the base in step a) is lithium diisopropylamide.

[0548] In some embodiments, the acid in step b) is acetic acid. In some embodiments, the reducing agent in step b) is sodium triacetoxyborohydride. In some embodiments, the acid in step b) is acetic acid and the reducing agent in step b) is sodium triacetoxyborohydride.

[0549] In some embodiments, the conversion in step c) is performed in the presence of aqueous hydrochloric acid.

[0550] In some embodiments, the Lewis acid in step d) is chlorotrimethylsilane. In some embodiments, the reducing agent is BH3-THF. In some embodiments, the Lewis acid in step d) is chlorotrimethylsilane and the reducing agent in step d) is BH3-THF.

[0551] In some embodiments, the reaction in step e) further comprises purifying compound 7.

[0552] In some embodiments, the base in step f) is lithium hexamethyldisilazide.

[0553] In some embodiments, the base in step g) is NaOH.

[0554] The present invention provides a method for preparing compound 2 having the following formula:

[0555]

[0556] The method comprises:

[0557] a) contacting 1H-pyrrolo[2,3-b]pyridine with an oxidizing agent to form 1H-pyrrolo[2,3-b]pyridine 7-oxide;

[0558] b) reacting 1H-pyrrolo[2,3-b]pyridine 7-oxide with a chlorinating agent to form 4-chloro-1H-pyrrolo[2,3-b]pyridine;

[0559] c) reacting 4-chloro-1H-pyrrolo[2,3-b]pyridine with triisopropylsilyl chloride in the presence of a base to form 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine;

[0560] d) reacting 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine with N,N-dimethylformamide in the presence of a base to form 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde;

[0561] e) reacting 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde with benzenesulfonyl chloride in the presence of a base to form 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde; and

[0562] f) reacting 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde with ethylene glycol in the presence of an acid to produce compound 2.

[0563] In some embodiments, the oxidizing agent in step a) is m-chloroperbenzoic acid or hydrogen peroxide. In some embodiments, the reaction is carried out in a suitable solvent. In some embodiments, the reaction is carried out in dichloromethane. In some embodiments, the reaction is carried out at low temperatures. In some embodiments, the reaction is carried out at temperatures between -5°C and 15°C or between 0°C and 10°C.

[0564] In some embodiments, the chlorinating agent in step b) is methanesulfonyl chloride, thionyl chloride, or N-chlorosuccinimide. In some embodiments, the reaction is carried out in a suitable solvent. In some embodiments, the reaction is carried out in DMF. In some embodiments, the reaction is carried out at an elevated temperature. In some embodiments, the reaction is carried out at ≥70°C, ≥80°C, or ≥90°C.

[0565] In some embodiments, the base in step c) is sodium hydride. In some embodiments, the reaction in step c) is carried out in a suitable solvent. In some embodiments, the reaction in step c) is carried out in THF. In some embodiments, the reaction in step c) is carried out at ambient temperature. In some embodiments, the reaction in step c) is carried out at ≤30°C or ≤25°C.

[0566] In some embodiments, the base in step d) is n-butyllithium, sec-butyllithium, or tert-butyllithium. In some embodiments, the reaction in step d) is carried out at low temperature. In some embodiments, the reaction in step d) is carried out at ≤30°C, ≤20°C, ≤10°C, or ≤5°C.

[0567] In some embodiments, the base in step e) is cesium carbonate. In certain embodiments, the reaction in step e) is carried out in a suitable solvent. In certain embodiments, the reaction in step e) is carried out in dimethylformamide. In some embodiments, the reaction in step e) is carried out at a temperature of ≤30°C, ≤20°C, ≤10°C, or ≤5°C. In some embodiments, the reaction in step e) is carried out in a suitable solvent at a temperature range of 0°C to ambient temperature.

[0568] In some embodiments, the acid in step f) is p-toluenesulfonic acid or HCl. In some embodiments, step f) is performed at elevated temperature. In some embodiments, step f) is performed at reflux.

[0569] The present invention provides a method for preparing compound 4 having the following formula:

[0570]

[0571] The method comprises:

[0572] a) contacting 2-amino-4-chloropyridine with a brominating agent to form 5-bromo-4-chloropyridin-2-amine;

[0573] b) contacting 5-bromo-4-chloropyridin-2-amine with an iodinating agent to form 5-bromo-4-chloro-3-iodopyridin-2-amine;

[0574] c) reacting 5-bromo-4-chloro-3-iodopyridin-2-amine with 4-(prop-2-ynyl)morpholine in the presence of a catalyst to form compound 9 having the following formula:

[0575]

[0576] d) reacting compound 9 with a base to form compound 10 having the following formula:

[0577]

[0578] e) reacting compound 10 with benzenesulfonyl chloride in the presence of a base to form compound 11 having the following formula:

[0579]

[0580] f) contacting compound 11 with an alkyl-magnesium halide agent to form a mixture and adding N,N-dimethylformamide to the mixture to produce compound 4.

[0581] In some embodiments, the brominating agent in step a) is N-bromosuccinimide. In some embodiments, the contacting in step a) is carried out in a suitable solvent. In some embodiments, the contacting in step a) is carried out in acetonitrile. In some embodiments, the contacting in step a) is carried out at low temperature. In some embodiments, the contacting in step a) is carried out at ≤20°C or ≤15°C. In some embodiments, the contacting in step a) is carried out at between 10-25°C or between 15-20°C.

[0582] In some embodiments, the iodinating agent in step b) is iodine. In some embodiments, the contacting in step b) is carried out in the presence of one or more acids. In some embodiments, the contacting in step b) is carried out in the presence of sulfuric acid and periodic acid. In some embodiments, the contacting in step b) is carried out at an elevated temperature. In some embodiments, the contacting in step b) is carried out at a temperature between 75-85° C. or 77-83° C.

[0583] In some embodiments, the catalyst in step c) is a transition metal catalyst. In some embodiments, the catalyst in step c) comprises a combination of CuI and Pd(PPh3)4. In some embodiments, the reaction in step c) is carried out in a suitable solvent. In certain embodiments, the reaction in step c) is carried out in toluene. In certain embodiments, the reaction in step c) is carried out at an elevated temperature. In certain embodiments, the reaction in step c) is carried out at ≥40°C, ≥50°C, or ≥60°C.

[0584] In some embodiments, the base in step d) is KOtBu. In some embodiments, the reaction in step d) is carried out in a suitable solvent. In some embodiments, the reaction in step d) is carried out in THF. In certain embodiments, the reaction in step d) is carried out at an elevated temperature. In certain embodiments, the reaction in step d) is carried out at a temperature between 25-40°C or between 30-35°C.

[0585] In some embodiments, the base in step e) is NaH. In some embodiments, the reaction in step e) is carried out in a suitable solvent. In some embodiments, the reaction in step e) is carried out in THF. In some embodiments, the reaction in step e) is carried out at a temperature between -5-10°C or 0-5°C.

[0586] In some embodiments, the alkyl-magnesium halide agent in step e) is isopropylmagnesium chloride. In some embodiments, the contacting in step f) is carried out in a suitable solvent. In some embodiments, the contacting in step f) is carried out in THF. In some embodiments, the contacting in step f) is carried out at a temperature between -15-5°C or -10-0°C.

[0587] The present invention provides a method for preparing compound 5 having the following formula:

[0588]

[0589] The method comprises:

[0590] a) contacting pentafluorobenzoic acid with an alkyl alcohol in the presence of thionyl chloride to form methyl pentafluorobenzoate;

[0591] b) reacting a pentafluorobenzoate with benzylamine in the presence of a base to form methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate;

[0592] c) contacting methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate with sodium methoxide to form a mixture, and adding water to the mixture to produce 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid;

[0593] d) heating 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid to produce N-benzyl-2,6-difluoro-3,5-dimethoxyaniline; and

[0594] e) reacting N-benzyl-2,6-difluoro-3,5-dimethoxyaniline with ammonium formate in the presence of palladium on carbon to form compound 5.

[0595] In some embodiments, the alkyl alcohol in step a) is methanol. In certain embodiments, the contacting in step a) is performed at elevated temperature. In some embodiments, the contacting in step a) is performed under reflux.

[0596] In some embodiments, the base in step b) is a tertiary amine. In some embodiments, the base in step b) is N,N-diisopropylethylamine. In some embodiments, the reaction in step b) is carried out in a suitable solvent. In some embodiments, the reaction in step b) is carried out in N-methylpyrrolidone. In some embodiments, the reaction in step b) is carried out at an elevated temperature. In some embodiments, the reaction in step b) is carried out at ≥55°C, ≥60°C, ≥65°C, or ≥70°C.

[0597] In some embodiments, the contacting in step c) is carried out in a suitable solvent. In some embodiments, the contacting in step c) is carried out in methanol. In some embodiments, the contacting in step c) is carried out at an elevated temperature. In some embodiments, the contacting in step c) is carried out at a temperature between 60-75°C or 76-70°C.

[0598] In some embodiments, the heating in step d) is performed between 65-95° C., between 70-90° C., or between 75-85° C. In some embodiments, the heating in step d) is performed neat. In some embodiments, the heating in step d) is performed in the absence of a solvent.

[0599] In some embodiments, the reaction in step e) is carried out in a suitable solvent. In some embodiments, the reaction in step e) is carried out in a mixture of ethanol and acetic acid. In certain embodiments, the reaction in step e) is carried out in a 6:1 mixture of ethanol and acetic acid. In certain embodiments, the reaction in step e) is carried out at an elevated temperature. In certain embodiments, the reaction in step e) is carried out at ≥40°C, ≥50°C, or ≥60°C.

[0600] The methods described herein can be monitored by any suitable method known in the art. For example, the monitoring can be performed by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible) or mass spectrometry; or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography to monitor product formation. The compound obtained by the reaction can be purified by any suitable method known in the art. For example, chromatography (medium pressure), HPLC or preparative thin layer chromatography on a suitable adsorbent (e.g., silica gel, alumina, etc.); distillation; sublimation, grinding or recrystallization. In general, the purity of the compound is determined by physical methods, such as measuring the melting point (in the case of a solid), obtaining an NMR spectrum or performing an HPLC separation. If the melting point is lowered, if the undesirable signal in the NMR spectrum is reduced, or if the irrelevant peaks in the HPLC trace are removed, the compound can be considered to have been purified. In some embodiments, the compound is substantially purified.

[0601] The preparation of compound can relate to the protection and deprotection of various chemical groups.The need for protection and deprotection and the selection of appropriate protecting groups can be easily determined by those skilled in the art. For example, the chemical action of protecting groups can be found in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons: New York, 2006, which is incorporated herein by reference in its entirety. As used herein, "amino protecting group" refers to any protecting group for protecting amines. Exemplary amino protecting groups include but are not limited to phenylsulfonyl, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), tert-butyloxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpentyl-3-yloxycarbonyl ( Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazine, methoxymethyl, tert-butoxymethyl (Bum), benzyloxymethyl (BOM) or 2-tetrahydropyranyl (THP), tris(C 1-4 alkyl)silyl (for example, tri(isopropyl)silyl), 1,1-diethoxymethyl or N-pivaloyloxymethyl (POM).

[0602] The reactions of the methods described herein can be carried out at a suitable temperature, which can be readily determined by a skilled artisan. The reaction temperature will depend, for example, on the melting and boiling points of the reagents and solvent (if present); the thermodynamics of the reaction (e.g., a strongly exothermic reaction may require low temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may require high temperatures).

[0603] In some embodiments, concentrating a solution as described herein refers to reducing the volume of the solution by evaporating the solvent, by heating the solution, by subjecting the solution to reduced pressure, or any combination thereof.

[0604] As used herein, the phrase "transition metal catalyst" refers to a metal catalyst wherein the metal is an element from Group VIII of the periodic table suitable for catalyzing carbon-carbon coupling reactions (e.g., palladium or nickel catalysts). Exemplary transition metal catalysts include, but are not limited to, PdCl2(PPh3)2, Pd(PPh3)4, dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})palladium (Pd-132), NiCl2(dppf), and NiCl2(dppp), wherein (dppf) refers to 1,1′-bis(diphenylphosphino)ferrocene and (dppp) refers to 1,3-bis(diphenylphosphino)propane.

[0605] Exemplary palladium catalysts include, but are not limited to, PdCl2(PPh3)2, Pd(PPh3)4, dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]-phosphoranyl})palladium (Pd-132), palladium / carbon, PdCl2, Pd(OAc)2, PdCl2(MeCN)2, tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1), Pd(dppf)Cl2 (e.g., Pd(dppf)Cl2-CH2Cl2), and tetrakis(tri(o-tolyl)phosphine)palladium(0).

[0606] In some embodiments, an antisolvent as described herein refers to a solvent in which Compound 1 is less soluble relative to another solvent or solvent mixture in solution. For example, the antisolvent can include, but is not limited to, benzene, cyclohexane, pentane, hexane, heptane (e.g., n-heptane), toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-xylene, o-xylene or p-xylene, octane, dihydroindane, nonane, or naphthalene.

[0607] The reaction of the method described herein can be carried out in a suitable solvent, and the suitable solvent can be easily selected by a person skilled in the art of organic synthesis. Suitable solvents can be generally non-reactive with starting material (reactants), intermediates or products at the temperature of the reaction (e.g., a temperature in the range of the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in a solvent or a mixture of more than one solvent. According to a specific reaction step, a solvent suitable for a specific reaction step can be selected. In some embodiments, such as when at least one of the reagents is a liquid or a gas, the reaction can be carried out in the absence of a solvent.

[0608] Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane (chloromethane), tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, α,α,α-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof, and the like.

[0609] Suitable ether solvents include dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether (diethylene glycol dimethyl ether), diethylene glycol diethyl ether, triethylene glycol dimethyl ether, benzyl ether, tert-butyl methyl ether, mixtures thereof, and the like.

[0610] Suitable protic solvents can include, for example, but are not limited to, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neopentyl alcohol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

[0611] Suitable aprotic solvents may include, for example, but are not limited to, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

[0612] Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o- or p-xylene, octane, indane, nonane or naphthalene.

[0613] The reactions of the methods described herein can be carried out in air or under an inert atmosphere. Typically, reactions involving reagents or products that are substantially reactive with air can be carried out using air-sensitive synthesis techniques well known to the skilled artisan.

[0614] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to temperatures (e.g., reaction temperatures) that are approximately the temperature of the room in which the reaction is carried out, for example, temperatures of about 20° C. to about 30° C. The term "elevated temperature" as used herein is understood in the art and generally refers to temperatures (e.g., reaction temperatures) that are above room temperature, for example, above 30° C.

[0615] Compound

[0616] Provided herein is a compound of formula F1:

[0617]

[0618] in:

[0619] P 1 is an amino protecting group;

[0620] R 1 is Cl, Br or I;

[0621] R 2 and R 3 Each independently is C 1-6 alkoxy; or

[0622] R 2 and R 3 together with the carbon atom to which it is attached, form 1,3-dioxolan-2-yl or 1,3-dioxan-2-yl; or

[0623] R 2 and R 3 Together they form an oxo group.

[0624] In some embodiments, the compound of Formula F1 has Formula F3:

[0625]

[0626] In some embodiments, the compound of Formula F1 has Formula F4:

[0627]

[0628] In some embodiments, provided herein is a compound having Formula F6:

[0629]

[0630] in:

[0631] P 1 is an amino protecting group;

[0632] R 1 is Cl, Br or I.

[0633] In some embodiments, the compound having formula F6 is compound 6:

[0634]

[0635] Provided herein is a compound having the formula F7:

[0636]

[0637] in:

[0638] P 1 is an amino protecting group;

[0639] R 1 is Cl, Br or I.

[0640] In some embodiments, the compound having F7 is Compound 7:

[0641]

[0642] In some embodiments, provided herein is a compound of formula F8:

[0643]

[0644] Among them, P 1 It is an amino protecting group.

[0645] In some embodiments, the compound of formula F8 is Compound 8:

[0646]

[0647] In some embodiments, provided herein is a compound of formula F9:

[0648]

[0649] where R 2 and R 5 are each independently Br, Cl or I.

[0650] In some embodiments, the compound of formula F9 is Compound 9:

[0651]

[0652] In some embodiments, provided herein is a compound of formula F10:

[0653]

[0654] where R 1 and R 4 are each independently Br, Cl or I; and R 6 is H or benzenesulfonyl.

[0655] In some embodiments, the compound having formula F10 is Compound 10:

[0656]

[0657] In some embodiments, the compound having formula F10 is compound 11:

[0658]

[0659] How to use

[0660] Compound 1 or a solid form thereof as described herein can inhibit the activity of an FGFR enzyme. For example, Compound 1 can be used to inhibit the activity of an FGFR enzyme in a cell, individual, or patient in need of inhibition by administering an inhibitory amount of Compound 1 to the cell, individual, or patient.

[0661] As an FGFR inhibitor, compound 1 can be used to treat various diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands. Compounds that inhibit FGFR will be useful in providing a means of preventing growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. Therefore, it is expected that compound 1 will prove useful in treating or preventing proliferative disorders, such as cancer. In particular, tumors with activated mutants of receptor tyrosine kinases or upregulated receptor tyrosine kinases may be particularly sensitive to the inhibitors.

[0662] In certain embodiments, the present disclosure provides a method of treating an FGFR-mediated disorder in a patient in need thereof, comprising the step of administering Compound 1 or a pharmaceutically acceptable composition thereof to the patient.

[0663] For example, Compound 1 or a solid form thereof can be used to treat cancer. Exemplary cancers include bladder cancer, breast cancer (e.g., hormone R positive, triple negative), cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer (e.g., gastrointestinal stromal tumor), head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and oral cancer, squamous head and neck cancer), kidney cancer (e.g., renal cell carcinoma, urothelial carcinoma, sarcoma, Wilms tumor), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma, hepatic angiosarcoma, hepatoblastoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial cancer, bronchial adenoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, parathyroid cancer, neuroendocrine cancer (e.g., pheochromocytoma, Merkel cell carcinoma), cell cancer), neuroendocrine cancer), skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0664] Other exemplary cancers include hematopoietic malignancies such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), myelodysplastic syndrome, chronic eosinophilic leukemia, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt's lymphoma.

[0665] In certain embodiments, there is provided herein a method for treating a spinal cord / lymphoid neoplasm in a patient in need thereof. In certain embodiments, the spinal cord / lymphoid neoplasm is 8p11 myeloproliferative syndrome. As used herein, the term "8p11 myeloproliferative syndrome" (EMS) refers to a spinal cord / lymphoid neoplasm associated with eosinophilia and FGFR1 abnormalities or a spinal cord / lymphoid neoplasm (MLN) with FGFR1 rearrangement. Jackson, Courtney C. et al. Human Pathology, 2010, 41, 461-476, reviewed eight P eleven myeloproliferative syndromes. The defining feature of EMS is the presence of a transposition of the FGFR1 gene located at the chromosome 8p11 locus, and at least 10 additional transpositions and 1 insertion have been identified in EMS, each of which destroys FGFR1 and forms a novel fusion gene with various partners. See Jackson, Courtney C. et al. Human Pathology, 2010, 41, 461-476.

[0666] In some embodiments, the spinal cord / lymphoid neoplasm is characterized by an FGF / FGFR gene alteration. In certain embodiments, the spinal cord / lymphoid neoplasm exhibits an FGFR1 fusion. The FGFR1 fusion may be a translocation, an interstitial deletion, or a chromosomal inversion. In some embodiments, the FGFR1 fusion is an FGFR1 translocation. In certain embodiments, the spinal cord / lymphoid neoplasm exhibits an 8p11 translocation. In certain embodiments, the 8p11 translocation is associated with activation of FGFR1. In some embodiments, the spinal cord / lymphoid neoplasm exhibits an FGF / FGFR alteration that is not an FGFR1 translocation. In certain embodiments, the patient has failed at least one prior treatment for the spinal cord / lymphoid neoplasm (e.g., 8p11 myeloproliferative syndrome). In some embodiments, the prior treatment is surgery or radiotherapy. In some embodiments, the patient has a history of hepatitis. In some embodiments, the hepatitis is chronic hepatitis B or hepatitis C. In some embodiments, the patient does not have a history of hepatitis.

[0667] In certain embodiments, provided herein is a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 or a solid form thereof. In certain embodiments, the cancer is selected from bladder cancer, breast cancer, cervical cancer, small intestine cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, vulvar cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, myeloproliferative neoplasm, chronic myeloid lymphoma, acute lymphoblastic lymphoma, T-lymphoblastic lymphoma, hairy cell lymphoma, Burkitt's lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0668] In certain embodiments, the cancer is bladder cancer (eg, urothelial carcinoma, squamous cell carcinoma, adenocarcinoma).

[0669] In certain embodiments, liver cancer is cholangiocarcinoma (e.g., intrahepatic, hilar or perihilar, distal extrahepatic). As used herein, cholangiocarcinoma is the same as cholangiocarcinoma or cholangiocarcinoma. In certain embodiments, cholangiocarcinoma is advanced or metastatic cholangiocarcinoma. In certain embodiments, cholangiocarcinoma is cholangiocarcinoma that is not surgically resectable. In certain embodiments, cholangiocarcinoma is intrahepatic cholangiocarcinoma. In certain embodiments, cholangiocarcinoma is extrahepatic cholangiocarcinoma. In certain embodiments, cholangiocarcinoma exhibits FGFR2 tyrosine kinase fusion, which is defined as a certain molecular subtype as described in Arai, Yasuhito et al. Hepatology, 2014, 59, 1427-1434. In some embodiments, cholangiocarcinoma is characterized by tumors with FGF / FGFR gene alterations. In some embodiments, the tumor exhibits FGFR2 fusion. FGFR2 fusion can be translocation, interstitial deletion, or chromosomal inversion. In some embodiments, FGFR2 fusion is FGFR2 translocation. FGFR2 translocation can be selected from the group including but not limited to: FGFR2-BICC1, FGFR2-AHCYL1, FGFR2-MACF1, FGFR2 intron 17 rearrangement. In some embodiments, the tumor exhibits FGF / FGFR alterations that are not FGFR2 translocations. In some embodiments, the cholangiocarcinoma does not exhibit tumors with FGF / FGFR gene alterations.

[0670] Other cancers treatable with Compound 1 or a solid form thereof include ocular tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, leiomyosarcoma, urothelial carcinoma (e.g., ureteral carcinoma, urethral carcinoma, bladder carcinoma, urachal carcinoma), and osteosarcoma.

[0671] Compound 1 or a solid form thereof can also be used to inhibit tumor metastasis.

[0672] In some embodiments, Compound 1 or a solid form as described herein can be used to treat Alzheimer's disease, HIV, or tuberculosis.

[0673] In addition to oncogenic neoplasms, the compounds of the present invention may be used to treat skeletal and cartilage cell disorders including, but not limited to, achondroplasia, hypochondrosis, dwarfism, thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutisgyrate syndrome, Pfeiffer syndrome, and craniosynostosis.

[0674] The compounds provided herein can also be used to treat fibrotic diseases, such as those in which the disease symptoms or conditions are characterized by fibrosis. Exemplary fibrotic diseases include cirrhosis of the liver, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and wound healing.

[0675] In some embodiments, the compounds provided herein can be used to treat hypophosphatemic disorders, such as X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets, or tumor-induced rickets.

[0676] In some embodiments, there is provided herein a method for increasing the survival time or progression-free survival time of a patient, the method comprising administering a compound provided herein to the patient. In some embodiments, the patient suffers from cancer. In some embodiments, the patient suffers from a disease or condition described herein. In some embodiments, the patient suffers from bile duct cancer. In some embodiments, there is provided herein a method for increasing the survival time or progression-free survival time of a patient suffering from bile duct cancer, wherein the feature of bile duct cancer is FGFR2 fusion, the method comprising administering a compound provided herein to the patient. As used herein, progression-free survival time refers to the length of time that a patient lives during and after treatment of a solid tumor while suffering from the disease but the disease does not get worse. Progression-free survival time can refer to the length of time from the first administration of a compound to earlier death or disease progression. The progression of the disease can be determined by RECIST version 1.1 (Solid Tumor Response Evaluation Criteria), as evaluated by an independent central radiological review committee. In some embodiments, administration of the compound results in a progression-free survival of greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, administration of the compound results in a progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, administration of the compound increases progression-free survival by at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and by less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0677] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a portion of a tissue sample removed from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that is alive in an organism such as a mammal.

[0678] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" an FGFR enzyme with a compound described herein (e.g., Compound 1) includes administering a compound described herein to an individual or patient (such as a human) having FGFR, and, for example, introducing a compound described herein (e.g., Compound 1) into a sample containing cells or a purified preparation containing the FGFR enzyme.

[0679] As used herein, the terms "subject" or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0680] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or agent, such as any of the solid forms disclosed herein or salts thereof, that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. An appropriate "effective" amount in any individual case can be determined using techniques known to those skilled in the art.

[0681] 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 humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0682] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0683] As used herein, the terms "treating" and "treatment" refer to inhibiting a disease; e.g., inhibiting a disease, disorder or condition in a subject experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms), or ameliorating a disease; e.g., ameliorating a disease, disorder or condition in a subject experiencing or exhibiting the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0684] It will be appreciated that certain features of the present invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written as multiple separate embodiments). Conversely, various features of the present invention, which are, for brevity, described herein in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0685] Combination therapy

[0686] One or more additional agents or treatments (such as antiviral agents, chemotherapeutic agents or other anticancer agents, immunopotentiators, immunosuppressants, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or tyrosine kinase inhibitors) can be used in combination with Compound 1 for the treatment of FGFR-related diseases, disorders or conditions, or diseases or conditions as described herein. The agents can be combined with the compounds of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0687] Compound 1 or a solid form thereof as described herein can be combined with one or more other kinase inhibitors for the treatment of diseases affected by multiple signaling pathways, such as cancer. For example, the combination can include one or more inhibitors of the following kinases to treat cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FL In some embodiments, the present invention relates to a FGFR inhibitor comprising a kinase inhibitor or a kinase inhibitor of a PIK3 / Akt / mTOR signaling pathway. The kinase inhibitors of the present invention may be PI3K, Akt (including Akt1, Akt2 and Akt3) and mTOR kinase.

[0688] In some embodiments, Compound 1, or a solid form thereof, as described herein, can be used in combination with one or more inhibitors of enzymes or protein receptors such as HPK1, SBLB, TUT4, A2A / A2B, CD47, CDK2, STING, ALK2, LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 to treat diseases and conditions. Exemplary diseases and conditions include cancer, infection, inflammation, and neurodegenerative disorders.

[0689] In some embodiments, compound 1 or its solid form as described herein can be used in combination with the therapeutic agent of targeting epigenetic regulatory factor.The example of epigenetic regulatory factor includes bromodomain inhibitor, histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetylase and DNA methyltransferase.Histone deacetylase inhibitor includes for example vorinostat (vorinostat).

[0690] For the treatment of cancer and other proliferative diseases, Compound 1 or a solid form thereof as described herein can be used in combination with targeted therapies, including JAK kinase inhibitors (Ruxolitinib, additional JAK1 / 2 and JAK1 selective inhibitors, baricitinib, or INCB39110), Pim kinase inhibitors (e.g., INCB53914), PI3 kinase inhibitors (including PI3K-δ selective inhibitors and broad-spectrum PI3K inhibitors, e.g., INCB50465 and INCB54707), PI3K-γ inhibitors (such as PI3K-γ selective inhibitors), MEK inhibitors, CSF1R inhibitors, TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors, interleukin receptor inhibitors, cyclin-dependent kinase inhibitors, B RAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromodomain and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors such as INCB54329 or INCB57643), LSD1 inhibitors (e.g., INCB59872 or INCB60003), arginase inhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat, NLG919, or BMS-986205), and PARP inhibitors (e.g., olaparib or rucaparib).

[0691] For the treatment of cancer and other proliferative diseases, Compound 1 or its solid forms as described herein can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. Compound 1 or its solid forms can also be used in combination with medical therapies, such as surgery or radiation therapy, e.g., gamma-irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes. Examples of suitable chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, baricitinib, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, intravenous busulfan, intravenous, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, nitrogen mustard, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin-diphtheria toxin conjugate diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, folinic acid, leuprolide acetate acetate), levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, nelarabine, niraparib, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronate, panobinostat, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodiumdisodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide , testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0692] In some embodiments, compound 1 or its solid form as described herein can be used in combination with immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors for immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (eg, INCAGN2385), TIM3 (eg, INCB2390), VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from the following: CD27, CD28, CD40, ICOS, OX40 (eg, INCAGN1949), GITR (eg, INCAGN1876), and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from the following: A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3 and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from the following: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

[0693] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0694] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the small molecule PD-L1 inhibitor has an IC50 of less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assay described in U.S. Patent Publication Nos. US20170107216, US20170145025, US20170174671, US20170174679, US 20170320875, US20170342060, US20170362253, and US 20180016260, each of which is incorporated herein by reference in its entirety for all purposes.

[0695] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012, nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, ipilimumab, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. One or more other anticancer agents include antibody therapeutics, such as 4-1BB (e.g., urelumab, utomilumab).

[0696] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736. In some embodiments, the PD-L1 inhibitor is INCB086550.

[0697] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0698] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.

[0699] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166.

[0700] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562. In some embodiments, the OX40L fusion protein is MEDI6383.

[0701] In some embodiments, the salt of compound 1 as described herein can be used in combination with one or more agents for treating diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0702] Suitable antiviral agents contemplated for use in combination with Compound 1 may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0703] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil (d4T); dipivoxil (bis(POM)-PMEA) [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Roche). 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0704] Suitable agents for use in combination with Compound 1 to treat cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapy, or radiotherapy. Compound 1 can be effective in combination with anti-hormonal agents for the treatment of breast cancer and other tumors. Suitable examples are anti-estrogen agents, including but not limited to tamoxifen and toremifene; aromatase inhibitors, including but not limited to letrozole, anastrozole, and exemestane; adrenal steroids (e.g., prednisone), progesterone (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Anti-hormonal agents suitable for treating prostate and other cancers can also be combined with Compound 1. These antihormonal agents include antiandrogens, including but not limited to flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogs, including leuprolide, goserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide); and agents that inhibit androgen production (e.g., abiraterone).

[0705] Compound 1 can be combined with other agents targeting membrane receptor kinases or used sequentially with them, especially for patients who have developed primary or acquired resistance to targeted therapies. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1 or Flt-3, as well as against cancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors against EGFR include gefitinib and erlotinib, and inhibitors against EGFR / Her2 include but are not limited to dacomitinib, afatinib, lapatinib, and neratinib. Antibodies against EGFR include but are not limited to cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met can be used in combination with FGFR inhibitors. These substances include onartumzumab, tivantnib, and INC-280. Agents directed against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib and those directed against Alk (or EML4-ALK) include crizotinib.

[0706] Angiogenesis inhibitors can be effective in combination with FGFR inhibitors in some tumors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins against VEGF include bevacizumab and aflibercept. Inhibitors of VEGFR kinases and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0707] Activation of intracellular signaling pathways occurs frequently in cancer, and agents targeting components of these pathways have been combined with receptor-targeting agents to enhance efficacy and reduce resistance. Examples of agents that can be combined with Compound 1 include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0708] Agents for PI3 kinase include, but are not limited to, pilaralisib, idelalisib, and buparlisib. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus, and everolimus can be combined with FGFR inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). One or more inhibitors of JAK (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinase (e.g., palbociclib), HDAC (e.g., panobinostat), PARP (e.g., olaparib), and proteasome (e.g., bortezomib, carfilzomib) can also be combined with Compound 1. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0709] Other suitable agents for use in combination with Compound 1 include chemotherapy combinations such as platinum-based doublets (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel in combination with particles for lung cancer and other solid tumors.

[0710] Suitable chemotherapeutic or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide, TM ), ifosfamide, melphalan, mechlorethamine, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0711] Other agents suitable for use in combination with Compound 1 include: dacarbazine (DTIC), optionally with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen," which consists of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. Compound 1 can also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF).

[0712] Suitable chemotherapeutic or other anticancer agents include, for example, antimetabolites (including but not limited to folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0713] Suitable chemotherapeutic or other anticancer agents also include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL), and oxazolidinone. TM ), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.

[0714] Other cytotoxic agents include navibene, CPT-11, anastrozole, letrozole, capecitabine, reloxafine, cyclophosphamide, ifosfamide, and droloxafine.

[0715] Also suitable are cytotoxic agents, such as epipodophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutics; folinic acid; tegafur; and hematopoietic growth factors.

[0716] The one or more other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules (such as CTLA-4, 4-1BB), PD-1 and PD-L1 antibodies, or antibodies to cytokines (IL-10, TGF-β, etc.).

[0717] Still other anticancer agents include those that block the migration of immune cells, such as antagonists of chemokine receptors including CCR2 and CCR4.

[0718] Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0719] Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0720] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0721] Drug preparations and dosage forms

[0722] When used as a medicament, compound 1 as described herein can be administered in the form of a pharmaceutical composition, which refers to a combination of compound 1 as described herein and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including ocular and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, transepidermal, and transdermal), ocular, oral, or parenteral. Methods of ocular delivery may include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via a balloon catheter or an ocular insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include dermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers; aqueous, powder, or oily bases; thickeners, etc. may be necessary or desirable.

[0723] The present disclosure also includes pharmaceutical compositions containing a combination of Compound 1 as an active ingredient and one or more pharmaceutically acceptable carriers. In preparing the compositions described herein, the active ingredient is typically mixed with an excipient, diluted by the excipient, or sealed in such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When an excipient acts as a diluent, it can be a solid, semisolid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), cream containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0724] When preparing a formulation, the active compound may be ground to provide an appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0725] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and hydroxy-propyl benzoate; sweeteners; and flavoring agents. The compositions described herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by procedures known in the art.

[0726] The compositions can be formulated in unit dosage form, each dose containing from about 5 to about 100 mg, more usually from about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0727] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the actual amount of compound administered will generally be determined by a physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0728] For the preparation of solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of Compound 1. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the present disclosure.

[0729] The tablets or pills of the present disclosure may be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action. For example, a tablet or pill may comprise an inner dose and an outer dose component, the latter being in the form of a film coating on the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to be transported intact to the duodenum or delayed in release. A variety of materials may be used for such enteric layers or coatings, including mixtures of many polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0730] Liquid forms into which Compound 1 and compositions as described herein can be incorporated for oral or injection administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0731] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. As described above, liquid or solid compositions may contain suitable pharmaceutically acceptable excipients. In some embodiments, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. The compositions may be aerosolized using an inert gas. Aerosolized solutions may be breathed directly from a nebulizing device or the nebulizing device may be connected to a mask curtain or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0732] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration (such as prophylaxis or treatment), the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and will be determined by the attending clinician based on factors such as the severity of the disease, the patient's age, weight, and general condition, and the like.

[0733] The composition administered to the patient may be in the form of the pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution may be packaged for use as is or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will typically be between 3 and 11, more preferably 5 to 9 and most preferably 7 to 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formation of a pharmaceutical salt.

[0734] The therapeutic dose of compound 1 may vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of compound 1 in the pharmaceutical composition may vary according to many factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, compound 1 may be provided in a physiologically buffered aqueous solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg to about 1 g per kilogram of body weight per day. In some embodiments, the dosage range is about 0.01 mg to about 100 mg per kilogram of body weight per day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dose can be inferred from a dose-response curve obtained from an in vitro or animal model test system.

[0735] Compound 1 can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent such as an antiviral agent, a vaccine, an antibody, an immunopotentiator, an immunosuppressant, an anti-inflammatory agent, and the like.

[0736] In some embodiments, Compound 1 is administered orally. In some embodiments, Compound 1 is administered once daily. In some embodiments, Compound 1 is administered at a daily dose of about 5 mg to about 20 mg. In some embodiments, Compound 1 is administered at a daily dose of about 10 mg to about 15 mg. In some embodiments, Compound 1 is administered at a daily dose of about 9 mg. In some embodiments, Compound 1 is administered at a daily dose of about 13.5 mg. In some embodiments, Compound 1 is administered in tablet form. In some embodiments, the tablet contains about 0.5 mg to about 10 mg of Compound 1. In some embodiments, the tablet contains about 0.5 mg to about 5 mg of Compound 1. In some embodiments, the tablet contains about 2 mg, about 4.5 mg, about 9 mg, about 13.5 mg, or about 18 mg of Compound 1. In some embodiments, the tablet contains about 0.5 mg of Compound 1. In some embodiments, the tablet contains about 2 mg of Compound 1. In some embodiments, the tablet contains about 4.5 mg of Compound 1. In some embodiments, the tablet contains about 9 mg of Compound 1. In some embodiments, the tablet contains about 13.5 mg of Compound 1. In some embodiments, the tablet contains about 18 mg of Compound 1.

[0737] In some embodiments, Compound 1 is administered once daily on a continuous dosing regimen. In some embodiments, Compound 1 is administered on a 21-day dosing regimen, wherein the 21-day dosing regimen comprises:

[0738] (a) a first period of time, wherein Compound 1 is administered once daily for 14 days; and

[0739] (b) A second period of time in which Compound 1 was not administered for 7 days.

[0740] In some embodiments, Compound 1 is administered on a continuous 21-day dosing regimen, wherein the 21-day dosing regimen comprises:

[0741] (a) a first period of time, wherein Compound 1 is administered once daily for 14 days; and

[0742] (b) A second period of time in which Compound 1 was not administered for 7 days.

[0743] Example

[0744] In the following examples, X-ray powder diffraction analysis was performed on a Rigaku MiniFlex X-ray powder diffractometer (XRPD). The general experimental procedure for XRPD is: (1) X-ray radiation from copper, Use K β filter; (2) X-ray power, 30 kV, 15 mA; and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions of XRPD were: start angle 3 degrees; stop angle 45 degrees; sampling 0.02 degrees; and scanning speed 2 degrees / min.

[0745] Differential Scanning Calorimetry (DSC) was performed on a TA Instruments Differential Scanning Calorimeter, Model Q200, with an autosampler. The DSC instrument conditions were as follows: 30-300°C, 10°C / min; T-zero aluminum sample pan and cover; and nitrogen flow, 50 mL / min.

[0746] Thermogravimetric analysis (TGA) was performed on a TA Instruments Thermogravimetric Analyzer, Model Q500. General TGA experimental conditions included a temperature ramp from 20°C to 600°C at 20°C / min; a nitrogen purge at a gas flow rate of 40 mL / min, followed by a purge flow rate for the remainder of the time; a sample purge flow rate of 60 mL / min; and a platinum sample pan.

[0747] Example 1

[0748] Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (Compound 1)

[0749] Process 1.

[0750]

[0751] Step 1: Synthesis of 4-((4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine

[0752] To a 1-L flask under N2 was added 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL). To this mixture was added a 2.0 M solution of lithium diisopropylamide in THF / heptane / phenylethane (77.4 g, 95 mL, 190 mmol, 1.4 equivalents) at -70°C. The mixture was stirred at -70°C for 1 hour. To the mixture was added a solution of N-formylmorpholine (29.7 g, 258 mmol, 1.9 equivalents) in THF (22.2 g, 25 mL) dropwise. The reaction was allowed to proceed within 30 minutes after the addition. LC / MS indicated the clean formation of the desired product, 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde. The reaction was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 equiv) and the dry ice cooling was removed. Morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 equiv) and acetic acid (74.0 g, 70 mL, 1231 mmol and 9.0 equiv) were added to the mixture at 0°C (internal temperature increased from 0°C to 18°C) and stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 equiv) was added and the reaction mixture temperature was increased from 20°C to 32°C. The mixture was stirred at room temperature for 30 min. HPLC and LC / MS indicated the reaction was complete. Water (100g, 100mL) and 2.0M sodium carbonate (NaCO) aqueous solution (236g, 200mL, 400mmol, 2.9 equivalents) (exhaust gas!) are slowly added successively. The mixture is stirred for about 30min. Separate the organic layer and add water (250g, 250mL) and heptane (308g, 450mL). Gained slurry is stirred for 1h and solid is collected by filtration. The wet cake is washed twice with heptane (75.00mL x 2, 51.3gx 2), then dried overnight at 50 DEG C in an oven to obtain the desired product 4-((4-chloro-5-(1,3-dioxolane-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (52.00g, 81.8% yield) as a light brown solid: C 21 H 23 LCMS calculated value of ClN2O5S [M+H]+ :464.00;Experimental value:464.0; 1 H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.38(m,2H),7.72(m,1H),7.64(m,2H),6.83(s ,1H),6.13(s,1H),4.12(m,2H),4.00(m,2H),3.92(s,2H),3.55(m,4H),2.47(m,4H).

[0753] Step 2: Synthesis of 4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0754] A 2L reactor with a thermocouple, an addition funnel, and a mechanical stirrer was charged with 4-((4-chloro-5-(1,3-dioxolane-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature of 19.5 ° C.) to obtain a solution. Aqueous hydrochloric acid (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 equivalents) was added to the resulting solution at room temperature over 7 min. After stirring at room temperature for more than 23 h, the double-layer reaction mixture became a dense colorless suspension. When HPLC shows that the reaction is complete, the slurry is cooled to 0-5 DEG C and in about 10min, sodium hydroxide aqueous solution (1N, 104g, 100mL, 100mmol and 2.32 equivalents) is added to adjust the pH value of the reaction mixture to 10-11. N-heptane (164g, 240mL) is added and the reaction mixture is stirred at room temperature for 1h. Solid is collected by filtration and wet cake is washed with water (2x 40mL), heptane (2x 40ml), then dried under vacuum in an oven at 50 DEG C, providing the desired product 4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (16.9g, 93% yield) as a light brown solid: C 19 H 19 LCMS calculated value of ClN3O4S [M+H] + :420.00;Experimental value:420.0; 1H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.76(s,1H),8.42(m,2H),7.74(m,1H),7.65(m,2H),6.98(s,1H),3.96(m,2H),3.564(m,4H),2.51(m,4H).

[0755] Step 3: Synthesis of N-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline

[0756] A 2-L reactor equipped with a thermocouple, nitrogen inlet, and mechanical stirrer was charged with N,N-dimethylformamide (450 mL, 425 g), 4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (30.0 g, 71.45 mmol), and 2,6-difluoro-3,5-dimethoxyaniline (14.2 g, 75.0 mmol). To this suspension (internal temperature 20°C) was added dropwise chlorotrimethylsilane (19.4 g, 22.7 mL, 179 mmol) over 10 minutes at room temperature (internal temperature 20-23°C). The suspension became a solution within 5 minutes after the addition of chlorotrimethylsilane. The solution was stirred at room temperature for 1.5 hours and then cooled to 0-5°C in an ice bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 equivalent) was added dropwise over 30 min through another funnel while maintaining the temperature at 0-5 ° C. After the addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice bath cooling within 20 min, followed by the slow addition of ammonium hydroxide solution (28% NH , 15.3 g, 17 ml, 252 mmol, 3.53 equivalent) to a pH of 9-10 while maintaining the temperature below 10 ° C. Water (250 mL, 250 g) was added through another funnel. The slurry was stirred for 30 min and the solid was collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x 2, 90 ml x 2). The product was suction dried overnight to give the desired product, N-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): C 27 H 28 LCMS calculated value of ClF2N4O5S [M+H] + :593.10;Experimental value:593.1; 1H NMR(400MHz,DMSO-d6)δ8.36(m,2H),8.28(s,1H),7.72(m,1H),7.63(m,2H),6.78(s,1H),6 .29(m,1H),5.82(m,1H),4.58(m,2H),3.91(s,2H),3.76(s,6H),3.56(m,4H),2.47(m,4H).

[0757] Step 4: Synthesis of 1-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea

[0758] A 2-L 3-neck round-bottom flask equipped with a thermocouple, a nitrogen bubbler inlet, and a magnetic stirrer was charged with N-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5 ° C. Ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 eq) was added to the mixture over 30 seconds. The temperature was maintained at 0.7 ° C after charging. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 eq) was added dropwise over 35 min while maintaining the temperature below 2 ° C. The mixture is warmed to room temperature and stirred overnight.After adding 24h, display product is 93.7%, unreacted SM is 0.73% and major impurity (diisocyanate adduct) is 1.3%.Mixture is cooled with ice bath and successively uses sodium hydroxide (NaOH) solution (1.0M, 235mL, 244g, 235mmol, 2.08 equivalents) lasts 20min and uses saturated sodium bicarbonate (NaHCO ) aqueous solution (1.07M, 85mL, 91g, 0.091mol, 0.80 equivalents) lasts 10min quenching.Add water (550mL, 550g) and liquid becomes a phase. The mixture was stirred for 2 h and the solid was collected by filtration, washed with water (165 mL, 165 g) to give 1-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (70.3 g, 93.7% yield).

[0759] Crude 1-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (68.5g, 103mmol) is added to acetonitrile (616mL, 485g). The mixture is heated to 60-65°C and an amber dilute suspension is obtained. The solid is filtered out with diatomaceous earth and the diatomaceous earth is washed with acetonitrile (68.5mL, 53.8g). Water (685g, 685ml) is added to the light yellow filtrate to form a slurry. The slurry is stirred at room temperature overnight and filtered. The solid is added to water (685mL, 685g) and stirred at 60°C for 2h. The solid is filtered and a slurry is formed again in heptane (685mL, 469g) overnight. The product was dried in an oven at 50 °C under vacuum for 48 h to provide 1-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (62.2 g, 90.8% yield, 99.9% purity by HPLC area %) as a colorless solid. KF was 0.028%. Acetonitrile (according to 1 H NMR) was about 1.56%, DCM (according to 1 HNMR) 2.0%: C 30 H 33 LCMS calculated for ClF2N5O6S [M+H] + :EM:664.17;Exp:664.2; 1 H NMR(400MHz,DMSO-d6)δ8.33(m,2H),8.31(s,1H),7.72(m,1H),7.64(m,1H),6.96(m,2H),6.73(s,1H),6 .43(m,1H),4.87(s,2H),3.90(s,2H),3.77(s,6H),3.54(m,4H),3.03(m,2H),2.46(m,4H),0.95(m,3H).

[0760] Step 5: Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one

[0761] A 2000 mL flask equipped with a thermocouple, a nitrogen inlet, and a mechanical stirrer was charged with dry 1-((4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-1-(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0.11%) and tetrahydrofuran (1200 mL, 1063 g). To this suspension was added a 1.0 M solution of lithium hexamethyldisilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 equiv) at room temperature. The mixture became a solution after the addition of the base. The reaction mixture was stirred for 2 h and HPLC showed that the starting material was undetectable. To this mixture was added 1.0 M hydrochloric acid (18.1 mL, approximately 18.1 g, 18.1 mmol, 0.4 equivalents). The solution was concentrated to 600 mL and water (1200 mL, 1200 g) was added. A slurry was formed after the addition of water. The slurry was stirred at room temperature for 30 min and the solid was collected by filtration. The wet cake was washed twice with water (60 mL x 2, 60 g x 2) and dried at 50 ° C overnight to give 3- (2,6-difluoro-3,5-dimethoxyphenyl) -1-ethyl-8- (morpholin-4-ylmethyl) -7- (phenylsulfonyl) -1,3,4,7-tetrahydro-2H-pyrrolo [3', 2': 5,6] pyrido [4,3-d] pyrimidin-2-one (26.58 g, 93.7% yield as is): THF was added according to 1 H NMR 0.32%, KF 5.26%, adjusted yield 88.5%: C 30 H 32 LCMS calculated for F2N5O6S [M+H] + :EM:628.20;Exp:628.2; 1 H NMR(400MHz,DMSO-d6)δ8.41(m,2H),8.07(s,1H),7.70(m,1H),7.63(m,2H),7.05(m,1H),6.89(s ,1H),4.76(s,2H),4.09(m,2H),3.93(s,2H),3.89(s,6H),3.60(m,4H),2.50(m,4H),1.28(m,3H).

[0762] Step 6: Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one

[0763] To a stirred suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in 1,4-dioxane (100 ml, 103 g) in a 500 ml flask equipped with a nitrogen inlet, a condenser, a thermocouple, and a heating mantle was added 1 M aqueous sodium hydroxide solution (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 ° C for 18 h. LCMS showed that the reaction was complete. Water (100 mL, 100 g) was added to obtain a concentrated suspension. This slurry was stirred at room temperature for 1 h and filtered. The filter cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The filter cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50° C. under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): C 24 H 28 LCMS calculated for F2N5O4 [M+H] + : 488.20; experimental value: 488.2.

[0764] Example 2. Synthesis of 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0765] Process 2.

[0766]

[0767] Step 1: Synthesis of 1H-pyrrolo[2,3-b]pyridine-7-oxide

[0768] Meta-chloroperbenzoic acid (105.5 Kg, 612 mol, 1.2 equivalents) was added to a solution of 1H-pyrrolo [2,3-b] pyridine (60 Kg, 507.6 mol) in dichloromethane (600 L) at 0-10 ° C for 5 h under stirring. After the addition was complete, the mixture was stirred at 0-10 ° C for 3 h. The resulting solid was collected by filtration, washed with heptane, and dried to give 1H-pyrrolo [2,3-b] pyridine 7-oxide. The mother liquor was concentrated and the residue was treated with dichloromethane: heptane (2: 3), and filtered to recover additional material. Crude 1H-pyrrolo [2,3-b] pyridine -7- oxide (72 Kg, 96% purity) was obtained and used in the next step without purification.

[0769] Step 2: Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine

[0770] Crude 1H-pyrrolo [2,3-b] pyridine -7- oxide (72Kg, 253mol) is dissolved in DMF (360L) and heated at 50 ° C. A solution of methanesulfonyl chloride (85.2Kg, 746mol, 3.0 equivalents) is added dropwise to the solution while maintaining the temperature below 70 ° C. After stirring at 90 ° C for 2h, the reaction solution is cooled to room temperature and added to the ice / water of 720Kg. At 0 ° C, the mixture is neutralized with 6.0M NaOH. The resulting precipitate is collected by filtration and washed with water. The solid is mixed with 72L water, 48L ethanol and 29L 30% NaOH, and stirred at room temperature for 1-2h. Water (144L) is added, and the mixture is processed with 37% HCl to adjust the pH value to about 1. The product was collected by filtration and dried to give 4-chloro-1H-pyrrolo[2,3-b]pyridine (crude 26 kg, 97% purity, used without purification): 1 HNMR (400MHz, CDCl3) δ11.30(s,1H),8.25(m,1H),7.44(m,1H),7.16(m,1H),6.65(m,1H).

[0771] Step 3: Synthesis of 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

[0772] A solution of crude 4-chloro-1H-pyrrolo[2,3-b]pyridine (24 Kg, 155.2 mol) in THF (216 L) was stirred at 0 ° C. NaH (60%, 7.56 Kg, 188.6 mol, 1.3 equivalents) was added portionwise under N2. After the addition, the mixture was stirred at room temperature for 1 h. Triisopropylsilyl chloride (39.6 Kg, 188.6 mol, 1.3 equivalents) was added dropwise while maintaining the temperature below 25 ° C. After stirring for 20 h, the mixture was quenched with 144 L of water and extracted with 144 L of heptane. The aqueous layer was back-extracted with 72 L of methyl tert-butyl ether. The combined organic layers were dried over anhydrous MgSO4 and concentrated under vacuum to obtain crude 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine as a liquid. The material was used without purification, but its water content was controlled to be below 0.1%.

[0773] Step 4: Synthesis of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0774] A 1000 L cryogenic reactor was charged with crude 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 Kg, approximately 138 mol) and anhydrous THF (150 Kg). The mixture was cooled to -75°C and stirred under N2 while S-BuLi (1.3 M solution in cyclohexane, 230 L, 300 mol, 2.2 equiv) was added dropwise over approximately 6.0 h while maintaining the internal temperature below -60°C. The mixture was stirred at -75°C for an additional 2 h. N,N-dimethylformamide (30.4 Kg, 416.1 mol, 3.0 equiv) was added dropwise over approximately 3.0 h to maintain the internal temperature below -65°C. After stirring at -65 to -75 ° C for 2h, the mixture was quenched by dropwise addition of a solution of 20% HCl in isopropanol (115Kg, 635mol, 4.5 equivalents). The mixture was then stirred overnight at room temperature (20-25 ° C). The pH value was adjusted to 7-8 by loading saturated NaHCO 3. The formed precipitate was collected by filtration. The filter cake was washed with 76L water to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (14Kg, 58% yield): 1 HNMR (400MHz, DMSO-d6) δ12.54(s,1H),10.35(s,1H),8.67(s,1H),7.74(m,1H),6.72(m,1H).

[0775] Step 5: Synthesis of 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0776] A 500L reactor was charged with N,N-dimethylformamide (108L) and 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (10.8Kg, 59.8mol) and cooled to 0-5°C. Cesium carbonate (39Kg, 120mol) was added to the resulting concentrated slurry at 0-5°C. The slurry was stirred at 0°C for approximately 20min and the mixture became an amber slurry. Benzenesulfonyl chloride (11.6Kg, 65.8mol, 1.1 equivalents) was added dropwise to the slurry via an addition funnel below 10°C. The resulting slurry was stirred for 1h below 10°C and HPLC indicated that the reaction was complete. Extended stirring at room temperature overnight had little effect on the reaction mixture profile. Water (160L) was added to this mixture and the slurry was stirred for 1h. The solid was collected by filtration (slowly). The filter cake was washed with water and dried in an oven under vacuum to give 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (17.8 Kg, 93% yield) as a light brown solid: C 14 H 10 LCMS calculated value of ClN2O3S [M+H] + :321.00;Experimental value:320.9; 1 HNMR(400MHz, DMSO-d6)δ:10.34(s,1H),8.78(s,1H),8.18(m,3H),7.77(m,1H),7.66(m,2H),7.05(m,1H).

[0777] Step 6: Synthesis of 4-chloro-5-(1,3-dioxolan-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine

[0778] Toluene (270L), 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxaldehyde (27Kg, 84.2mmol), monohydrated p-toluenesulfonic acid (217g, 1.26mol, 0.015 equivalent) and 1,2-ethylene glycol (73.7Kg, 1187mol, 14.1 equivalent) are loaded into a 1000L reactor. The mixture is stirred and heated to reflux to remove water (some ethylene glycol is also removed as the reaction progresses), for 9h (LCMS shows that the reaction is complete). After stirring at room temperature overnight, the mixture is diluted with ethyl acetate (135L) and washed with saturated NaHCO solution. Each layer is separated and the organic layer is washed with a 10% NaCl aqueous solution and concentrated. Heptane (108L) is added and a slurry is formed. Solid is collected by filtration. The solid is dissolved in dichloromethane (108L) and filtered to remove mechanical impurities. The filtrate was concentrated, then dissolved in 67.5 L (2.5 V) of hot ethyl acetate and stirred for 2 h. The mixture was cooled when a solid was formed. The solid was collected by filtration to obtain 4-chloro-5-(1,3-dioxolane-2-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (22 Kg, 70% yield) as an off-white solid: C 16 H 14 LCMS calculated value of ClN2O4S [M+H] + : 365.03; experimental value: 365.1; 1 HNMR (400MHz, DMSO-d6) δ8.51(s,1H),8.13(m,2H),8.07(m,1H),7.73(m,1H),7.63(m,2H),6.90(m,1H),6.13(s,1H),4.12(m,2H),3.98(m,2H).

[0779] Example 3. Alternative Synthesis of 4-chloro-2-(morpholin-4-ylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0780] Process 3.

[0781]

[0782] Step 1: Synthesis of 5-bromo-4-chloropyridin-2-amine

[0783] N-bromosuccinimide (131.5 g, 738.9 mmol, 0.95 equivalent) was added to a slurry of 2-amino-4-chloropyridine (100 g, 777.8 mmol, 1.0 equivalent) in acetonitrile (500 mL, 5 relative volumes) at 15-20 ° C for 2 h, and the temperature was maintained at 15-20 ° C. The reactant was stirred for 30 min and the conversion was checked by HPLC. Depending on the conversion, 0-5 mol% of N-bromosuccinimide was added and the mixture was stirred for another 15 min. After HPLC indicated that the conversion was complete, the reaction mixture was heated and acetonitrile (300 mL) was distilled out at normal pressure. Water (250 mL) was added and the temperature was adjusted to 50-55 ° C and a slurry was formed. The resulting slurry was stirred for 30 min and water (350 mL) was added over 1 h. The slurry was cooled to 20-25 ° C, stirred for 1 h and the solid was collected by filtration. The wet cake was washed with a mixture of water (75 mL) and acetonitrile (25 mL) to give the wet product 5-bromo-4-chloropyridin-2-amine (191 g, 92.1% purity according to HPLC area %). The wet product was dissolved in acetic acid (500 mL, 5 relative volumes based on 2-amino-4-chloropyridine, 55-70° C.) and the solution was used directly in the next step.

[0784] Step 2: Synthesis of 5-bromo-4-chloro-3-iodopyridin-2-amine

[0785] A solution of 5-bromo-4-chloropyridin-2-amine in acetic acid (191 g of 5-bromo-4-chloropyridin-2-amine in 500 mL of acetic acid) was distilled under reduced pressure at 40-60° C. to remove the solvent. Sulfuric acid (39.7 g, 96% w / w, 388.9 mmol, 0.5 eq) and iodine (76.2 g, 300.3 mmol, 0.386 eq) were then added and the temperature was adjusted to 77-83° C. At this temperature, a solution of periodic acid (50% w / w, 54.89 g, 120.4 mmol, 0.155 eq) was added over a period of 2-3 h. The reaction was stirred at 77-83° C. for 2-3 h and the conversion was checked by HPLC (SM <1.0% a / a). At 75-85°C, the reaction mixture is quenched by adding solid ammonium sulfite in portions of 4.53 g (0.05 equivalents) until the KI / starch test is negative. Typically, two portions (0.1 equivalents) of ammonium sulfite are required. The end of the quench can also be observed by the absence of a purple color of iodine. The reaction mixture is then diluted with water (200 mL, 2.0 relative vols, at room temperature) and the temperature is lowered to approximately 50°C. The product is precipitated. At 45-60°C, the pH is adjusted to 3.0-3.5 with aqueous ammonia (required 25%-w / w in water, approximately 63.6 g, 0.93 mol, 1.2 equivalents). Neutralization is strongly exothermic. The slurry is stirred at 45-50°C for 30 min and then the solid is collected by filtration. The filter cake is washed with typically approximately 600 mL of water and then with 2-propanol (200 mL). The wet product was dried in a vacuum chamber at 60° C. to give 5-bromo-4-chloro-3-iodopyridin-2-amine (213.5 g, 82.3% yield) as a yellow to beige solid: LCMS calculated for C5H4BrClIN2 [M+H] + : 332.82;Experimental value: 332.8; 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 1H), 6.60 (s, 2H).

[0786] Step 3: Synthesis of 5-bromo-4-chloro-3-(3-morpholinoprop-1-yn-1-yl)pyridin-2-amine

[0787] 5-Bromo-4-chloro-3-iodopyridine-2-amine (50g, 150mmol, 1.0 equivalent), 4-(prop-2-ynyl)morpholine (22.5g, 180mmol, 1.20 equivalent), diisopropylamine (18.2g, 180mmol, 1.2 equivalent) and 150mL of toluene were loaded into the reactor. The solution was carefully degassed and 3 vacuum argon cycles were applied. Then, CuI (0.29g, 1.5mmol, 1mol%) and Pd(PPh 3 ) 4 were added and the flask was purged with argon again. The mixture was stirred at 50 ℃ and spent the night (17h). Water (50mL, 1 volume) was added in bulk and the mixture was cooled to 20-25 ℃. The crude product was filtered off and washed successively with 10% aqueous ammonia (50 ml, 1.0 volume), water (50 ml, 1 volume), toluene (25 ml, 0.5 volume) and with 2-isopropanol (50 ml, 1.0 volume). After drying under vacuum at 50° C., 5-bromo-4-chloro-3-(3-morpholinoprop-1-yn-1-yl)pyridin-2-amine (41.6 g, 87% yield) was obtained as a light brown solid: C 12 H 14 LCMS calculated for BrClIN5O [M+H] + :329.99;Experimental value:330.0; 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),6.69(s,2H),3.64(s,2H),3.61(m,4H),2.54(m,4H).

[0788] Step 4: Synthesis of 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine

[0789] A solution of KOtBu (18.1 g, 1.4 eq, 112.21 mmol) in tetrahydrofuran (114 ml, 3 vol) was heated to 30-35° C. while 5-bromo-4-chloro-3-(3-morpholinoprop-1-yn-1-yl)pyridin-2-amine (38 g, 114.9 mmol, 1.0 eq) was added portionwise at 30-35° C. over 1.0 h. After stirring for 2 h, the reaction was quenched with a solution of acetic acid (10.4 g, 172.4 mmol, 1.5 eq) in water (76 mL, 2 vol) and 76 mL of THF (76 mL) was removed by distillation. The solution was then heated to reflux and MeOH (38 mL, 1 vol) was added, and the resulting suspension was cooled to 23° C. over 1 h. After stirring at 23° C. for 0.5 h, the solid was filtered off and washed with water (38 ml, 1 volume) and MeOH (38 mL, 1 volume). 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (32.8 g, 86% yield) was obtained as a light brown powder after drying under vacuum at 50° C.: C 12 H 14 LCMS calculated for BrClIN5O [M+H] + : 329.99; experimental value: 329.8; 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.34(s,1H),6.40(s,1H),3.65(s,2H),3.58(m,4H),2.42(m,4H).

[0790] Step 5: Synthesis of 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine

[0791] A slurry of 4-((5-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (10 g, 30.25 mmol, 1.0 eq, assay 94%-w / w) and NaH (1.69 g, 60%, 42.35 mmol, 1.4 eq) in 38 mL of tetrahydrofuran was cooled to 0-5 ° C. while PhSO Cl (7.48 g, 42.35 mmol, 1.4 eq) was added over 1 h. After 1.5 h, HPLC indicated that the reaction was incomplete. Additional NaH (0.34 g, 0.3 eq) was added at which point gas evolution was observed. When HPLC showed the reaction was complete, the reaction mixture was quenched with a mixture of acetic acid (0.5 g) and water (15 mL) and methanol (15 mL). The pH was adjusted to 6.5 with caustic soda and the product was isolated by filtration. The wet cake was washed with 2-isopropanol (20 mL) and water (20 mL) and the wet product (14.8 g) was dried in a vacuum chamber to give 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (12.57 g, 86% yield) as a brown solid: C 18 H 18 LCMS calculated value of BrClIN3O3S [M+H] + :469.99;Experimental value:470.0; 1 H NMR (400MHz, DMSO-d6) δ8.56(s,1H),8.33(m,2H),7.73(m,1H),7.65(m,2H),6.83(s,1H),3.91(s,2H),3.53(m,4H),2.46(m,4H).

[0792] Step 6: Synthesis of 4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

[0793] To a suspension of 4-((5-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl)morpholine (5.0 g, 10.6 mmol, 1.0 equiv) in 50 mL of tetrahydrofuran was added iPrMgCl (6.9 mL, 2 M tetrahydrofuran solution, 13.80 mmol, 1.3 equiv) at -10 to 0 ° C. After stirring for 2 h, N,N-dimethylformamide (1.55 g, 21.2 mmol, 2.0 equiv) was added to the reaction solution at -5 to 0 ° C. for 0.5 h. The mixture was stirred at -5 to 0 ° C. for 0.5 h, then warmed to 23 ° C. for 0.5 h and stirred at 23 ° C. for 1 h. The pH was adjusted to 6-7 by adding 1.5 mL of acetic acid and 10 mL of water. 25 mL of MeOH and 15 mL of water were added to the biphasic mixture. After stirring for 1 h, the product was filtered off and washed with 20 mL of MeOH / water (1 / 1) and 30 mL of water. After drying under vacuum at 50° C., 4-chloro-2-(morpholinylmethyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.39 g, 76% yield) was obtained as an off-white powder: C 19 H 19 LCMS calculated value of ClN3O4S [M+H] + :420.07;Experimental value:420.0; 1 HNMR (400MHz, DMSO-d6) δ10.33(s,1H),8.76(s,1H),8.42(m,2H),7.74(m,1H),7.65(m,2H),6.98(s,1H),3.96(m,4H),3.564(m,4H),2.51(m,4H).

[0794] Example 4. Synthesis of 2,6-difluoro-3,5-dimethoxyaniline

[0795] Process 4.

[0796]

[0797] Step 1: Synthesis of methyl pentafluorobenzoate

[0798] To a solution of pentafluorobenzoic acid (40 Kg, 188.6 mol) in 68 L of methanol was added dropwise SOCl (29.2 Kg, 245.2 mol, 1.3 equivalents) at 20-50 ° C over 4.0 h. The mixture was then heated to reflux for 17 h. Methanol was removed by vacuum distillation, and the residue was dissolved in methyl tert-butyl ether (77 L). The solution was washed with saturated NaHCO (37 L), dried over MgSO, and evaporated to give methyl pentafluorobenzoate (39 kg, 91% yield) as a colorless oil: 1 H NMR (400MHz, CDCl3) δ3.90 (s, 3H).

[0799] Step 2: Synthesis of methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate

[0800] Methyl pentafluorobenzoate (39 Kg, 172.5 mol) and N,N-diisopropylethylamine (26.8 Kg, 207 mol, 1.2 equivalents) were dissolved in N-methylpyrrolidone (39 L). A solution of benzylamine (18.5 Kg, 172.5 mol, 1.0 equivalent) in 19.5 L of N-methylpyrrolidone was added dropwise over 3.5 h while maintaining the internal temperature below 50 ° C. The resulting thick yellow slurry was heated to 65 ° C and stirred for another 1 h. The mixture was poured into 195 L of aqueous acetic acid (10% acetic acid and 90% H2O), and the slurry was stirred for 1 h and filtered. The filter cake was washed with water and heptane and dried under vacuum at 35 ° C to give methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (38 Kg, 70% yield): 1 H NMR (400MHz, CDCl3) δ7.37(m,5H),4.67(m,2H),4.58(m,1H),3.93(s,3H).

[0801] Step 3: Synthesis of 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid

[0802] Methanol (72 L) containing methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (38 Kg, 121.3 mol) was stirred at room temperature under N2, and a solution of NaOMe in methanol (25 wt%, 110.8 Kg, 545.85 mol, 4.5 equivalents) was added dropwise over 3.0 h while maintaining the temperature below 50 °C. After heating to 65-70 °C for 18 h, 18 L of water was added to the reaction mixture and the resulting solution was stirred for 1 h. The solvent was removed by vacuum distillation. Water (54 L) was added and the resulting solution was acidified to pH 2 with 37% HCl. The mixture was extracted three times with ethyl acetate (54 Kg each time). The combined organic extracts were washed with water (43 L) and concentrated to dryness to form a solid. The solid was wet-triturated with heptane (43 L) to remove impurities. The solid was collected and dried under vacuum at 40 °C to give 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (35 Kg, 86% yield): 1 H NMR (400MHz, CDCl3) δ12.74(s,1H),7.37(m,5H),6.62(s,1H),4.67(m,2H),3.96(s,6H).

[0803] Step 4: Synthesis of n-benzyl-2,6-difluoro-3,5-dimethoxyaniline

[0804] 4-(Benzylamino)-3,5-difluoro-2,6-dimethoxybenzoic acid (17 Kg) was heated to 75-85°C under neat conditions for 3-4 hours under a nitrogen atmosphere. After the reaction was complete, 40 L of methyl tert-butyl ether and 20 L of 1 M NaOH were added. The mixture was stirred at room temperature for 30 minutes. The organic layer was separated and washed with water (20 L) and brine (20 L). The organic phase was concentrated under reduced pressure to give a crude product. The crude material was triturated with heptane and dried under vacuum at 35°C to give N-benzyl-2,6-difluoro-3,5-dimethoxyaniline (12 Kg, 82% yield): 1 H NMR (400MHz, CDCl3) δ7.35(m,5H),6.09(m,1H),4.53(m,2H),4.00(s,1H),3.85(s,6H).

[0805] Step 5: Synthesis of 2,6-difluoro-3,5-dimethoxyaniline

[0806] N-Benzyl-2,6-difluoro-3,5-dimethoxyaniline (24 kg, 85.9 mol) was dissolved in a mixed solvent of ethanol (120 L) and acetic acid (20 L), and ammonium formate (13.2 kg) and 1.68 kg of Pd / C were added. The mixture was heated at 50°C for 2-3 hours. The reaction mixture was then The mixture was stirred for 2 h in 4% ethanol and 8% t-butyl alcohol (15.2 kg, 93% yield) at room temperature.The mixture was filtered and dried under vacuum at 35 ° C to obtain 2,6-difluoro-3,5-dimethoxyaniline (15.2 kg, 93% yield) as a light brown solid: CH 10 LCMS calculated for F2NO2 [M+H] + :190.16;Experimental value:190.1; 1 H NMR (400MHz, DMSO-d6) δ6.16(m,1H),5.18(s,2H),3.78(s,6H).

[0807] Example 5

[0808] Preparation and characterization of Form I

[0809] A 100 L glass reactor and a 200 L glass reactor were assembled with an overhead stirrer, condenser, thermocouple, addition funnel, and nitrogen inlet, and each apparatus was purged with nitrogen. Methanol (1.39 L), methyl chloride (21.7 L), and crude 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (3330 g) were sequentially charged to the 100 L reactor, and the reaction mixture was heated to approximately 33 ° C and stirred at approximately 33 ° C for approximately 43 minutes until a clear solution was obtained. The reaction mixture was filtered through an in-line filter, and the reactor was rinsed through the filter using methyl chloride (2.1 L). The filtrate was partially concentrated under vacuum at about 30°C (using two rotary evaporators for convenience) to a target total volume of 15.5 L (about 4.6 L per kg of product loaded). The distillation residue (15.5 L) was charged to a 200 L reactor, using filtered methyl chloride (1.3 L) to aid transfer. The reaction mixture was heated to about 39°C and stirred for about 3 minutes until a clear solution was obtained. Finely filtered methyl tert-butyl ether (23.1 L) was charged while maintaining the reaction temperature at about 39°C. The reaction mixture was stirred at about 36°C for about 5.25 h, cooled to about 30°C, and stirred at about 23°C for about 10.5 hours. The reaction mixture was filtered, and the filter cake was washed with finely filtered methyl tert-butyl ether (3.3 L). The product was air-dried on the filter for approximately 3.25 h and then dried under vacuum at 25-50 °C to provide 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidin-2-one (3002 g, 91.0% yield) as a white to off-white solid: C 24 H 28 LCMS calculated for F2N5O4 [M+H] + :488.20;Experimental value:488.2; 1 H NMR(400MHz,DMSO-d6)δ11.74(s,1H),7.92(s,1H),7.05(m,1H),6.48(s,1H), 4.75(s,2H),4.15(m,2H),3.90(s,6H),3.60(m,6H),2.44(m,4H),1.33(m,3H).

[0810] Based on XRPD analysis, the solid product was confirmed to be a crystalline solid having Form I. Figure 1 The XRPD pattern of Form I is shown in and the peak data are given in Table 1 below.

[0811] Table 1. XRPD peak data for Form I

[0812]

[0813]

[0814] Form I exhibits a DSC thermogram having endothermic peaks at temperatures of about 201 °C and about 276 °C. Figure 2 The DSC thermogram of Form I is shown. Figure 3 The TGA thermogram of Form I is shown.

[0815] Example 6

[0816] Crystalline form screening methods and results

[0817] New crystalline forms of the compound of formula I were obtained by various screening methods described below. Unless otherwise stated, Form I as described above in Example 5 was used as starting material in the screens.

[0818] Solubility measurement

[0819] Form I was saturated in different solvent systems (Table 2) at 25°C and 50°C, stirred for 24 h and its solubility was measured by HPLC. Form I was found to be completely soluble (>50 mg / mL) in a number of solvents including DMF (50°C), DCM, chloroform, DMSO and DCM / MeOH (9 / 1) at 25°C and 50°C. It was also found to be soluble in most other solvents at 25°C, but was practically insoluble in water, heptane and hexane, and slightly soluble in MTBE, toluene, IPAc, methanol and IPA. Its solubility generally increased in all solvents at 50°C.

[0820] Table 2: Solubility Screening

[0821]

[0822] Note: 1. Solubility of Form II in DCM; 2. Solubility of Form III in 1,4-dioxane; 3. Solubility of Form VI in methanol; 4. Solubility of Form VII in MIBK; 5. Solubility of Form XIII in THF; 6. Solubility of Form VIII in acetone; 7. Solubility of Form IX in MTBE; 8. After stirring a clear solution of 60 mg of Form I in 1 mL of DMSO, a slurry was obtained and the solubility of the saturated solution was 6.13 mg / mL. 9. Solubility of Form X in ethyl acetate; 10. Solubility of Form XI in ethyl formate

[0823] Phase equilibrium screening at 25, 40, and 50°C

[0824] Phase equilibrium studies were designed to provide information on the dominant crystalline form for phase identification. Based on the solubility of Form I in various solvent systems (Table 2), equilibrium was achieved in a representative set of solvents at 25 ± 1 °C (Table 3), 40 °C (Table 4a), and 50 ± 1 °C (Table 4). After equilibrium, the supernatant was removed by centrifugation or the solid was filtered. XRPD was used to investigate the solid state morphology of the crystalline form.

[0825] Phase equilibrium at 25 °C produced several polymorphic forms, including Form II (DCM, 9:1 DCM-MeOH), Form III (1,4-dioxane, centrifugation), Form IV (1,4-dioxane, filtration), Form V (1,4-dioxane, crystalline solid from saturated solution), Form VI (MeOH), Form VII (MIBK), Form VIII (acetone and MEK), Form IX (MTBE), Form X (ethyl acetate), Form XI (ethyl formate), and partially amorphous or amorphous forms (DMF, DMSO, and water).

[0826] Phase equilibrium at 40°C yielded Form II (DCM, DCM / MeOH).

[0827] Phase equilibrium at 50°C produced two new polymorphic forms, including Form XII (1,4-dioxane) and Form XIII (THF). Form VII was produced from MIBK.

[0828] Table 3: Crystalline forms at phase equilibrium at 25°C

[0829]

[0830]

[0831] Table 4: Crystalline forms of phase equilibrium at 50°C

[0832]

[0833]

[0834] Table 4a: Crystalline forms at phase equilibrium at 40°C

[0835]

[0836] Evaporation screening at 25 and 50°C

[0837] Evaporation studies were performed to identify the dominant crystalline form during uncontrolled precipitation. Experiments that did not produce any particulate solids (i.e., clear films and oils) were not investigated further. XRPD was used at 25° C. and 50° C. to investigate the solid-state morphology of the crystalline form of the evaporated samples. The results are presented in Table 5 (25° C.) and Table 6 (50° C.).

[0838] Table 5: Crystal form identification by evaporation at 25°C

[0839]

[0840]

[0841] N / A: Not available. Ether clear solution or precipitate in an amount too small to be analyzed by XRPD.

[0842] Table 6: Crystal form identification by evaporation at 50°C

[0843]

[0844]

[0845] N / A: Not available. Ether clear solution or precipitate in an amount too small to be analyzed by XRPD.

[0846] Antisolvent addition screening

[0847] Saturated or near-saturated solutions of Compound 1 were prepared by adding Form 1 to a solvent. Antisolvents were added to induce precipitation. Heptane, hexane, MTBE, water, MeOH, IPA, IPAc, ethyl acetate, and toluene were selected as antisolvents. Experiments that did not produce any particulate solids after antisolvent addition were not further studied.

[0848] Antisolvent addition resulted in several polymorphic forms, including Form XVIII (chloroform / hexanes, DCM / toluene, and DCM-MeOH / toluene) and Form XIX (DCM / MeOH).

[0849] Table 7. Antisolvent Addition

[0850]

[0851]

[0852] Note: N / A: Not available, sample too small to analyze by XRPD

[0853] 1. The concentration of compound 1 in chloroform is 83.7 mg / mL

[0854] 2. The concentration of compound 1 in DCM is 92 mg / mL

[0855] 3. The concentration of compound 1 in DCM / MeOH (9:1) is 80 mg / mL

[0856] Add filter in reverse

[0857] Saturated or near-saturated solutions of Compound 1 were prepared in the solvents listed in Table 8 and added to a larger volume of a miscible antisolvent (i.e., heptane, hexane, MTBE, water, toluene, MeOH, IPA, and ethyl acetate). Experiments that did not produce any particulate solids after addition to the antisolvent were not further investigated.

[0858] Reverse addition yielded several polymorphic forms, including Form XX (DCM / MTBE), Form XXI (DCM / Toluene), and Form XXII (DCM-MeOH / MeOH), as well as Form IX (THF / MTBE).

[0859] Table 8. Reverse addition

[0860]

[0861]

[0862] Note: N / A: Not available, sample too small to analyze by XRPD

[0863] 1. The concentration of compound 1 in chloroform is 83.7 mg / mL

[0864] 2. The concentration of compound 1 in DCM is 55 mg / mL

[0865] 3. The concentration of compound 1 in DCM / MeOH (9:1) is 80 mg / mL

[0866] Quenching of saturated solution

[0867] The saturated solution was quenched to approximately -20°C to induce precipitation of the higher energy form. Representative solvents were selected based on solubility data measured at 25°C and 50°C. The solvents studied and the crystal form of the sample in each solvent are shown in Table 4.

[0868] Quenching of the saturated solution yields Form XXIII (dichloromethane).

[0869] Table 9. Crystal form identification by quenching

[0870]

[0871]

[0872] N / A: Ether clear solution or precipitate in amount too small to analyze by XRPD.

[0873] Example 7

[0874] Stability of crystalline form

[0875] Crystallization of saturated solutions under heating and cooling cycles

[0876] Saturated solutions were prepared at 30°C or 50°C and slowly cooled in a bath using a programmed circulating bath. The resulting slurry was then heated to 50°C over 2 hours and then cooled to 5°C over 2 hours. This process was repeated for 3 days and the solids were filtered for further analysis. The results are presented in Table 10.

[0877] During the heating and cooling cycles (Table 10), two new forms were identified, including Form XXIV (DMF) and Form XXV (DMSO).

[0878] Table 10: Crystallization of saturated solutions under heating and cooling cycles

[0879]

[0880]

[0881] Mixed samples of compound 1 polymorphs in IPA, EtOH, and acetonitrile

[0882] To evaluate the conversion of solid forms of Compound 1, a competitive slurry experiment was performed as follows: Form I (5 mg) was added to a saturated solution of Form I in a solvent as listed in Table 11, followed by the addition of 5 mg of Form II to each of Forms XXVI.

[0883] The slurry was stirred overnight, filtered and analyzed by XRPD.The results in Table 11 indicate that Form I appears to be most stable in IPA, ethanol and acetonitrile.

[0884] Table 11. Mixed samples in different solvents (competitive slurries)

[0885] solvent Solid state form Isopropyl alcohol (1.7 mL) Form I Ethanol (1.7 mL) Form I Acetonitrile (1.7 mL) Form I

[0886] Mixed sample of compound 1 polymorphs in dichloromethane / methanol (9 / 1)

[0887] Competitive slurry experiments were performed in dichloromethane / methanol (9 / 1) according to the procedure in Table 12. As shown by XRPD at various time points, including 15 minutes, 1 hour, 18 hours, and 3 days, the mixture of forms (Forms I to XXVI) converted to Form II after 15 minutes, indicating that Form II was consistently obtained. Form II is a stable polymorph in the solvent system.

[0888] Table 12. Competitive slurry experiments

[0889]

[0890] Form II converts to Form I in different solvents

[0891] As described in Table 13, Form II was converted to Form I in acetonitrile, ethanol, and IPA, respectively.

[0892] Table 13. Conversion of Form II to Form I in different solvents

[0893] Operation Number Form II Solvent (mL) result 1 18mg MeCN (0.7) Form I 2 18mg IPA (0.7) Form I 3 18mg EtOH (0.7) Form I

[0894] Example 8

[0895] Preparation and characterization of Form II

[0896] Approximately 3 mL of a saturated solution of Form I in DCM was evaporated in air at 50 ± 1 °C without stirring to give a solid that was characterized as Form II by XRPD, DSC, and TGA.

[0897] Table 14. XRPD Peak Data for Form II

[0898] 2-θ high I％ 6.8 3218 100 8.0 46 1.4 9.5 412 12.8 12.8 134 4.2 13.3 118 3.7 16.3 102 3.2 17.5 53 1.6 19.0 134 4.2 19.4 63 2 20.5 115 3.6 22.6 382 11.9 25.8 505 15.7 26.2 679 21.1 27.4 247 7.7 29.4 63 2

[0899] Form II exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 276°C. Figure 5 The DSC thermogram of Form II is shown. Figure 6 The TGA thermogram of Form II is shown.

[0900] Example 9

[0901] Preparation and characterization of Form II-a

[0902] About 3 mL of a saturated solution of Compound 1, Form I in DCM was evaporated in air at 25±1°C without stirring to give a solid, which was characterized as Form II-a by XRPD, DSC, and TGA.

[0903] Table 15. XRPD Peak Data for Form II-a

[0904] 2-θ high I％ 4.6 43 2.5 6.9 1742 100 9.4 751 43.1 10.1 53 3 12.9 197 11.3 13.3 246 14.1 14.5 115 6.6 15.1 131 7.5 16.3 391 22.4 17.5 265 15.2 19.0 221 12.7 19.9 449 25.8 22.0 196 11.3 22.5 577 33.1 24.3 116 6.7 26.1 977 56.1 27.4 260 14.9 30.6 106 6.1 36.6 75 4.3

[0905] Form II-a exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 275°C. Figure 8 The DSC thermogram of Form Ha is shown. Figure 9 The TGA thermogram of Form Ha is shown.

[0906] Example 10

[0907] Preparation and characterization of Form III

[0908] To about 5 mL of a turbid solution of Compound 1, Form I prepared in 1,4-dioxane was added about 20 mg of Compound 1, Form I, followed by stirring at 25±1° C. for 2 days and removing the supernatant by centrifugation. The solid was analyzed by XRPD to be Form III.

[0909] Table 16. XRPD Peak Data for Form III

[0910] 2-θ high I％ 3.5 532 50.1 6.7 151 14.2 7.4 37 3.5 8.5 203 19.1 9.3 56 5.3 9.9 113 10.7 10.7 109 10.3 11.3 38 3.6 13.9 627 59.1 15.0 388 36.6 15.3 493 46.5 16.0 170 16 16.8 366 34.5 18.6 1061 100 19.3 209 19.7 20.5 104 9.8 21.5 478 45.1 22.1 98 9.2 22.9 253 23.8 23.4 193 18.2 24.2 392 36.9 25.2 58 5.5 25.9 257 24.2 26.5 107 10.1 27.6 71 6.7 28.2 115 10.8 29.3 136 12.8 30.2 96 9 30.9 60 5.7 31.2 62 5.8 32.5 60 5.7 33.1 73 6.9 34.4 54 5.1 36.1 60 5.7 41.0 70 6.6 42.7 42 4 43.2 36 3.4

[0911] Form III exhibits a DSC thermogram having endothermic peaks at temperatures of about 101 °C, about 204 °C, and about 276 °C. Figure 11 The DSC thermogram of Form III is shown. Figure 12 The TGA thermogram of Form III is shown.

[0912] Example 11

[0913] Preparation and characterization of Form IV

[0914] To approximately 5 mL of a saturated or turbid solution of Compound 1, Form I prepared in 1,4-dioxane was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25±1° C. for 6 days, which was filtered and analyzed by XRPD as Form IV.

[0915] Table 17. XRPD Peak Data for Form IV

[0916]

[0917]

[0918] Form IV exhibits a DSC thermogram having endothermic peaks at temperatures of about 109°C, about 203°C, and about 278°C. Figure 14 The DSC thermogram of Form IV is shown. Figure 15 The TGA thermogram of Form IV is shown.

[0919] Example 12

[0920] Preparation and characterization of Form V

[0921] A saturated solution of Compound 1, Form I was placed in a fume hood for over 30 days to give a crystalline solid that was filtered and analyzed as Form V by XRPD.

[0922] Table 18. XRPD Peak Data for Form V

[0923] 2-θ high I％ 6.7 833 1.3 7.4 64827 100 9.5 70 0.1 10.9 518 0.8 11.5 823 1.3 12.4 104 0.2 13.8 761 1.2 14.8 17728 27.3 15.3 750 1.2 16.1 243 0.4 17.0 268 0.4 17.4 850 1.3 18.2 140 0.2 19.2 226 0.3 20.2 219 0.3 20.5 840 1.3 21.3 2445 3.8 22.0 1989 3.1 22.3 11335 17.5 23.2 478 0.7 23.9 313 0.5 24.2 148 0.2 25.9 331 0.5 26.3 217 0.3 26.7 649 1 27.2 195 0.3 28.1 331 0.5 29.2 690 1.1 30.0 88 0.1 30.4 94 0.1 31.6 137 0.2 33.1 219 0.3 34.4 87 0.1 35.2 91 0.1 36.8 184 0.3 37.6 829 1.3 42.9 219 0.3

[0924] Form V exhibits a DSC thermogram having endothermic peaks at temperatures of about 91 °C, about 203 °C, and about 276 °C. Figure 17 The DSC thermogram of Form V is shown.

[0925] Example 13

[0926] Preparation and characterization of Form VI

[0927] To approximately 5 mL of a saturated or turbid solution of Compound 1, Form I prepared in methanol was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 3 days, which was filtered and analyzed by XRPD as Form VI.

[0928] Table 19. XRPD Peak Data for Form VI

[0929] 2-θ high I％ 7.8 102 10.3 9.1 757 76.6 9.5 388 39.3 10.2 230 23.3 11.4 279 28.2 12.1 278 28.1 12.6 106 10.7 13.4 188 19 14.4 464 47 15.9 234 23.7 17.6 514 52 18.6 458 46.4 19.2 324 32.8 19.9 443 44.8 20.4 77 7.8 21.0 75 7.6 22.3 716 72.5 22.7 265 26.8 23.4 66 6.7 24.1 83 8.4 25.4 536 54.3 26.2 988 100 27.5 207 21 29.1 136 13.8 31.1 67 6.8 36.6 64 6.5

[0930] Form VI exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 275°C. Figure 19 Shown is the DSC thermogram of Compound 1, Form VI. Figure 20 Shown is the TGA thermogram of Compound 1, Form VI.

[0931] Example 14

[0932] Preparation and characterization of Form VII

[0933] To approximately 5 mL of a saturated or turbid solution of Compound 1, Form I prepared in methyl isobutyl ketone was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25±1° C. for 3 days, which was filtered and analyzed by XRPD as Form VII.

[0934] Table 20. XRPD Peak Data for Form VII

[0935] 2-θ high I％ 8.2 116 15.1 9.8 768 100 12.3 96 12.5 15.4 519 67.6 16.0 84 10.9 16.2 132 17.2 17.4 93 12.1 17.9 223 29 18.8 375 48.8 19.6 554 72.1 20.1 357 46.5 21.1 266 34.6 22.3 191 24.9 22.8 127 16.5 23.1 130 16.9 23.7 112 14.6 24.3 236 30.7 25.5 139 18.1 26.7 74 9.6 27.6 48 6.3 29.3 62 8.1 29.7 67 8.7 30.5 40 5.2 32.1 37 4.8 35.9 32 4.2 38.6 58 7.6 42.1 56 7.3

[0936] Form VII exhibits a DSC thermogram having endothermic peaks at temperatures of about 88°C, about 201°C, and about 276°C. Figure 22 The DSC thermogram of Form VII is shown. Figure 23 The TGA thermogram of Form VII is shown.

[0937] Example 15

[0938] Preparation and characterization of Form VIII

[0939] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in acetone was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 3 days, which was filtered and analyzed by XRPD as Form VIII.

[0940] Table 21. XRPD Peak Data for Form VIII

[0941] 2-θ high I％ 9.1 953 39.6 9.9 196 8.1 15.2 409 17 16.7 650 27 18.2 2409 100 18.6 589 24.4 20.2 2079 86.3 21.4 196 8.1 22.5 768 31.9 23.8 64 2.7 24.6 701 29.1 25.4 83 3.4 26.8 376 15.6 27.5 123 5.1 29.8 376 15.6 30.6 64 2.7 31.4 239 9.9 32.0 61 2.5 34.8 87 3.6 35.9 162 6.7 40.0 50 2.1

[0942] Form VIII exhibits a DSC thermogram with endothermic peaks at temperatures of about 201 °C and about 277 °C. Figure 25 Shown is the DSC thermogram of Compound 1, Form VIII. Figure 26 Shown is the TGA thermogram of Compound 1, Form VIII.

[0943] Example 16

[0944] Preparation and characterization of Form VIII-a

[0945] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in methyl ethyl ketone was added approximately 30 mg of Compound 1, Form I, followed by stirring at 50±1° C. for 2 days, which was filtered and analyzed by XRPD as Form VIII-a.

[0946] Table 22. XRPD Peak Data for Form VIII-a

[0947]

[0948]

[0949] Example 17

[0950] Preparation and characterization of Form IX

[0951] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in MTBE was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 3 days, which was filtered and analyzed by XRPD as Form IX.

[0952] Table 23. XRPD Peak Data for Form IX

[0953] 2-θ high I％ 8.5 424 31 9.2 982 71.8 12.1 521 38.1 13.9 304 22.2 14.6 813 59.5 15.6 692 50.6 16.8 361 26.4 18.6 893 65.3 19.3 413 30.2 22.4 1188 86.9 22.9 1367 100 24.6 528 38.6 26.1 107 7.8 29.4 259 18.9 30.1 98 7.2 31.4 339 24.8 32.8 62 4.5 35.7 67 4.9

[0954] Form IX exhibits a DSC thermogram having endothermic peaks at temperatures of about 201 °C and about 276 °C. Figure 29 The DSC thermogram of Form IX is shown. Figure 30 The TGA thermogram of Form IX is shown.

[0955] Example 18

[0956] Preparation and characterization of Form X

[0957] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in ethyl acetate was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 3 days, which was filtered and analyzed as Form X by XRPD.

[0958] Table 24. XRPD Peak Data for Form X

[0959] 2-θ high I％ 4.9 113 9.6 10.1 971 82.7 11.3 167 14.2 12.3 95 8.1 13.7 63 5.4 14.6 696 59.3 15.4 603 51.4 15.7 1174 100 17.2 186 15.8 18.1 974 83 19.5 245 20.9 20.0 637 54.3 22.3 912 77.7 23.8 234 19.9 25.3 370 31.5 25.7 495 42.2 26.3 579 49.3 30.3 56 4.8 30.9 56 4.8 32.0 128 10.9 34.4 101 8.6 37.8 46 3.9

[0960] Form X exhibits a DSC thermogram having endothermic peaks at temperatures of about 202°C and about 276°C. Figure 32 The DSC thermogram of Form X is shown. Figure 33 The TGA thermogram of Form X is shown.

[0961] Example 19

[0962] Preparation and characterization of Form XI

[0963] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in ethyl formate was added approximately 20 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 3 days, which was filtered and analyzed by XRPD as Form XI.

[0964] Table 25. XRPD Peak Data for Form XI

[0965] 2-θ high I％ 3.9 381 42.9 4.3 231 26 7.5 548 61.6 8.6 70 7.9 11.8 70 7.9 13.0 889 100 13.7 167 18.8 15.0 156 17.5 16.5 104 11.7 17.3 377 42.4 19.1 207 23.3 19.9 340 38.2 21.4 557 62.7 22.2 117 13.2 22.8 442 49.7 23.7 86 9.7 24.6 68 7.6 25.2 646 72.7 26.2 418 47 26.9 255 28.7 27.7 178 20 29.4 131 14.7 30.3 115 12.9 31.0 83 9.3 31.5 66 7.4 33.3 125 14.1 33.9 67 7.5 35.7 78 8.8 37.4 54 6.1 40.3 59 6.6 42.6 56 6.3

[0966] Form XI exhibits a DSC thermogram having endothermic peaks at temperatures of about 141 °C and about 279 °C. Figure 35 The DSC thermogram of Form XI is shown. Figure 36 The TGA thermogram of Form XI is shown.

[0967] Example 20

[0968] Preparation and characterization of Form XII

[0969] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in 1,4-dioxane was added approximately 30 mg of Compound 1, Form I, followed by stirring at 50±1° C. for 2 days, which was filtered and analyzed by XRPD as Form XII.

[0970] Table 26. XRPD Peak Data for Form XII

[0971] 2-θ high I％ 3.9 151 12.4 7.5 161 13.3 9.8 199 16.4 11.5 112 9.2 12.9 233 19.2 14.1 721 59.4 14.9 87 7.2 17.3 391 32.2 18.3 797 65.7 20.5 128 10.6 22.1 1213 100 22.7 719 59.3 23.6 140 11.5 24.3 408 33.6 26.3 844 69.6 26.9 178 14.7 28.3 69 5.7 30.5 138 11.4 32.6 71 5.9 34.1 154 12.7 36.3 89 7.3 37.8 119 9.8 39.5 70 5.8

[0972] Form XII exhibits a DSC thermogram with endothermic peaks at temperatures of about 105°C and about 276°C. Figure 38 The DSC thermogram of Form XII is shown. Figure 39 The TGA thermogram of Form XII is shown.

[0973] Example 21

[0974] Preparation and characterization of Form XIII

[0975] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in THF was added approximately 30 mg of Compound 1, Form I, followed by stirring at 50 ± 1 °C for 2 days, which was filtered and analyzed by XRPD as Form XIII.

[0976] Table 27. XRPD Peak Data for Form XIII

[0977] 2-θ high I％ 4.0 162 11.3 7.7 1438 100 10.9 166 11.5 11.6 175 12.2 14.2 302 21 15.2 629 43.7 15.7 1150 80 16.6 78 5.4 17.8 368 25.6 19.0 424 29.5 21.9 922 64.1 22.2 436 30.3 23.1 1034 71.9 25.6 595 41.4 26.1 1333 92.7 31.6 89 6.2 34.8 80 5.6 37.0 143 9.9

[0978] Form XIII exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 276°C. Figure 41 The DSC thermogram of Form XIII is shown. Figure 42 The TGA thermogram of Form XIII is shown.

[0979] Example 22

[0980] Preparation and characterization of Form XIII-a

[0981] About 10 mL of a saturated solution of Compound 1, Form I prepared in THF at 35 °C was quenched to about -20 °C and maintained at that temperature for 3 h to give a thin slurry that was filtered and analyzed by XRPD as Form XIII-a.

[0982] Table 28. XRPD Peak Data for Form XIII-a

[0983] 2-θ high I％ 3.6 132 4.8 6.9 1047 38.2 7.7 2739 100 8.3 289 10.6 9.5 156 5.7 10.4 760 27.7 10.9 208 7.6 11.4 169 6.2 12.1 259 9.5 14.4 241 8.8 15.2 864 31.5 17.3 223 8.1 18.6 425 15.5 19.7 565 20.6 20.1 177 6.5 20.6 113 4.1 21.5 687 25.1 22.3 297 10.8 22.6 562 20.5 23.0 459 16.8 25.5 541 19.8 26.2 942 34.4 27.5 233 8.5 28.3 160 5.8 31.2 88 3.2

[0984] Form XIII-a exhibits a DSC thermogram with endothermic peaks at temperatures of about 75°C and about 276°C. Figure 44 The DSC thermogram of Form XIIIa is shown.

[0985] Example 23

[0986] Preparation and characterization of Form XIV

[0987] Approximately 2.0 mL of a saturated solution of Compound 1, Form I in DMF was evaporated in air at 25 ± 1 °C without stirring and the resulting solid was analyzed by XRPD as Form XV.

[0988] Table 29. XRPD Peak Data for Form XIV

[0989] 2-θ high I％ 7.0 722 84.5 8.6 175 20.5 9.2 179 21 9.6 249 29.2 10.3 241 28.2 11.5 218 25.5 12.2 173 20.3 12.8 79 9.3 13.5 62 7.3 14.1 854 100 14.5 289 33.8 16.1 488 57.1 16.8 55 6.4 17.6 246 28.8 18.3 240 28.1 18.7 198 23.2 19.3 283 33.1 20.0 805 94.3 20.9 136 15.9 22.0 661 77.4 22.3 407 47.7 22.9 339 39.7 23.6 123 14.4 24.0 70 8.2 25.8 774 90.6 26.2 365 42.7 27.5 97 11.4 29.0 106 12.4 30.2 66 7.7 33.2 45 5.3 34.7 90 10.5 36.7 47 5.5

[0990] Form XIV exhibits a DSC thermogram having endothermic peaks at temperatures of about 78°C, about 118°C, and about 277°C. Figure 46 The DSC thermogram of Form XIV is shown. Figure 47 The TGA thermogram of Form XIV is shown.

[0991] Example 24

[0992] Preparation and characterization of Form XV

[0993] Approximately 2.0 mL of a saturated solution of Compound 1, Form I in DMSO was evaporated in air at 25 ± 1 °C without stirring and the resulting solid was analyzed by XRPD as Form XV.

[0994] Table 30. XRPD Peak Data for Form XV

[0995] 2-θ high I％ 3.9 120 8.1 8.9 172 11.6 9.2 419 28.2 14.3 59 4 15.2 59 4 15.6 279 18.8 16.6 183 12.3 18.5 1485 100 19.8 74 5 20.3 294 19.8 21.1 122 8.2 21.4 470 31.6 21.8 289 19.5 22.4 1467 98.8 23.2 86 5.8 23.8 133 9 24.5 221 14.9 24.9 220 14.8 25.5 129 8.7 25.8 218 14.7 27.2 136 9.2 28.0 97 6.5 29.4 129 8.7 30.0 320 21.5 31.1 339 22.8 31.9 267 18 32.4 208 14 33.2 342 23 33.7 135 9.1 35.1 93 6.3 36.0 55 3.7 36.7 109 7.3 37.2 70 4.7 38.7 83 5.6 40.0 56 3.8 42.8 160 10.8 43.1 126 8.5

[0996] Form XV exhibits a DSC thermogram with endothermic peaks at temperatures of about 119°C and about 276°C. Figure 49 The DSC thermogram of Form XV is shown. Figure 50 The TGA thermogram of Form XV is shown.

[0997] Example 25

[0998] Preparation and characterization of Form XVI

[0999] Approximately 4.0 mL of a saturated solution of Compound 1, Form I in THF was evaporated in air at 50±1° C. without stirring and the resulting solid was analyzed by XRPD as Form XVI.

[1000] Table 31. XRPD Peak Data for Form XVI

[1001]

[1002]

[1003] Form XVI exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 276°C. Figure 52 The DSC thermogram of Form XVI is shown. Figure 53 The TGA thermogram of Form XVI is shown.

[1004] Example 26

[1005] Preparation and characterization of Form XVII

[1006] Approximately 2.0 mL of a saturated solution of Compound 1, Form I in DMSO was evaporated in air at 50±1° C. without stirring and the resulting solid was analyzed by XRPD as Form XVII.

[1007] Table 32. XRPD Peak Data for Form XVII

[1008]

[1009]

[1010] Form XVII exhibits a DSC thermogram with endothermic peaks at temperatures of about 119°C and about 276°C. Figure 55 The DSC thermogram of Form XVII is shown. Figure 56 The TGA thermogram of Form XVII is shown.

[1011] Example 27

[1012] Preparation and characterization of Form XVIII

[1013] To approximately 1 mL of a saturated solution of Compound 1, Form I prepared in chloroform was added 3.0 mL of hexanes to give a slurry that was filtered and analyzed by XRPD as Form XVIII.

[1014] Table 33. XRPD Peak Data for Form XVIII

[1015]

[1016]

[1017] Form XVIII exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 276°C. Figure 58 The DSC thermogram of Form XVIII is shown. Figure 59 The TGA thermogram of Form XVIII is shown.

[1018] Example 28

[1019] Preparation and characterization of Form XIX

[1020] To approximately 0.5 mL of a saturated solution of Compound 1, Form I prepared in DCM was added 5.0 mL of methanol to give a slurry that was filtered and analyzed by XRPD as Form XIX.

[1021] Table 34. XRPD Peak Data for Form XIX

[1022] 2-θ high I％ 3.9 188 4.2 4.7 44 1 6.7 986 22.1 8.5 83 1.9 9.4 459 10.3 10.0 1260 28.3 11.3 189 4.2 12.0 151 3.4 12.6 106 2.4 13.6 593 13.3 14.3 257 5.8 14.9 232 5.2 15.7 106 2.4 16.7 205 4.6 17.4 971 21.8 18.0 4459 100 19.4 186 4.2 20.2 1645 36.9 20.5 420 9.4 21.4 1036 23.2 22.1 980 22 22.8 252 5.7 23.4 161 3.6 24.0 186 4.2 24.8 397 8.9 25.0 682 15.3 26.0 263 5.9 26.9 357 8 27.3 105 2.4 28.1 77 1.7 28.6 216 4.8 30.2 207 4.6 31.3 188 4.2 31.7 362 8.1 33.8 108 2.4 34.6 53 1.2 35.7 56 1.3 37.3 91 2 39.0 112 2.5 40.1 67 1.5 41.8 63 1.4 42.2 57 1.3

[1023] Form XIX exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 276°C. Figure 61 The DSC thermogram of Form XIX is shown. Figure 62 The TGA thermogram of Form XIX is shown.

[1024] Example 29

[1025] Preparation and characterization of Form XX

[1026] To 4.0 mL of MTBE was added 0.8 mL of a saturated solution of Compound 1, Form I prepared in dichloromethane to give a slurry that was filtered and analyzed by XRPD as XX.

[1027] Table 35. XRPD Peak Data for Form XX

[1028] 2-θ high I％ 3.6 121 1.4 9.2 8874 100 12.1 349 3.9 13.9 395 4.5 14.7 3145 35.4 15.6 1104 12.4 16.9 507 5.7 18.6 2044 23 19.4 187 2.1 21.1 84 0.9 22.3 1340 15.1 22.5 2189 24.7 23.0 5723 64.5 24.7 1414 15.9 25.5 232 2.6 26.1 140 1.6 28.3 66 0.7 29.5 1207 13.6 30.1 146 1.6 31.4 456 5.1 32.0 219 2.5 32.8 326 3.7 34.8 56 0.6 36.0 185 2.1 37.1 121 1.4 38.2 113 1.3 38.8 63 0.7 41.9 265 3

[1029] Form XX exhibits a DSC thermogram having endothermic peaks at temperatures of about 108°C, about 202°C, and about 277°C. Figure 64 The DSC thermogram of Form XX is shown. Figure 65 The TGA thermogram of Form XX is shown.

[1030] Example 30

[1031] Preparation and characterization of Form XXI

[1032] To 4.0 mL of toluene was added 0.8 mL of a saturated solution of Compound 1, Form I prepared in dichloromethane to give a slurry that was filtered and analyzed by XRPD as XXI.

[1033] Table 36. XRPD Peak Data for Form XXI

[1034] 2-θ high I％ 3.9 150 5.9 6.5 158 6.3 6.9 116 4.6 9.2 81 3.2 10.3 2523 100 11.3 130 5.2 12.2 187 7.4 13.2 319 12.6 14.2 1367 54.2 17.5 439 17.4 19.4 379 15 20.7 1031 40.9 21.5 112 4.4 22.6 1331 52.8 24.2 2072 82.1 26.5 149 5.9 27.1 458 18.2 28.5 147 5.8 33.3 57 2.3 35.8 77 3.1 36.8 125 5 42.9 102 4

[1035] Form XXI exhibits a DSC thermogram having endothermic peaks at temperatures of about 201 °C and about 277 °C. Figure 67 Shown is the DSC thermogram of Compound 1, Form XXI.

[1036] Example 31

[1037] Preparation and characterization of Form XXII

[1038] To 4.0 mL of methanol was added 0.8 mL of a saturated solution of Compound 1, Form I, prepared in a mixture of dichloromethane and methanol (9:1) to give a slurry that was filtered and analyzed by XRPD as XXII.

[1039] Table 37. XRPD Peak Data for Form XXII

[1040] 2-θ high I％ 3.5 118 6.1 4.7 70 3.6 6.8 1950 100 7.9 59 3 9.4 861 44.2 10.1 553 28.4 11.4 533 27.3 12.1 407 20.9 12.6 152 7.8 13.3 230 11.8 14.3 571 29.3 15.8 301 15.4 17.5 620 31.8 18.0 229 11.7 18.5 620 31.8 19.2 399 20.5 19.8 521 26.7 20.3 154 7.9 20.9 97 5 22.2 874 44.8 22.6 291 14.9 23.5 71 3.6 24.0 93 4.8 25.3 599 30.7 26.1 1022 52.4 27.4 214 11 29.0 159 8.2 30.9 79 4.1 31.6 51 2.6 34.5 47 2.4 36.4 64 3.3 39.5 46 2.4 40.0 50 2.6

[1041] Form XXII exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 276°C. Figure 69 Shown is the DSC thermogram of Compound 1, Form XXII.

[1042] Example 32

[1043] Preparation and characterization of Form XXIII

[1044] About 2 mL of a saturated solution of Compound 1, Form I in DCM was chilled to about -20 °C and maintained at that temperature for 3 h to give a slurry that was filtered and analyzed by XRPD as Form XXIII.

[1045] Table 38. XRPD Peak Data for Form XXIII

[1046] 2-θ high I％ 6.7 251 2.9 8.7 59 0.7 12.0 6208 72.1 12.7 7944 92.2 13.2 817 9.5 14.3 714 8.3 16.4 360 4.2 17.3 214 2.5 18.9 1521 17.7 19.6 923 10.7 21.0 3317 38.5 22.7 520 6 24.9 2536 29.4 25.6 8613 100 26.5 311 3.6 28.7 293 3.4 29.6 78 0.9 30.7 193 2.2 31.1 187 2.2 34.5 72 0.8 35.4 90 1 36.4 150 1.7 37.6 145 1.7 39.9 84 1 42.8 104 1.2 43.7 217 2.5

[1047] Form XXIII exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 277°C. Figure 71 The DSC thermogram of Form XXIII is shown. Figure 72 The TGA thermogram of Form XXIII is shown.

[1048] Example 33

[1049] Preparation and characterization of Form XXIV

[1050] A saturated solution of Compound 1, Form I in approximately 3 mL of DMF was prepared at 30° C. to 50° C. and slowly cooled to 25° C. in a bath using a programmed circulating bath. The resulting solution was heated to 50° C. over 2 hours and then cooled to 5° C. over 2 hours. This process was repeated for 76 hours and the solid was isolated by filtration and analyzed as Form XXIV by XRPD.

[1051] Table 39. XRPD Peak Data for Form XXIV

[1052]

[1053]

[1054] Form XXIV exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 277°C. Figure 74 The DSC thermogram of Form XXIV is shown. Figure 75 The TGA thermogram of Form XXIV is shown.

[1055] Example 34

[1056] Preparation and characterization of Form XXV

[1057] A saturated solution of Compound 1, Form I in approximately 2 mL of DMSO was prepared at 30° C. to 50° C. and slowly cooled to 25° C. in a bath using a programmed circulating bath. The resulting solution was heated to 50° C. over 2 hours and then cooled to 5° C. over 2 hours. This process was repeated for 76 hours and the solid was isolated by filtration and analyzed as Form XXV by XRPD.

[1058] Table 40. XRPD Peak Data for Form XXV

[1059]

[1060]

[1061] Form XXV exhibits a DSC thermogram with endothermic peaks at temperatures of about 113 °C and about 276 °C. Figure 77 The DSC thermogram of Form XXV is shown.

[1062] Example 35

[1063] Preparation and characterization of Form XXVI

[1064] Form V was dried under vacuum at 50 °C for 3 days to afford Form XXVI.

[1065] Table 41. XRPD Peak Data for Form XXVI

[1066] 2-θ high I％ 6.8 1089 98.6 9.4 198 17.9 9.9 1104 100 10.6 74 6.7 12.7 66 6 13.3 49 4.4 17.5 50 4.5 19.9 246 22.3 21.8 51 4.6 22.5 64 5.8 25.7 115 10.4 26.1 216 19.6 27.4 112 10.1 30.2 33 3 39.9 53 4.8

[1067] Example 36

[1068] Preparation and characterization of amorphous compound 1

[1069] To approximately 5 mL of a turbid solution of Compound 1, Form I prepared in water was added approximately 30 mg of Compound 1, Form I, followed by stirring at 25 ± 1 °C for 2 days, which was filtered and determined to be amorphous by XRPD.

[1070] Example A

[1071] FGFR enzyme assay

[1072] The inhibitor performance of compound 1 is measured in enzyme assay, and enzyme assay uses FRET measurement to measure peptide phosphorylation and detect product formation.Compound 1 is serially diluted in DMSO and the volume of 0.5 μ L is transferred to the hole of 384 orifice plates.For FGFR3, the FGFR3 enzyme (Millipore) of 10 μ L volumes diluted in assay buffer (50mM HEPES, 10mM MgCl , 1mM EGTA, 0.01% Tween-20 (Tween-20), 5mM DTT, pH 7.5) is added to plate and pre-incubated 5-10 minute.Suitable control (enzyme blank and enzyme without inhibitor) is included on plate.By the 10 μ L solution containing biotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO:1) and ATP (ultimate concentration is respectively 500nM and 140 μ M) in assay buffer is added to hole and initiates analysis.Plate is hatched 1 hour at 25 ℃. The reaction was terminated by adding 10 μL of quench solution (50 mM Tris, 150 mM NaCl, 0.5 mg / mL BSA, pH 7.8; 30 mM EDTA and 3.75 nM Eu-antibody PY20 and 180 nM PC-streptavidin in Perkin Elmer Lance reagent) per well. The plate was allowed to equilibrate for approximately 1 hour, and then the wells were scanned on a PheraStar plate reader (BMG Labtech).

[1073] FGFR1 and FGFR2 were measured under the same conditions, with the following variations in enzyme and ATP concentrations: 0.02 nM and 210 μM for FGFR1, and 0.01 nM and 100 μM for FGFR2. Enzymes were purchased from Millipore or Invitrogen.

[1074] Data were analyzed using GraphPad Prism 3. IC values ​​were obtained by fitting the data to a sigmoidal dose-response equation with a variable slope. 50 Y=lowest value+(highest value-lowest value) / (1+10^((LogIC 50 =X)*HillSlope), where X is the logarithm of the concentration and Y is the response. 50 Compounds with concentrations of 1 μM or less were considered active.

[1075] According to the analysis described above, it was found that compound 1 of the present invention is an inhibitor of one or more of FGFR1, FGFR2 and FGFR3. The IC values ​​are provided in Table 1 below. 50 Data. The symbol "+" indicates IC 50 Less than 100 nM and the symbol "++" indicates IC 50 100 to 500 nM.

[1076] Table 42

[1077]

[1078] Example B

[1079] FGFR cell proliferation / survival assay

[1080] Viability assay is used to measure the ability of exemplary compounds to suppress the growth of cells that depend on FGFR signal transduction and survive. Recombinant cell lines that overexpress human FGFR3 are produced by stably transfecting mouse pro-B Ba / F3 cells (available from Deutsche Sammlung von Mikroorganismen und Zellkulturen) with a plasmid encoding full-length human FGFR3. Cells are selected in order for puromycin resistance and proliferation in the presence of heparin and FGF1. Single cell clones are separated and characterized for the functional expression of FGFR3. This Ba / F3-FGFR3 clone is used for cell proliferation analysis, and the compound is screened for the ability of compound to inhibit cell proliferation / survival. Ba / F3-FGFR3 cells are seeded into 96-well black cell culture plates with 3500 cells / well in the RPMI1640 culture medium containing 2% FBS, 20 μg / mL heparin and 5ng / mL FGF1. Cells were treated with 10 μL of a 10-fold serial dilution of compound (from 5 mM DSMO in serum-deficient medium) to a final volume of 100 μL per well. After 72 hours of incubation, 100 μL of Cell Titer was added to measure cellular ATP levels. Reagent (Promega Corporation) was added to each well. After 20 minutes of incubation under shaking, luminescence was read on a plate reader. Luminescence readings were converted to percent inhibition relative to DMSO-treated control wells, and IC was calculated using GraphPad Prism software by fitting the data to a sigmoidal dose-response equation with a variable slope. 50 IC 50Compounds with a concentration of 10 μM or less were considered active. Similar proliferation assays were performed on cell lines representing various tumor types, including KMS-11 (multiple myeloma, FGFR3 translocation), RT112 (bladder cancer, FGFR3 overexpression), KatoIII (gastric cancer, FGFR2 gene amplification), and H-1581 (lung cancer, FGFR1 gene amplification). In some experiments, the MTS reagent Cell Titer was added. AQueous single solution reagent (Promega Corporation) was used to a final concentration of 333 μg / mL in place of Cell Titer Glo and read on a plate reader at 490 / 650 nm. 50 Compounds with concentrations of 5 μM or less were considered active.

[1081] Example C

[1082] Cell-based FGFR phosphorylation analysis

[1083] The inhibitory effect of the compound on FGFR phosphorylation in relevant cell lines (Ba / F3-FGFR3, KMS-11, RT112, KatoIII, H-1581 cancer cell line and HUVEC cell line) can be evaluated using an immunoassay specific for FGFR phosphorylation. Depending on the cell line, cells are starved for 4 to 18 hours in a medium containing reduced serum (0.5%) and without FGF1, and then treated with various concentrations of individual inhibitors for 1-4 hours. For some cell lines, such as Ba / F3-FGFR3 and KMS-11, cells are stimulated for 10 minutes with heparin (20 μg / mL) and FGF1 (10 ng / mL). Whole cell protein extracts were prepared by incubation at 4° C. in a lysis buffer containing protease and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgCl 2 , 10% glycerol, 1% Triton X-100, 1 mM sodium orthovanadate, 1 mM sodium fluoride, aprotinin (2 μg / mL), leupeptin (2 μg / mL), pepstatin A (2 μg / mL), and phenylmethylsulfonyl fluoride (1 mM)]. Cell debris was cleared from the protein extracts by centrifugation at 14,000×g for 10 minutes and quantified using BCA (bicinchoninic acid) microplate assay reagent (Thermo Scientific).

[1084] The phosphorylation of the FGFR receptor in the protein extract was determined using immunoassay, including western blot, enzyme-linked immunosorbent assay (ELISA) or bead-based immunoassay (Luminex). For the detection of phosphorylated FGFR2, commercial ELISA kit DuoSet IC people's phospho-FGF R2α ELISA analysis (R&D Systems, Minneapolis, MN) can be used. For the analysis, Kato III cells were plated in 96-well flat-bottom tissue culture treated plates (Corning, Corning, NY) in the presence or absence of a certain concentration range of test compounds in 0.2% FBS supplemented Iscove's medium (50,000 cells per 100 μL per well) and incubated at 37°C, 5% CO2 for 4 hours. The analysis was stopped by adding 200 μL of cold PBS and centrifugation. Washed cells were lysed in cell lysis buffer (Cell Signaling, #9803) containing protease inhibitors (Calbiochem, #535140) and PMSF (Sigma, #P7626) on wet ice for 30 min. Cell lysates were frozen at -80°C and aliquots were tested using the DuoSet IC Human Phospho-FGF R2α ELISA Assay Kit. Data were analyzed using GraphPad prism3. IC values ​​were obtained by fitting the data to a sigmoidal dose-response equation with a variable slope. 50 value.

[1085] For the detection of phosphorylated FGFR3, carry out the immunoassay based on beads.Anti-human FGFR3 mouse mAb (R&DSystems, catalog number (Cat. No.) MAB7661) is bound to Luminex MAGplex microspheres, bead region 20 and is used as capture antibody.RT-112 cells are seeded into multi-well tissue culture plates and cultured until 70% convergence.Cells are washed with PBS and starved 18 hours in RPMI+0.5% FBS.At 37 ℃, 5% CO2, cells are treated with the serial dilution compound of 10 times of concentration of 10 μ L for 1 hour, then stimulated 10min with 10ng / mL human FGF1 and 20 μ g / mL heparin.Cells are washed with cold PBS and dissolved and centrifuged with cell extraction buffer (Invitrogen).Clear supernatant is frozen at-80 ℃ until analyzed.

[1086] For described analysis, cell lysate is diluted 1:10 in analysis diluent and is hatched 2 hours in 96 well filter plates together with the beads that capture antibody is combined on plate oscillator at room temperature.Use vacuum manifold that plate is washed three times and at room temperature under vibration, hatch 1 hour together with anti-phospho-FGF R1-4 (Y653 / Y654) rabbit polyclonal antibody (R&D Systems catalog number AF3285).By plate washing three times.Add the reporter antibody goat anti-rabbit-RPE binding antibody (Invitrogen catalog number LHB0002) of dilution and under vibration, hatch 30 minutes.By plate washing three times.Bead is suspended in washing buffer solution at room temperature under vibration and continues 5 minutes, then is set to each sample counting 50 events, and gate is set to read on the Luminex 200 instrument of 7500-13500.Data are represented with mean fluorescent intensity (MFI).The MFI value of the sample of compound treatment divided by DMSO control is determined to suppress percentage, and uses GraphPad Prism software to calculate IC 50 IC 50 Compounds with concentrations of 1 μM or less were considered active.

[1087] Example D

[1088] FGFR cell-based signaling analysis

[1089] The activation of FGFR leads to the phosphorylation of Erk protein. The detection of pErk is monitored using Cellu'Erk HTRF (homogeneous time-resolved fluorescence) analysis (CisBio) according to the manufacturer's protocol. KMS-11 cells are seeded into 96-well plates at 40,000 cells / well in RPMI culture medium containing 0.25% FBS and starved for 2 days. The culture medium is aspirated and the cells are treated with 30 μL of 1-fold concentration of serially diluted compounds (from the 5mM DSMO point with serum-deficient culture medium dilution) to a final volume of 30 μL per well and incubated at room temperature for 45 min. Stimulate cells by adding 10 μL of heparin (100 μg / mL) and FGF1 (50 ng / mL) to each well and incubate at room temperature for 10 min. After dissolution, aliquots of the cell extract are transferred to 384-well low-capacity plates, and 4 μL of detection reagent are added, followed by incubation at room temperature for 3 hours. The plates were read on a PheraStar instrument with settings for HTRF. Normalized fluorescence readings were converted to percent inhibition relative to DMSO-treated control wells, and IC was calculated using GraphPad Prism software. 50 IC 50 Compounds with concentrations of 1 μM or less were considered active.

[1090] Example E

[1091] VEGFR2 kinase assay

[1092] 40 μL enzyme reactions were performed in black 384-well polystyrene plates at 25°C for 1 hour. Each well was dotted with 0.8 μL of DMSO containing the test compound. The assay buffer contained 50 mM Tris, pH 7.5, 0.01% Tween-20, 10 mM MgCl2, 1 mM EGTA, 5 mM DTT, 0.5 μM biotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1), 1 mM ATP, and 0.1 nM enzyme (Millipore catalog number 14-630). The enzyme was quenched by adding 20 μL of 225 nM LANCE streptavidin. The reaction was stopped with APC (PerkinElmer catalog number CR130-100) and 4.5 nM LANCE Eu-W1024 anti-phosphotyrosine (PY20) antibody (PerkinElmer catalog number AD0067) in stop buffer (50 mM Tris, pH = 7.8, 150 mM NaCl, 0.5 mg / mL BSA, 45 mM EDTA). After incubation for 20 minutes at room temperature, the plate was read on a PheraStar FS plate reader (BMG Labtech). GraphPad Prism was used to calculate the IC by fitting the data to a sigmoidal dose-response equation with a variable slope. 50 IC 50 Compounds with concentrations of 1 μM or less were considered active.

[1093] Example F

[1094] Clinical Study Evaluating Compound 1 in the Treatment of Patients with Advanced / Metastatic or Surgically Unresectable Cholangiocarcinoma

[1095] This embodiment describes an ongoing Phase 2 clinical study to evaluate the efficacy of compound 1 in subjects with advanced / metastatic or surgically unresectable cholangiocarcinoma who have FGFR 2 translocation and who have failed at least one previous treatment. The study further evaluated the efficacy of compound 1 in subjects with advanced / metastatic or surgically unresectable cholangiocarcinoma with different molecular subgroups. The study also evaluated the safety of compound 1 in subjects with advanced / metastatic or surgically unresectable cholangiocarcinoma. Another goal is to identify and evaluate the covariates that can affect the pharmacokinetics of compound 1 in this subject population by population pharmacokinetic analysis. The study also considers exposure-response analysis for the main efficacy and safety parameters. This study further explores the pharmacodynamics and potential biomarkers of compound 1 in subjects with advanced / metastatic or surgically unresectable cholangiocarcinoma, and evaluates the impact of compound 1 on the quality of life of these subjects.

[1096] The study is an open label, monotherapy study of compound 1 with FGFR2 transposition, with other FGF / FGFR changes in patients with late / metastatic or surgically unresectable cholangiocarcinoma or subjects who are changed to negative for FGF / FGFR. The study recruited approximately 100 subjects to queue A (FGFR2 transposition), 20 subjects to queue B (other FGF / FGFR changes) and 20 subjects to queue C (only the U.S., which are changed to negative for FGF / FGFR). Subjects received 13.5mg of compound 1 once a day (QD) dosage of 2-week therapy and 1-week stop therapy schedule. Treatment will start on the 1st day. Subjects undergo regular safety evaluations and regular efficacy evaluations during treatment. Subjects are allowed to continue to apply with 21-day cycles until reported disease progression or unacceptable toxicity.

[1097] Compound 1 was self-administered as a QD oral treatment on a 2-week on-treatment and 1-week off-treatment schedule. Each dose of Compound 1 was taken upon waking or immediately after a 2-hour fast; subjects fasted for another 1 hour after taking Compound 1. Tablets were available in 2 mg and 4.5 mg strengths. The starting dose was 13.5 mg. One cycle was defined as 21 days. In addition to Compound 1, each tablet contained microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[1098] Study subjects were those with advanced / metastatic or surgically unresectable cholangiocarcinoma with FGFR2 translocation, with other FGF / FGFR alterations, or who were negative for any FGF / FGFR alteration and had failed at least 1 prior therapy.

[1099] The main inclusion criteria included males and females aged 18 years or older. Subjects had histologically or cytologically confirmed advanced / metastatic or surgically unresectable cholangiocarcinoma. Subjects in cohort A had FGFR2 translocation with a fusion partner documented in the central laboratory report. Subjects in cohort B had other FGF / FGFR alterations. Subjects in cohort C (US only) were negative for FGF / FGFR alterations. Additional main inclusion criteria included radiographically measurable disease according to RECIST version 1.1; documentation of FGF / FGFR gene alteration status; documented disease progression after at least 1 line of prior systemic therapy; ECOG performance status of 0 to 2; life expectancy greater than or equal to 12 weeks; adequate liver function; adequate renal function; serum phosphate ≤ institutional ULN; and serum calcium within the institutional normal range.

[1100] Major exclusion criteria included prior treatment with a selective FGFR inhibitor; history and / or current evidence of ectopic mineralization / calcification, including but not limited to soft tissue, kidney, intestine, myocardium, or lung, excluding calcified lymph nodes and asymptomatic arterial or cartilage / tendon calcifications; current evidence of clinically significant corneal or retinal disorders confirmed by ophthalmologic examination; and use of any potent CYP3A4 inhibitor or inducer (ketoconazole was permitted) within 14 days or 5 half-lives (whichever was shorter) prior to the first dose of study drug.

[1101] The study schedule and procedures are included in the research visits regularly arranged at the clinical site as part of the 21-day cycle. The research visits are started with pre-screening to obtain FGF / FGFR status (if unknown) (the results of screening within about 2 years are effective). Screening is carried out on the -28th day to the -1st day. Cycle 1 is carried out on the 1st day, the 8th day and the 15th day. Cycle 2+ is started on the 1st day. From the date of the last dose, 30 days (+5 days) of safety tracking are carried out. Every 9 weeks, the subject who stops due to reasons other than disease progression is followed up on disease state. After stopping, survival time is followed up every 12 weeks. Screening is allowed to be carried out for up to 28 days, and then continuous treatment is carried out with continuous 21-day cycles, as long as the subject benefits and does not meet any criteria for withdrawing from the study, and after the last dose of the study drug, 30 days (+5 days) of safety tracking are carried out. The research visits include collecting samples for hematology, chemistry, coagulation, endocrine monitoring, lipid and urinalysis tests. In addition, HIV screening (required for the subject outside the U.S.) and hepatitis screening (serology) are carried out when screening. Pregnancy testing will also be performed at screening, on Day 1 of each cycle prior to dosing, and at the end of treatment. FGF / FGFR status can be determined locally.

[1102] Tumor tissue was assessed by a central laboratory to confirm FGF / FGFR alteration status. Blood samples for population pharmacokinetic analysis and whole blood pharmacodynamic and related studies were collected at various time points during the study and analyzed at the central laboratory or designated institution.

[1103] Adverse event assessments, vital signs, electrocardiograms, physical examinations, comprehensive visual inspections of ECOG performance status, and tumor and disease response assessments were performed by the study site. Disease status was objectively assessed at screening. Subsequently, disease status was assessed every 2 cycles for the first 4 cycles and every 3 cycles thereafter, including RECIST radiation response assessments. A central radiology team provided centralized readings based on all assessments.

[1104] The primary endpoint of the study was the objective response rate (ORR) in subjects with FGFR2 translocations, as determined by central genomic laboratory results. The objective response rate was defined as the proportion of subjects who achieved a complete response (CR; disappearance of all target lesions) or a partial response (PR; a 30% or greater decrease in the sum of the longest diameters of lesions) according to RECIST, version 1.1. Clinical responses were determined by an independent radiology review committee.

[1105] Secondary endpoints included ORR in subjects with FGF / FGFR alterations that were not FGFR2 translocations (cohort B); ORR in all subjects with FGF / FGFR alterations (cohorts A and B); ORR in subjects with negative FGF / FGFR alterations (cohort C [US only]); progression-free survival (first dose to progressive disease or death; all cohorts); duration of response (time from CR or PR date until progressive disease; all cohorts); disease control rate (CR+PR+stable disease; all cohorts); overall survival (first dose to death from any cause; all cohorts); and population pharmacokinetics (all cohorts). In addition, safety and tolerability (all cohorts) were evaluated by assessing the frequency, duration, and severity of adverse events; by reviewing the results of physical examinations, changes in vital signs, and electrocardiograms; and by clinical laboratory blood and urine sample assessments.

[1106] Exploratory endpoints included analysis of baseline and post-treatment characteristics of tumor and blood samples related to response, resistance, and safety, including examination of plasma markers and tumor and blood cell characteristics. Additional exploratory endpoints included comparison of local genomic testing results with central genomic testing results. Finally, exploratory endpoints included quality of life assessments (European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire [EORTC QLQ]-C30 and EORTC QLQ-BIL21).

[1107] The primary analysis is to conduct on the subjects with FGFR2 transposition. It is planned to conduct the final analysis of the primary endpoint of ORR in approximately 100 subjects with FGFR2 transposition records from the central genomic laboratory. Under the assumption that a 33% rate is intervened, assuming 10% tracking loss, a sample size of approximately 100 subjects will provide> 95% of the possibility of having a 95% confidence interval with a lower limit of> 15%. Up to 20 subjects will be recruited in queues B and C (US only), respectively. If the potential ORR is 30%, this will provide> 80% of the chance of observing at least 4 responders in each queue.

[1108] Safety analyses were conducted on all patients who were enrolled in the study and received at least one dose of study drug; efficacy analyses were conducted on all patients who were enrolled in the study and received at least one dose of study drug and who had known FGF / FGFR alterations or negative FGF / FGFR alterations as determined by a central genomic laboratory.

[1109] The proportion of subjects with ORR and DCR will be estimated with 95% CI. PFS, DOR, and OS will be analyzed by the Kaplan-Meier method.

[1110] For Cohort A (FGFR2 translocation), a futility analysis will be performed when approximately 25 subjects have been enrolled in the cohort and have at least one tumor assessment or have permanently discontinued study treatment. If two or fewer responders are observed, Cohort A can be stopped for futility, for which an ORR > 15% is claimed based on a probability of less than 10% for a 60-subject cohort.

[1111] Cohorts B (other FGF / FGFR alterations) and C (US only; negative for FGF / FGFR alterations) may be discontinued if 1 or fewer responders are observed within the first 10 subjects with at least 2 cycles of data.

[1112] Initial data

[1113] The following initial data were obtained from a total of 91 patients in Cohort A, 22 patients in Cohort B, and 18 patients in Cohort C. Analysis of Cohort A data focused on the first 47 patients enrolled in Cohort A who were followed for greater than or equal to 8 months.

[1114] The median number of treatment cycles in Cohort A was 11 (range: 1-23); the median treatment duration was 217 days (range: 14-489 days). The median number of cycles in Cohort B was 2.5 (1-14); and the median treatment duration was 47.5 days (range: 7-287 days). The median number of cycles in Cohort C was 2.0 (1-7); and the median treatment duration was 39 days (range: 7-142 days).

[1115] The patient settings by cohort are summarized in Table 43 below.

[1116] Table 43.

[1117]

[1118] Baseline and disease characteristics presented for all cohorts are shown in Table 44. In cohort A, the median age of patients was 55 years (range: 26-76), 53.2% were female, and 98% had iCCA. In addition:

[1119] 98% of patients had ≤1 ECOGP

[1120] 49% of patients received ≥2 prior therapies

[1121] 94% of patients were from outside Asia

[1122] 66% of patients had stage 4 disease at the time of enrollment

[1123] ●A patient with a history of chronic hepatitis B or hepatitis C.

[1124] Table 44. Baseline and disease characteristics

[1125]

[1126]

[1127] The FGFR translocations in the patients are shown in Table 45. The most common FGFR2 translocation was FGFR2-BICC1 (29.8%), followed by FGFR2-AHCYL1 (4.3%), FGFR2-MACF1 (4.3%), and FGFR2 intron 17 rearrangement (4.3%).

[1128] Table 45. FGFR2 translocation in cohort A.

[1129]

[1130]

[1131] Preliminary efficacy data are shown in Table 46 below.

[1132] Table 46. Primary and secondary endpoints according to patient cohort (assessed by independent observer).

[1133]

[1134] NE = Not evaluable, upper limit not reached.

[1135] Table 46 shows the preliminary results of the primary endpoint. The ORR in Cohort A was 40.4%. 19 patients (40.4%) had a confirmed PR. 21 patients (44.7%) had a best response of stable disease.

[1136] For the secondary endpoint, the median duration of response (DOR) had not yet been reached in Cohort A; the likelihood of maintaining a response greater than or equal to six months was 86.2%. The disease control rate (DCR) was 85.1% in Cohort A. The DCRs in Cohorts B and C were 45.5% and 22.2%, respectively.

[1137] Figure 79 Shown are the best percent change in target lesion size from baseline according to the independent observer in patients with CCA and FGFR2 translocation (cohort A). Figure 80 Shown are the duration of treatment and responses confirmed by an independent observer in patients with CCA and FGFR2 translocation (cohort A).

[1138] Figure 81 The Kaplan-Meier estimates of progression-free survival (PFS) in cohorts A, B, and C are shown. PFS is defined as the time length from the start of study drug (Day 1) until the earlier death or disease progression according to RECIST as evaluated by an independent central radiological review committee. The inspection of PFS is subsequently carried out in the following cases: there is no baseline tumor evaluation, there is no sufficient baseline reaction evaluation, there is no progression, the research stops due to unrecorded progress, starts a new anticancer treatment, and after more than one lost evaluation, dies or progresses. As shown in Table 47 below, in cohort A, median PFS is 9.2 months. In cohorts B and C, median PFS is respectively 2.1 and 1.7 months. In cohort A, median OS is 15.8 months. In cohorts B and C, median OS is respectively 6.8 and 4.0 months.

[1139] Table 47.

[1140]

[1141] Table 48. Number of patients at risk

[1142]

[1143] Safety and tolerability

[1144] The most common treatment-emergent adverse events (TEAEs) in all patients were hyperphosphatemia (60.7%), alopecia (41.6%), diarrhea (39.3%), decreased appetite (37.1%), fatigue (36.0%), and dysgeusia (36.0%). Hyperphosphatemia was managed with diet, phosphate binders, or dose modifications. TEAEs of grade 3 or higher in greater than 5% of all patients included hypophosphatemia (13.5%), hyponatremia (7.9%), abdominal pain (6.7%), and arthralgia (6.7%). Five patients had TEAEs with fatal outcomes, none of which were related to study treatment: in cohort A, one patient died of failure to thrive; in cohort B, three patients died of abdominal distension, sepsis, malignant neoplasm progression, dyspnea, and pleural effusion; and in cohort C, one patient died of cholangitis. The most common TEAEs and TRAEs are shown in Table 49 below.

[1145]

[1146] in conclusion

[1147] In this interim analysis of patients from a cohort with at least 8 months of follow-up, Compound 1 was generally well tolerated and demonstrated preliminary efficacy in previously treated patients with CCA who had FGFR2 translocation. The ORR was 40.4%. The most common TEAEs included hyperphosphatemia, alopecia, and diarrhea. These results support continued development of Compound 1 as a treatment for patients with CCA who had FGFR2 translocation.

[1148] Example G. Clinical Study Evaluating Compound 1 in the Treatment of Patients with Spinal Cord / Lymphoid Neoplasms with FGFR1 Rearrangements

[1149] This example describes an ongoing Phase 2 clinical study to evaluate the efficacy of Compound 1 in subjects with spinal cord / lymphoid neoplasms who have an FGFR1 rearrangement. The study further evaluated the safety of Compound 1 in subjects with spinal cord / lymphoid neoplasms who have an FGFR1 rearrangement. Additional exploratory objectives were to evaluate the pharmacokinetics, biomarkers, and quality of life of subjects with spinal cord / lymphoid neoplasms who were treated with Compound 1.

[1150] This study is an open-label, monotherapy study of compound 1 in subjects with spinal cord / lymphoid neoplasia with FGFR1 rearrangement. Subjects received a once-daily (QD) dose of 13.5 mg of compound 1 on a 2-week schedule of using therapy and 1-week stopping therapy. In addition, administration was adjusted so that newly recruited subjects received continuous administration of 13.5 mg of compound 1 (not maintaining the planned dose). If there were no persistent grade 2 or higher-grade related TEAEs, subjects receiving treatment according to the previous pattern could be switched to continuous administration after completing at least 3 cycles.

[1151] All potential subjects must have a record of the 8p11 translocation of known activated FGFR1 by the research site's own cytogenetic laboratory. After providing the record, the subject undergoes screening to meet the inclusion / exclusion criteria of the rest. After the subject has completed screening and has been recruited into the study, treatment begins on Cycle 1 Day 1. The subject undergoes regular safety evaluations and regular efficacy evaluations during treatment.

[1152] Subjects were allowed to continue dosing in 21-day cycles until no longer benefiting from therapy or unacceptable toxicity was reported.

[1153] Compound 1 was self-administered as a QD oral treatment on a 2-week on-treatment and 1-week off-treatment schedule or continuously (without maintaining the planned dose). Each dose of Compound 1 was taken upon waking or immediately after a 2-hour fast; subjects fasted for another 1 hour after taking the study drug. Tablets were available in 2 mg and 4.5 mg strengths. The starting dose was 13.5 mg. One cycle was defined as 21 days of treatment. In addition to Compound 1, each tablet contained microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.

[1154] The study population is a subject with spinal cord / lymphoid neoplasms with FGFR1 rearrangement. The main inclusion criteria include: males and females aged 18 years or older; a lymphoid or spinal cord neoplasm with 8p11 rearrangement known to cause FGFR1 activation based on a local standard diagnostic cytogenetic assessment before signing the informed consent for this study; a life expectancy of at least 12 weeks; and an ECOG performance status of 0 to 2. In addition, only subjects who are not candidates for stem cell transplantation or who have relapsed after stem cell transplantation and have delayed lymphocyte infusion and who have progressed and are not candidates for other disease-modifying therapies are suitable for the study. All relapsed / refractory subjects must have evidence of cytogenetic or hematological disease and no evidence of residual toxicity (e.g., graft-versus-host disease requiring treatment).

[1155] The main exclusion criteria included prior treatment with a selective FGFR inhibitor; a history of calcium and phosphate hemostatic disorders or systemic mineral imbalance with ectopic soft tissue calcification (exceptions: calcification commonly observed in soft tissues such as skin, kidney, tendon, or blood vessels due to injury, disease, and aging in the absence of systemic mineral imbalance); active CNS disease; and use of any effective cytochrome P450 3A4 inhibitor or inducer within 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug. Additional main exclusion criteria included current evidence of clinically significant corneal disorders / keratopathy (including but not limited to blister / band keratopathy, corneal abrasions, inflammation / ulceration, and keratoconjunctivitis, etc.) or retinal disorders (including but not limited to macular / retinal degeneration, diabetic retinopathy, retinal detachment, etc.) as confirmed by ophthalmological examination.

[1156] The study schedule and procedures are included in the research visits regularly arranged at the clinical site as part of the 21-day cycle. The research visits include screening (-28 days to -1 day);Cycle 1 (1st day, 8th day and 15th day [± 3 days]);Cycle 2+ (1st day [± 3 days]);The treatment ends (after permanently stopping the study drug);Safety tracking (30 days [+ 5 days] from the date of the last dose);Disease state (according to the nursing standard tracking subject until record progress);And survival time tracking (every 12 weeks). The research visits may include collecting samples for chemistry, hematology, coagulation, lipid analysis (lipid panel), endocrine monitoring and urinalysis testing. In addition, hepatitis screening (serology) is carried out when screening, and pregnancy test is carried out when screening, before dosage is applied and at the end of treatment, on the 1st day of each cycle. The sample of bone marrow aspirate or peripheral blood is sent to the central laboratory for confirming FGFR1 rearrangement, and is sent to the central lesion laboratory for analysis. In addition, each site provided slides and / or digitized images of bone marrow aspirates at baseline and upon response and sent them to the central disease team for review. Adverse event assessments, physical examinations, vital signs, ECGs, comprehensive visual inspections, ECOG performance status, and disease response assessments were performed by the study site.

[1157] After the subject is qualified by the research site laboratory, screening can be started. Screening is allowed to proceed for up to 28 days, followed by continuous treatment in a continuous 21-day cycle, as long as the subject benefits (as judged by the treating physician) and has not yet met any criteria for exiting the study. Safety tracking is 30 days (+5 days) after the last dose of study drug. In addition, the total survival time of the subject is tracked after stopping treatment with the study drug. The study participation time is expected to be an average of about 6 months for each individual subject.

[1158] The primary endpoint of the study was to determine the overall clinical benefit rate by achieving one of the following: complete response (CR; normalization of BM (bone marrow) and peripheral blood and complete regression of EMD (extramedullary disease)), partial response (PR; normalization of peripheral blood, complete regression of EMD and 50% reduction in BM blasts), complete hematologic response (CHR; normalization of peripheral blood), cytogenetic response, myeloid response or clinical benefit (erythroid response, platelet response, neutrophil response, eosinophil response and / or EMD response). A complete myeloid response was defined as the myeloid criteria required for a complete response in the absence of normalization of peripheral blood. A partial myeloid response was defined as a 50% reduction in BM blasts, but still >5%, or a decrease in the grade of reticulin fibrosis compared to baseline based on ≥2 BM assessments ≥2 months apart (if no excess blasts were present at baseline). A complete cytogenetic response (CCyR) was defined as 0% metaphase or FISH for 8p11 translocation. Partial cytogenetic response (PCyR) was defined as a ≥50% reduction in metaphase or FISH for 8p11 translocation compared to baseline.

[1159] Secondary endpoints included duration of response / benefit; progression-free survival; overall survival; and safety and tolerability as assessed by the frequency, duration, and severity of adverse events (assessed by review of physical examination findings, changes in vital signs, and electrocardiograms, as well as by clinical laboratory blood and urine samples). Exploratory endpoints included population PK parameters, tumor molecular and gene expression profiles; peripheral blood molecular and gene expression analysis, cytokine and plasma biomarker levels at baseline and changes with treatment; and quality of life assessments (European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire-30 and Myeloproliferative Neoplasm Symptom Assessment Form).

[1160] The final analysis of the primary endpoint of overall clinical benefit rate was planned to include approximately 46 subjects. Assuming a 35% rate of intervention and assuming 10% loss to follow-up, a sample size of 46 subjects would provide a >80% probability of a 95% confidence interval with a lower limit of >15%.

[1161] The overall clinical benefit rate, defined as the proportion of subjects achieving CR, PR, cytogenetic response, CHR, myeloid response, or clinical benefit, will be estimated with 95% confidence intervals. Progression-free survival, duration of response / benefit, and overall survival will be analyzed using the Kaplan-Meier method.

[1162] Initial data

[1163] The following initial data were obtained from a total of 14 patients. One patient did not have a FGFR 8p11 rearrangement known to result in FGFR1 activation and was excluded from the efficacy analysis. Patients received a median of 6 cycles of Compound 1 (range: 2-25 cycles).

[1164] The patient settings by cohort are summarized in Table 50 below.

[1165] Table 50. Patient Settings

[1166]

[1167] A summary of the demographics and disease characteristics of the patients treated is shown in Table 51 below.

[1168] Table 51. Baseline demographics and disease characteristics (N=14)

[1169]

[1170] a One patient in the MLN group did not have an FGFR1 8p11 rearrangement known to cause FGFR1 activity and was excluded from the efficacy analysis but was included in the safety analysis.

[1171] b A patient was identified as having not received prior treatment

[1172] The clinical and cytogenetic responses of the treated patients are shown in Table 52 below.

[1173] Table 52. Clinical and cytogenetic responses

[1174]

[1175] CBC = complete blood count; NGS = next-generation sequencing; PD = progressive disease; SD = stable disease

[1176] a The listed fusion partners were determined retrospectively by NGS and were not used to assess patient eligibility.

[1177] b CR: complete regression of bone marrow (BM) with <5% blasts and normocellularity, normal CBC, EMD; PR, same as CR except BM blasts (and blast equivalents) are reduced by 50%, but <5% remain fibrotic and dysplastic.

[1178] c CCyR: 0% abnormal metaphase; PCyR: ≥50% reduction in abnormal metaphase

[1179] dNot present at baseline.

[1180] Figure 82 A summary of clinical and cytogenetic responses is also shown in Table 53. As shown in Table 53 below, 11 of 13 evaluable patients (85%) achieved a clinical response, including both clinical and cytogenetic responses.

[1181] Table 53. Best Response

[1182] Best Response ORR CR(n) PR(n) <![CDATA[Clinical response a > 85％ 7 4 <![CDATA[Cytogenetic response b > 77％ 6 4

[1183] a CR: complete regression of bone marrow with <5% blasts and normocellularity, normal CBC, EMD; PR is the same as CR, except that bone marrow blasts (and blast equivalents) are reduced by 50%, but <5% remain fibrotic and dysplastic.

[1184] b CCyR, abnormal metaphase is 0%; PCyR, abnormal metaphase is reduced by ≥50%.

[1185] Figure 83 and Figure 84 Shown are the results of a patient with myeloproliferative and T-lymphoblastic lymphoma (TLL) before treatment with Compound 1 ( Figure 83 ) and after ( Figure 84 ) baseline PET scan. The patient is a 50-year-old male with myeloproliferation and TLL, who has received CHOEP chemotherapy (chemotherapy using cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone), and has no reaction. The patient exhibits para-aortic lymphadenopathy and large spleen. His cytogenetics shows ZMYM2-FGFR1 fusion. After 13.5mg is given compound 1 every day (2 weeks of use, 1 week of stopping), at 4 months (when cycle 6 begins), according to PET scan, the patient achieves complete cytogenetics relief and complete lymph node relief. In addition, splenomegaly subsides. The patient is still treated after more than 1.5 years, and side effects are minimal.

[1186] Safety and tolerability

[1187] Compound 1 was generally well tolerated. The most common treatment-related adverse events (TRAEs) were hyperphosphatemia (n=9; 64%; managed with diet and phosphate binders), diarrhea (n=5; 36%), alopecia (n=4; 29%), increased blood alkaline phosphatase (n=3, 21%), dyspepsia and fatigue, and stomatitis (n=2 each; 14%). Three patients had grade 3 TRAEs: diarrhea (n=1; leading to dose reduction); leukopenia (n=1); and increased alkaline phosphatase (n=1; leading to discontinuation of compound 1). Two patients had fatal TEAEs unrelated to treatment. One patient died due to multiple organ failure and disease progression. One patient died due to chloroma, spinal cord sarcoma, and septic shock.

[1188] in conclusion

[1189] Compound 1 showed clinical and cytogenetic activity. The clinical response rate was 65% (CR in 7 patients and PR in 4 patients). The major cytogenetic response rate was 77% (CCyR in 6 patients and PCyR in 4 patients). Compound 1 was generally well tolerated by patients in the study.

[1190] From the foregoing description, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is incorporated herein by reference in its entirety.

[1191] In summary, the present invention includes but is not limited to the following:

[1192] 1. A solid form of Compound 1 having the formula:

[1193]

[1194] wherein the solid form has crystalline Form I.

[1195] 2. The solid form of claim 1 , having one or more characteristic X-ray powder diffraction (“XRPD”) peaks selected ...

Claims

1. A solid form of Compound 1 having the formula: wherein the solid form has crystalline Form I.

2. The solid form of claim 1, having one or more characteristic X-ray powder diffraction ("XRPD") peaks selected from about 6.8, about 12.9, about 25.4, about 25.8, about 26.2, and about 27.5 degrees 2-theta.

3. The solid form of claim 1 or 2, having an XRPD pattern with characteristic peaks substantially as shown in FIG. 1 .

4. The solid form of any one of claims 1-3, having at least one endothermic peak at a temperature of about 276°C in a differential scanning calorimetry ("DSC") thermogram.

5. The solid form of any one of claims 1-3, having a DSC thermogram substantially as shown in Figure 2.

6. The solid form of any one of claims 1-3, having a thermogravimetric analysis ("TGA") thermogram substantially as shown in FIG.

3.

7. A solid form of Compound 1 having the formula: wherein the solid form has crystalline Form II, Form III, Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII, Form XIX, Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV or Form XXVI.

8. A solid form of Compound 1 having the formula: wherein the solid form is amorphous.

Images