salts of FGFR inhibitors

Abstract

To provide salt forms of the Fibroblast Growth Factor Receptors (FGFR) inhibitor, which is useful in the treatment of FGFR mediated diseases such as cancer.SOLUTION: The present invention provides a salt which is a salicylate 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, or a hydrate or solvate thereof. The salt is crystalline. The salt has at least one characteristic XRPD peak selected from 10.4° ±0.2° (2θ), 11.8° ±0.2° (2θ), 12.1° ±0.2° (2θ), 13.4° ±0.2° (2θ), and 13.9° ±0.2° (2θ).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a salt form (including a method for preparing the same) of a fibroblast growth factor receptor (FGFR) inhibitor (3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one), which is useful in the treatment of FGFR-mediated diseases (such as cancer). [Background technology]

[0002] Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases that bind to fibroblast growth factor (FGF) ligands. There are four ligand-binding FGFR proteins (FGFR1-4), and these FGFR proteins are involved in regulating many physiological processes, including tissue development, angiogenesis, wound healing, and metabolic regulation. Upon binding to a ligand, these receptors dimerize and undergo phosphorylation, stimulating protein kinase activity and recruiting numerous intracellular docking proteins. These interactions promote the activation of an array of intracellular signaling pathways crucial for cell growth, proliferation, and survival (including Ras-MAPK, AKT-PI3K, and phospholipase C) (as outlined in Eswarakumar et al., Cytokine & Growth Factor Reviews, 2005). Abnormal activation of these pathways, due to overexpression of FGF ligands or FGFRs, or activating mutations in FGFRs, can lead to tumorigenesis, tumor progression, and resistance to conventional cancer treatments. In human cancers, genetic changes that cause ligand-independent receptor activation have been reported, including gene amplification, chromosomal translocations, and somatic mutations. Large-scale DNA sequencing of thousands of tumor samples has revealed that one of the most frequently mutated components in human cancers is a component of the FGFR pathway. Many of these activating mutations are identical to germline mutations that cause skeletal dysplasia syndromes. Mechanisms that cause abnormal ligand-dependent signaling in human diseases include FGF overexpression and altered FGFR splicing that enhances the receptor's chaotic ligand-binding ability (outlined in Knights and Cook Pharmacology & Therapeutics, 2010 and Turner and Grose, Nature Reviews Cancer, 2010). Therefore, developing FGFR-targeted inhibitors may be useful in the clinical treatment of diseases in which FGF or FGFR activity is elevated.

[0003] Cancer types in which FGF / FGFR is involved include, but are not limited to, carcinomas (e.g., those of the bladder, breast, cervix, colorectal, endometrium, stomach, head and neck, kidney, liver, lung, ovary, and prostate), hematopoietic malignancies (e.g., multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, myeloproliferative neoplasms, and Waldenström macroglobulinemia), and other neoplasms (e.g., glioblastoma, melanoma, and rhabdomyosarcoma). In addition to its role in oncogenic neoplasms, FGFR activation is also involved in skeletal and chondrocyte disorders, which include, but are not limited to, achondroplasia and craniosynostosis.

[0004] Specifically, the FGFR4-FGF19 signaling pathway is involved in the pathogenesis of several cancers, including hepatocellular carcinoma (Heinzle et al., Cur. Pharm. Des. 2014, 20:2881). In transgenic mice, ectopic expression of FGF19 was shown to induce tumor formation in the liver, and it was revealed that neutralizing antibodies against FGF19 inhibit tumor growth in mice. Furthermore, overexpression of FGFR4 has been observed in multiple 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).

[0005] Currently, FGFR inhibitors are being developed to treat cancer. For example, the 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one molecule and other small molecule inhibitors of FGFR have been reported, and these reports have been published, for example, in the United States. This can be seen in Publications No. 2012 / 0165305, No. 2014 / 0045814, No. 2013-0338134, No. 2014 / 0171405, No. 2014 / 0315902, No. 2016 / 0115164, No. 2016 / 0244448, No. 2016 / 0244449, and No. 2016 / 0244450. Therefore, there is a need for novel FGFR inhibitor molecular salts to prepare pharmaceutically useful formulations and dosage forms with appropriate properties (e.g., properties related to facilitating the manufacture of safe, effective, and high-quality pharmaceuticals). [Overview of the Initiative]

[0006] The present invention relates to salts of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0007] The present invention further focuses on the D-(-)-tartrate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0008] The present invention further focuses on the L-(+)-tartrate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0009] The present invention further focuses on the salicylate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0010] The present invention further relates to the hydrochloride salt of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0011] The present invention further focuses on the hydrobromide salt of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0012] The present invention further relates to the fumarate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0013] The present invention further focuses on the phosphate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0014] The present invention further relates to the benzenesulfonate of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one.

[0015] The present invention further targets the ethanesulfonate 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.

[0016] The present invention further targets the maleate 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.

[0017] The present invention further targets the adipate 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.

[0018] The present invention further targets the crystalline forms of the salts described herein.

[0019] The present invention further targets a pharmaceutical composition comprising the salt or crystalline form described herein and at least one pharmaceutically acceptable carrier.

[0020] The present invention further targets a treatment method using the salts and crystalline forms described herein. The present disclosure also provides the use of the salts and crystalline forms described herein in the manufacture of a medicament for use in treatment. The present disclosure also provides the salts and crystalline forms described herein for use in treatment.

[0021] The present invention further targets a process for preparing the salts and crystalline forms described herein.

Brief Description of the Drawings

[0022] [Figure 1] 1H NMR of the D-(-)-tartrate of Compound 1 is shown. [Figure 2] The XRPD pattern of compound 1 D-(-)-tartrate is shown. [Figure 3] The DSC thermogram of compound 1 D-(-)-tartrate is shown. [Figure 4] The TGA thermogram of compound 1 D-(-)-tartrate is shown. [Figure 5] The 1H NMR spectrum of compound 1 L-(+)-tartrate is shown. [Figure 6] The XRPD pattern of compound 1 L-(+)-tartrate is shown. [Figure 7] The DSC thermogram of compound 1 L-(+)-tartrate is shown. [Figure 8] The TGA thermogram of compound 1 L-(+)-tartrate is shown. [Figure 9] The 1H NMR spectrum of compound 1 salicylate is shown. [Figure 10] The XRPD pattern of compound 1 salicylate is shown. [Figure 11] The DSC thermogram of compound 1 salicylate is shown. [Figure 12] The TGA thermogram of compound 1 salicylate is shown. [Figure 13] The XRPD pattern of compound 1 hydrochloride is shown. [Figure 14] The DSC thermogram of compound 1 hydrochloride is shown. [Figure 15] The TGA thermogram of compound 1 hydrochloride is shown. [Figure 16] The 1H NMR spectrum of compound 1 hydrobromide is shown. [Figure 17] The XRPD pattern of compound 1 (hydrobromide) is shown. [Figure 18] The DSC thermogram of compound 1, hydrobromide, is shown. [Figure 19] The TGA thermogram of compound 1, hydrobromide, is shown. [Figure 20] The 1H NMR spectrum of compound 1 fumarate is shown. [Figure 21]The XRPD pattern of compound 1 fumarate is shown. [Figure 22] The DSC thermogram of compound 1 fumarate is shown. [Figure 23] The TGA thermogram of compound 1 fumarate is shown. [Figure 24] The 1H NMR spectrum of compound 1 phosphate is shown. [Figure 25] The XRPD pattern of compound 1 phosphate is shown. [Figure 26] The DSC thermogram of compound 1 phosphate is shown. [Figure 27] The TGA thermogram of compound 1 phosphate is shown. [Figure 28] The 1H NMR spectrum of compound 1, benzenesulfonate, is shown. [Figure 29] The XRPD pattern of compound 1, benzenesulfonate, is shown. [Figure 30] The DSC thermogram of compound 1, benzenesulfonate, is shown. [Figure 31] The TGA thermogram of compound 1, benzenesulfonate, is shown. [Figure 32] The ¹H NMR spectrum of compound 1, ethanesulfonate, is shown. [Figure 33] The XRPD pattern of compound 1, ethanesulfonate, is shown. [Figure 34] The DSC thermogram of compound 1, ethanesulfonate, is shown. [Figure 35] The TGA thermogram of compound 1, ethanesulfonate, is shown. [Figure 36] The 1H NMR spectrum of compound 1 maleate is shown. [Figure 37] The XRPD pattern of compound 1 maleate is shown. [Figure 38] The DSC thermogram of compound 1 maleate is shown. [Figure 39] The TGA thermogram of compound 1 maleate is shown. [Figure 40] The XRPD pattern of compound 1 adipine is shown. [Figure 41] The DSC thermogram of compound 1 adipinate is shown. [Modes for carrying out the invention]

[0023] The present invention particularly focuses on the salt of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one (compound 1), the structure of compound 1 is shown below. [ka] Compound 1 is described in U.S. Patent No. 9,611,267, which is incorporated herein by reference in its entirety. Hydrates and solvates of salts of Compound 1 are also provided herein.

[0024] Compound 1 and its salts can be isolated as one or more solid forms. The solid forms described herein (e.g., crystalline forms) have many advantages, such as desirable properties (e.g., ease of handling, ease of processing, storage stability, and ease of purification). Furthermore, crystalline forms may be effective in improving the performance characteristics of pharmaceuticals (e.g., solubility profile, shelf life, and bioavailability).

[0025] In some embodiments, the salt of compound 1 is an acidic salt of compound 1. In some embodiments, the acid is L-(+)-tartaric acid, D- (-) - Selected from tartaric acid, salicylic acid, fumaric acid, benzenesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, and phosphoric acid.

[0026] In some embodiments, the salt of the present invention is the tartrate of Compound 1 (such as the D-(-)-tartrate form or the D-tartrate form). The D-tartrate form of Compound 1 is referred herein to as "Compound 1 D-tartaric acid salt," "Compound 1 D-(-)-tartrate form," "Compound 1 D-tartaric acid," or "Compound 1 D-tartrate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one D-tartrate.

[0027] In some embodiments, the salt of the present invention is the tartrate of Compound 1 (such as the L-(+)-tartrate form or the L-tartrate form). The L-tartrate form of Compound 1 is referred herein to as "Compound 1 L-tartaric acid salt," "Compound 1 L-(+)-tartrate form," "Compound 1 L-tartaric acid," or "Compound 1 L-tartrate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one L-tartrate.

[0028] In some embodiments, the salt of the present invention is a salicylate of Compound 1. The salicylate form of Compound 1 is referred herein to as "Compound 1 salicylic acid salt," "Compound 1 salicylic acid," or "Compound 1 salicylate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one salicylate.

[0029] In some embodiments, the salt of the present invention is the hydrochloride salt (or hydrochloride form) of Compound 1. The hydrochloride form of Compound 1 is referred herein to as "Compound 1 hydrochloric acid salt," "Compound 1 hydrochloric acid," or "Compound 1 hydrochloride." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one hydrochloride.

[0030] In some embodiments, the salt of the present invention is the hydrobromide salt of Compound 1. The hydrobromide salt form of Compound 1 is referred herein to as "Compound 1 hydrobromic acid salt," "Compound 1 hydrobromic acid," or "Compound 1 hydrobromide." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one hydrobromide salt.

[0031] In some embodiments, the salt of the present invention is the fumaric acid (trans-butenioic acid) salt of Compound 1. The fumarate form of Compound 1 is referred herein to as "Compound 1 fumaric acid salt," "Compound 1 fumaric acid," or "Compound 1 fumarate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one fumarate.

[0032] In some embodiments, the salt of the present invention is a phosphate of Compound 1. The phosphate form of Compound 1 is referred to herein as "Compound 1 phosphoric acid salt," "Compound 1 phosphate," or "Compound 1 phosphate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one phosphate.

[0033] In some embodiments, the salt of the present invention is the benzenesulfonate of Compound 1. The benzenesulfonate form of Compound 1 is referred herein to as "Compound 1 benzenesulfonate," "Compound 1 benzenesulfonic acid," or "Compound 1 besylate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one besylate.

[0034] In some embodiments, the salt of the present invention is an ethanesulfonate of Compound 1. The ethanesulfonate form of Compound 1 is referred herein to as "Compound 1 ethanesulfonate salt," "Compound 1 ethanesulfonic acid," or "Compound 1 esylate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one ethanesulfonate.

[0035] In some embodiments, the salt of the present invention is the maleate of Compound 1. The maleate form of Compound 1 is referred herein to as "Compound 1 maleic acid salt," "Compound 1 maleic acid," or "Compound 1 maleate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one maleate.

[0036] In some embodiments, the salt of the present invention is the adipic acid salt of Compound 1. The adipic acid salt form of Compound 1 is referred herein to as "Compound 1 adipic acid salt," "Compound 1 adipic acid," or "Compound 1 adipate." Another name for this salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one adipic acid salt.

[0037] The salts of the present invention can be isolated as one or more solid forms. As used herein, the term “solid form” refers to the salts of the present invention in either an amorphous or crystalline state (“crystalline form” or “crystalline solid”), the crystalline salts of the present invention may optionally contain a solvent or water in the crystal lattice to form, for example, a solvated crystalline form or a hydrated crystalline form. In some embodiments, the salts of the present invention are in the crystalline state described herein. As used herein, the term “hydrated” is intended to refer to a crystalline form that contains one or more water molecules in the crystal lattice. Examples of “hydrated” crystalline forms include hemihydrates, monohydrates, dihydrates, and the like. The meaning of this term also includes other hydrated forms (such as channel hydrates and the like).

[0038] In some embodiments, the salts of the present invention may be prepared by any suitable method for preparing acid addition salts. For example, compound 1 of a free base and the desired acid may be mixed in a solvent or molten state. Alternatively, the acid addition salt of compound 1 may be converted to a different acid addition salt by anion exchange. The salts of the present invention prepared in a solvent system may be isolated by precipitation from the solvent. Precipitation and / or crystallization may be induced, for example, by evaporation, temperature reduction, addition of a poor solvent, or a combination thereof.

[0039] In some embodiments, the salts of the present invention are crystalline, and such crystals include anhydrous crystalline forms, hydrated crystalline forms, non-solvated crystalline forms, or solvated crystalline forms. Examples of hydrates include hemihydrates, monohydrates, dihydrates, and the like. In some embodiments, the crystalline salts are anhydrous and unsolvated. "Anhydrous" means that the crystalline salt does not contain bound water in its crystalline lattice structure; that is, such compounds do not form crystalline hydrates.

[0040] In some embodiments, the salt of the present invention is substantially isolated. "Substantially isolated" means that the salt is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, an increase in the content of the salt of the present invention in the composition. Substantial isolation may include the weight percentage content of the salt in the composition being 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%.

[0041] The salts of this invention include all salts that contain atomic isotopes. Isotopes include atoms that have the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium.

[0042] The salt form of the present invention is highly crystalline and possesses desirable properties, such as facilitating the purification of the drug by crystallization and, if necessary, recrystallization. Furthermore, the crystalline form tends to have improved stability, making it easier to pulverize or micronize the drug during formulation. The crystalline salt also tends to have excellent solubility and is more suitable for reproducible production with a clear acid / base ratio, thus facilitating the preparation of liquid formulations for oral and intravenous use.

[0043] As used herein, the terms “crystal” or “crystalline form” refer to the crystalline solid form of a compound, which includes, but is not limited to, crystalline forms with a single component or with multiple components (e.g., solvates, hydrates, inclusions, and cocrystals). As used herein, “crystalline form” is intended to refer to a particular lattice arrangement of a crystalline material. Different crystalline forms of the same material typically have different crystal lattices (e.g., unit cells), and these lattice differences are attributed to different physical properties specific to each of these crystalline forms. In some cases, different lattice arrangements result in different water or solvent content. Different crystal lattices can be identified by methods that characterize the solid state (e.g., powder X-ray diffraction (XRPD)). Other methods for characterization (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption / desorption (DVS), solid-state NMR, and similar) are also helpful in identifying crystalline forms and determining stability and solvent / water content.

[0044] The crystalline forms of a substance include both solvated (e.g., hydrated) and non-solvated (e.g., anhydrous) forms. The hydrated form is a crystalline form in which water is present in the crystal lattice. Hydrated forms can be stoichiometric hydrates, in which water is present in the lattice at a specific water / molecular ratio, as seen in hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, in which the water content is variable and depends on external conditions (such as humidity).

[0045] As used herein, the term “substantially crystalline” means that the majority by weight of a sample or preparation of the salt (or its hydrate or solvate) of the present invention is crystalline, and the remainder of the sample is in an amorphous form (e.g., non-crystalline form) of the same compound. In some embodiments, a substantially crystalline sample has a degree of crystallinity of at least about 95% (e.g., about 5% is in an amorphous form of the same compound), preferably at least about 96% (e.g., about 4% is in an amorphous form of the same compound), more preferably at least about 97% (e.g., about 3% is in an amorphous form of the same compound), even more preferably at least about 98% (e.g., about 2% is in an amorphous form of the same compound), even more preferably at least about 99% (e.g., about 1% is in an amorphous form of the same compound), and most preferably about 100% (e.g., about 0% is in an amorphous form of the same compound). In some embodiments, the term “sufficiently crystalline” means that the degree of crystallinity is at least about 99% or about 100%.

[0046] Crystal morphology is most commonly characterized by XRPD. The reflection (peak) pattern of XRPD is typically considered a fingerprint of a particular crystal morphology. It is widely known that the relative intensity of XRPD peaks can vary considerably depending, among other things, on sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the specific instrument used. In some cases, depending on the type or setting of the instrument (e.g., whether or not 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 with a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrument differences and other factors may affect the 2θ value. Therefore, the assignment of peaks (such as those reported herein) may vary by ± about 0.2°(2θ), and the term “substantially” as used herein in relation to XRPD is intended to encompass the aforementioned variations.

[0047] Similarly, temperature observations associated with DSC, TGA, or other thermal experiments can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. For example, in DSC, it is known that the observed temperature depends on the rate of temperature change, as well as the sample preparation method and the specific instrument used. Therefore, the values ​​reported herein with respect to DSC thermograms can vary by ±3°C as described above. Accordingly, the crystal morphologies reported herein with DSC thermograms "substantially" shown in any of the figures should be understood to include such variations.

[0048] The salts and compounds disclosed herein may include all those that contain atomic isotopes. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. The salts and compounds of the present invention may also include all those that contain atomic isotopes in intermediate or final compounds. Isotopes include atoms with 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 of the present invention may be exchanged with or replaced by isotopes of that atom in proportion to natural or unnatural abundances. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be exchanged with or replaced by deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain one, two, three, four, five, six, seven, or eight deuterium atoms. In this technical field, methods for synthesizing organic compounds to include isotopes are known.

[0049] As used herein, the term "approximately" refers, unless otherwise specified, to a numerical value or range of values ​​given to describe a particular solid state (e.g., a specific temperature or temperature range (such as one describing melting, dehydration, or glass transition), a mass change (such as a mass change depending on temperature or humidity), a solvent content or water content (e.g., in terms of mass or percentage), or a peak position (e.g., in terms of analysis).13 When used in relation to ¹³C NMR, DSC, TGA, and XRPD, etc., such values ​​or ranges of values ​​indicate that they deviate to a degree that would be reasonable for a person skilled in the art, but still may describe a particular solid-state. Specifically, when used in this context, the term “approximately” indicates that a numerical 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% from the stated value or range of values, but still may describe a particular solid-state. When used with respect to a °(2θ) value, the term “approximately” refers to + / -0.2°(2θ).

[0050] The term "pharmaceutically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is suitable for use in contact with human and animal tissues within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and that the benefit / risk ratio is reasonable.

[0051] As used herein, the term “melting point” refers to an endothermic event or endothermal event (e.g., one observed in a DSC experiment). An endothermic event is a process or reaction in which a sample absorbs energy from its surroundings (e.g., energy in the form of heat, as seen in a DSC experiment). An exothermic event is a process or reaction in which a sample releases energy. Heat absorption and release processes can be detected by DSC. In some embodiments, the term “melting point” is used to describe the main endothermic event appearing in a particular DSC thermogram.

[0052] As used herein, the term “room temperature” is understood in the art and generally refers to a temperature approximately the same as the temperature of the room in which the reaction takes place (e.g., the reaction temperature), such a temperature is, for example, about 20°C to about 30°C.

[0053] As used herein, the term “high temperature” is understood in the art and generally refers to temperatures above room temperature (e.g., reaction temperature), such as temperatures above 30°C.

[0054] D-(-)-tartrate The D-(-)-tartrate of compound 1 can be prepared by any suitable method for preparing D-(-)-tartrate addition salts. For example, compound 1 can be mixed with D-(-)-tartaric acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of D-(-)-tartaric acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of D-(-)-tartaric acid. In certain embodiments, compound 1 is mixed with about 1.1 molar equivalents of D-(-)-tartaric acid.

[0055] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0056] In some embodiments, the crystallization solvent is a 1:1 (v / v) mixture of methanol and dichloromethane.

[0057] In some embodiments, the crystallization solvent is heated to a temperature of at least about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. For example, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0058] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 48 hours, but the time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0059] In some embodiments, the precipitation and / or crystallization of the D-(-)-tartrate is carried out by filtering the salt from the solution.

[0060] The crystalline D-(-)-tartrate form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0061] In some embodiments, crystalline D-(-)-tartrates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 2.

[0062] In some embodiments, the D-(-)-tartrate of compound 1 has at least one characteristic XRPD peak selected from about 7.4°(2θ), about 10.5°(2θ), about 12.9°(2θ), about 13.6°(2θ), about 14.8°(2θ), and about 16.4°(2θ).

[0063] In some embodiments, the D-(-)-tartrate of compound 1 has at least two characteristic XRPD peaks selected from about 7.4°(2θ), about 10.5°(2θ), about 12.9°(2θ), about 13.6°(2θ), about 14.8°(2θ), and about 16.4°(2θ).

[0064] In some embodiments, the D-(-)-tartrate of compound 1 has at least three characteristic XRPD peaks selected from approximately 7.4°(2θ), approximately 10.5°(2θ), approximately 12.9°(2θ), approximately 13.6°(2θ), approximately 14.8°(2θ), and approximately 16.4°(2θ).

[0065] In some embodiments, the D-(-)-tartrate of compound 1 has at least one characteristic XRPD peak selected from about 7.4°(2θ), about 10.5°(2θ), about 12.9°(2θ), about 13.6°(2θ), about 14.8°(2θ), about 16.4°(2θ), about 18.9°(2θ), about 21.3°(2θ), about 22.1°(2θ), about 22.8°(2θ), about 25.0°(2θ), about 25.8°(2θ), about 26.6°(2θ), and about 27.4°(2θ).

[0066] In some embodiments, the D-(-)-tartrate of compound 1 has at least two characteristic XRPD peaks selected from approximately 7.4°(2θ), approximately 10.5°(2θ), approximately 12.9°(2θ), approximately 13.6°(2θ), approximately 14.8°(2θ), approximately 16.4°(2θ), approximately 18.9°(2θ), approximately 21.3°(2θ), approximately 22.1°(2θ), approximately 22.8°(2θ), approximately 25.0°(2θ), approximately 25.8°(2θ), approximately 26.6°(2θ), and approximately 27.4°(2θ).

[0067] In some embodiments, the D-(-)-tartrate of compound 1 has at least three characteristic XRPD peaks selected from approximately 7.4°(2θ), approximately 10.5°(2θ), approximately 12.9°(2θ), approximately 13.6°(2θ), approximately 14.8°(2θ), approximately 16.4°(2θ), approximately 18.9°(2θ), approximately 21.3°(2θ), approximately 22.1°(2θ), approximately 22.8°(2θ), approximately 25.0°(2θ), approximately 25.8°(2θ), approximately 26.6°(2θ), and approximately 27.4°(2θ).

[0068] In some embodiments, D-(-)-tartrate exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 276°C. In some embodiments, D-(-)-tartrate has a DSC thermogram substantially shown in Figure 3. In some embodiments, D-(-)-tartrate has a TGA thermogram substantially shown in Figure 4.

[0069] In some embodiments, the D-(-)-tartrate of compound 1 exhibits a DSC thermogram having at least one characteristic XRPD peak selected from about 7.4, about 10.5, about 12.9, about 13.6, about 14.8, and about 16.4, and an endothermic peak at a temperature of about 276°C.

[0070] In some embodiments, the D-(-)-tartrate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0071] L-(+)-tartrate The L-(+)-tartrate of compound 1 can be prepared by any suitable method for preparing L-(+)-tartrate addition salts. For example, compound 1 can be mixed with L-(+)-tartaric acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of L-(+)-tartaric acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of L-(+)-tartaric acid. In certain embodiments, compound 1 is mixed with about 1.1 molar equivalents of L-(+)-tartaric acid.

[0072] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0073] In some embodiments, the crystallization solvent is a 1:1 (v / v) mixture of methanol and dichloromethane.

[0074] In some embodiments, the crystallization solvent is heated to a temperature of at least about 50°C. In some embodiments, a temperature of about 50°C to about 80°C is used. In some embodiments, a temperature of about 40°C to about 60°C is used. In some embodiments, a temperature of about 45°C to about 55°C is used. In some embodiments, a temperature of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C is used.

[0075] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 48 hours, but the time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0076] In some embodiments, the precipitation and / or crystallization of the L-(+)-tartrate is carried out by filtering the salt from the solution.

[0077] The crystalline L-(+)-tartrate form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0078] In some embodiments, crystalline L-(+)-tartrates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 6.

[0079] In some embodiments, the L-(+)-tartrate of compound 1 has at least one characteristic XRPD peak selected from about 3.8°(2θ), about 8.5°(2θ), about 9.1°(2θ), about 10.3°(2θ), and about 12.0°(2θ).

[0080] In some embodiments, the L-(+)-tartrate of compound 1 has at least two characteristic XRPD peaks selected from about 3.8°(2θ), about 8.5°(2θ), about 9.1°(2θ), about 10.3°(2θ), and about 12.0°(2θ).

[0081] In some embodiments, the L-(+)-tartrate of compound 1 has at least three characteristic XRPD peaks selected from about 3.8°(2θ), about 8.5°(2θ), about 9.1°(2θ), about 10.3°(2θ), and about 12.0°(2θ).

[0082] In some embodiments, the L-(+)-tartrate of compound 1 has at least one characteristic XRPD peak selected from approximately 3.8°(2θ), approximately 4.5°(2θ), approximately 8.5°(2θ), approximately 9.1°(2θ), approximately 10.3°(2θ), approximately 12.0°(2θ), approximately 12.3°(2θ), approximately 14.3°(2θ), approximately 15.7°(2θ), approximately 18.2°(2θ), approximately 18.8°(2θ), approximately 20.2°(2θ), approximately 21.3°(2θ), and approximately 22.5°(2θ).

[0083] In some embodiments, the L-(+)-tartrate of compound 1 has at least two characteristic XRPD peaks selected from approximately 3.8°(2θ), approximately 4.5°(2θ), approximately 8.5°(2θ), approximately 9.1°(2θ), approximately 10.3°(2θ), approximately 12.0°(2θ), approximately 12.3°(2θ), approximately 14.3°(2θ), approximately 15.7°(2θ), approximately 18.2°(2θ), approximately 18.8°(2θ), approximately 20.2°(2θ), approximately 21.3°(2θ), and approximately 22.5°(2θ).

[0084] In some embodiments, the L-(+)-tartrate of compound 1 has at least three characteristic XRPD peaks selected from approximately 3.8°(2θ), approximately 4.5°(2θ), approximately 8.5°(2θ), approximately 9.1°(2θ), approximately 10.3°(2θ), approximately 12.0°(2θ), approximately 12.3°(2θ), approximately 14.3°(2θ), approximately 15.7°(2θ), approximately 18.2°(2θ), approximately 18.8°(2θ), approximately 20.2°(2θ), approximately 21.3°(2θ), and approximately 22.5°(2θ).

[0085] In some embodiments, L-(+)-tartrate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 90°C, 211°C, and 266°C. In some embodiments, the endothermic peak is located at approximately 90°C. In some embodiments, the endothermic peak is located at approximately 211°C. In some embodiments, the endothermic peak is located at approximately 266°C. In some embodiments, L-(+)-tartrate has a DSC thermogram substantially shown in Figure 7. In some embodiments, L-(+)-tartrate has a TGA thermogram substantially shown in Figure 8.

[0086] In some embodiments, the L-(+)-tartrate of compound 1 has at least one characteristic XRPD peak selected from about 3.8, about 8.5, about 9.1, about 10.3, and about 12.0, and this L-(+)-tartrate exhibits a DSC thermogram with endothermic peaks at temperatures of about 90°C, about 211°C, and about 266°C.

[0087] In some embodiments, the L-(+)-tartrate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0088] Salicylates The salicylate of compound 1 can be prepared by any suitable method for preparing salicylate addition salts. For example, compound 1 can be mixed with salicylic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of salicylic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of salicylic acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of salicylic acid. In some embodiments, compound 1 is mixed with about 1.3 molar equivalents of salicylic acid.

[0089] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0090] In some embodiments, the crystallization solvent is methanol.

[0091] In some embodiments, the crystallization solvent is heated to a temperature of at least about 50°C. In some embodiments, a temperature of about 50°C to about 80°C is used. In some embodiments, a temperature of about 40°C to about 60°C is used. In some embodiments, a temperature of about 45°C to about 55°C is used. In some embodiments, a temperature of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C is used.

[0092] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 48 hours, but the time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0093] In some embodiments, the precipitation and / or crystallization of the salicylate is carried out by filtering the salt from the solution.

[0094] The crystalline salicylate form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0095] In some embodiments, crystalline salicylates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 10.

[0096] In some embodiments, the salicylate of compound 1 has at least one characteristic XRPD peak selected from about 10.4°(2θ), about 11.8°(2θ), about 12.1°(2θ), about 13.4°(2θ), and about 13.9°(2θ).

[0097] In some embodiments, the salicylate of compound 1 has at least two characteristic XRPD peaks selected from about 10.4°(2θ), about 11.8°(2θ), about 12.1°(2θ), about 13.4°(2θ), and about 13.9°(2θ).

[0098] In some embodiments, the salicylate of compound 1 has at least three characteristic XRPD peaks selected from about 10.4°(2θ), about 11.8°(2θ), about 12.1°(2θ), about 13.4°(2θ), and about 13.9°(2θ).

[0099] In some embodiments, the salicylate of compound 1 has at least one characteristic XRPD peak selected from approximately 10.4°(2θ), approximately 11.8°(2θ), approximately 12.1°(2θ), approximately 13.4°(2θ), approximately 13.9°(2θ), approximately 15.1°(2θ), approximately 18.2°(2θ), approximately 20.1°(2θ), approximately 21.7°(2θ), approximately 22.6°(2θ), approximately 23.2°(2θ), approximately 24.3°(2θ), approximately 24.8°(2θ), approximately 27.0°(2θ), and approximately 27.4°(2θ).

[0100] In some embodiments, the salicylate of compound 1 has at least two characteristic XRPD peaks selected from approximately 10.4°(2θ), approximately 11.8°(2θ), approximately 12.1°(2θ), approximately 13.4°(2θ), approximately 13.9°(2θ), approximately 15.1°(2θ), approximately 18.2°(2θ), approximately 20.1°(2θ), approximately 21.7°(2θ), approximately 22.6°(2θ), approximately 23.2°(2θ), approximately 24.3°(2θ), approximately 24.8°(2θ), approximately 27.0°(2θ), and approximately 27.4°(2θ).

[0101] In some embodiments, the salicylate of compound 1 has at least three characteristic XRPD peaks selected from approximately 10.4°(2θ), approximately 11.8°(2θ), approximately 12.1°(2θ), approximately 13.4°(2θ), approximately 13.9°(2θ), approximately 15.1°(2θ), approximately 18.2°(2θ), approximately 20.1°(2θ), approximately 21.7°(2θ), approximately 22.6°(2θ), approximately 23.2°(2θ), approximately 24.3°(2θ), approximately 24.8°(2θ), approximately 27.0°(2θ), and approximately 27.4°(2θ).

[0102] In some embodiments, salicylates exhibit a DSC thermogram with an endothermic peak at a temperature of approximately 212°C. In some embodiments, salicylates have a DSC thermogram substantially shown in Figure 11. In some embodiments, salicylates have a TGA thermogram substantially shown in Figure 12.

[0103] In some embodiments, the salicylate of compound 1 has at least one characteristic XRPD peak selected from about 10.4, about 11.8, about 12.1, about 13.4, and about 13.9, and this salicylate exhibits a DSC thermogram with an endothermic peak at a temperature of about 212°C.

[0104] In some embodiments, the salicylate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0105] Hydrochloride The hydrochloride salt of compound 1 can be prepared by any suitable method for preparing hydrochloric acid addition salts. For example, compound 1 can be mixed with hydrochloric acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering it from the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of hydrochloric acid. In certain embodiments, compound 1 is mixed with about 1.25 equivalents of hydrochloric acid.

[0106] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0107] In some embodiments, the crystallization solvent is methanol.

[0108] In some embodiments, the crystallization solvent is heated to a temperature of at least about 50°C. In some embodiments, a temperature of about 50°C to about 80°C is used. In some embodiments, a temperature of about 40°C to about 60°C is used. In some embodiments, a temperature of about 45°C to about 55°C is used. In some embodiments, a temperature of about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C is used.

[0109] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 48 hours, but the time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0110] In some embodiments, the precipitation and / or crystallization of the hydrochloride salt is carried out by filtering the salt from the solution.

[0111] The crystalline hydrochloride form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0112] In some embodiments, the crystalline hydrochloride can be characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in Figure 13.

[0113] In some embodiments, the hydrochloride salt of compound 1 has at least one characteristic XRPD peak selected from about 6.8°(2θ), about 9.2°(2θ), about 12.9°(2θ), about 15.6°(2θ), and about 16.1°(2θ).

[0114] In some embodiments, the hydrochloride salt of compound 1 has at least two characteristic XRPD peaks selected from about 6.8°(2θ), about 9.2°(2θ), about 12.9°(2θ), about 15.6°(2θ), and about 16.1°(2θ).

[0115] In some embodiments, the hydrochloride salt of compound 1 has at least three characteristic XRPD peaks selected from about 6.8°(2θ), about 9.2°(2θ), about 12.9°(2θ), about 15.6°(2θ), and about 16.1°(2θ).

[0116] In some embodiments, the hydrochloride salt of compound 1 has at least one characteristic XRPD peak selected from approximately 4.2°(2θ), approximately 6.8°(2θ), approximately 9.2°(2θ), approximately 12.9°(2θ), approximately 15.6°(2θ), approximately 16.1°(2θ), approximately 17.2°(2θ), approximately 21.6°(2θ), approximately 22.2°(2θ), approximately 23.4°(2θ), approximately 24.7°(2θ), approximately 26.5°(2θ), and approximately 27.4°(2θ).

[0117] In some embodiments, the hydrochloride salt of compound 1 has at least two characteristic XRPD peaks selected from approximately 4.2°(2θ), approximately 6.8°(2θ), approximately 9.2°(2θ), approximately 12.9°(2θ), approximately 15.6°(2θ), approximately 16.1°(2θ), approximately 17.2°(2θ), approximately 21.6°(2θ), approximately 22.2°(2θ), approximately 23.4°(2θ), approximately 24.7°(2θ), approximately 26.5°(2θ), and approximately 27.4°(2θ).

[0118] In some embodiments, the hydrochloride salt of compound 1 has at least three characteristic XRPD peaks selected from approximately 4.2°(2θ), approximately 6.8°(2θ), approximately 9.2°(2θ), approximately 12.9°(2θ), approximately 15.6°(2θ), approximately 16.1°(2θ), approximately 17.2°(2θ), approximately 21.6°(2θ), approximately 22.2°(2θ), approximately 23.4°(2θ), approximately 24.7°(2θ), approximately 26.5°(2θ), and approximately 27.4°(2θ).

[0119] In some embodiments, the hydrochloride salt exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 120°C, approximately 189°C, and approximately 274°C. In some embodiments, the hydrochloride salt exhibits a DSC thermogram with an endothermic peak at approximately 120°C. In some embodiments, the hydrochloride salt exhibits a DSC thermogram with an endothermic peak at approximately 189°C. In some embodiments, the hydrochloride salt exhibits a DSC thermogram with an endothermic peak at approximately 274°C. In some embodiments, the hydrochloride salt has a DSC thermogram substantially shown in Figure 14. In some embodiments, the hydrochloride salt has a TGA thermogram substantially shown in Figure 15.

[0120] In some embodiments, the hydrochloride salt of compound 1 has at least three characteristic XRPD peaks selected from about 6.8, about 9.2, about 12.9, about 15.6, and about 16.1, and this hydrochloride salt exhibits a DSC thermogram with endothermic peaks at temperatures of about 120°C, about 189°C, and about 274°C.

[0121] In some embodiments, the hydrochloride salt of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0122] Hydrobromide The hydrobromide salt of compound 1 can be prepared by any suitable method for preparing hydrobromic acid addition salts. For example, compound 1 can be mixed with hydrobromic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of hydrobromic acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of hydrobromic acid.

[0123] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0124] In some embodiments, the crystallization solvent is methanol.

[0125] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0126] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0127] In some embodiments, the precipitation and / or crystallization of the hydrobromide salt is carried out by filtering the salt from the solution.

[0128] The crystalline hydrobromide form of compound 1 can be identified by its distinctive signature (e.g., related to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0129] In some embodiments, crystalline hydrobromides can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 17.

[0130] In some embodiments, the hydrobromide of compound 1 has at least one characteristic XRPD peak selected from about 7.3°(2θ), about 9.3°(2θ), about 13.9°(2θ), about 14.5°(2θ), and about 16.1°(2θ).

[0131] In some embodiments, the hydrobromide of compound 1 has at least two characteristic XRPD peaks selected from about 7.3°(2θ), about 9.3°(2θ), about 13.9°(2θ), about 14.5°(2θ), and about 16.1°(2θ).

[0132] In some embodiments, the hydrobromide of compound 1 has at least three characteristic XRPD peaks selected from about 7.3°(2θ), about 9.3°(2θ), about 13.9°(2θ), about 14.5°(2θ), and about 16.1°(2θ).

[0133] In some embodiments, the hydrobromide of compound 1 has at least one characteristic XRPD peak selected from about 6.8°(2θ), about 7.3°(2θ), about 9.3°(2θ), about 13.9°(2θ), about 14.5°(2θ), about 16.1°(2θ), about 21.5°(2θ), about 23.3°(2θ), about 23.8°(2θ), about 25.3°(2θ), and about 28.1°(2θ).

[0134] In some embodiments, the hydrobromide of compound 1 has at least two characteristic XRPD peaks selected from approximately 6.8°(2θ), approximately 7.3°(2θ), approximately 9.3°(2θ), approximately 13.9°(2θ), approximately 14.5°(2θ), approximately 16.1°(2θ), approximately 21.5°(2θ), approximately 23.3°(2θ), approximately 23.8°(2θ), approximately 25.3°(2θ), and approximately 28.1°(2θ).

[0135] In some embodiments, the hydrobromide of compound 1 has at least three characteristic XRPD peaks selected from approximately 6.8°(2θ), approximately 7.3°(2θ), approximately 9.3°(2θ), approximately 13.9°(2θ), approximately 14.5°(2θ), approximately 16.1°(2θ), approximately 21.5°(2θ), approximately 23.3°(2θ), approximately 23.8°(2θ), approximately 25.3°(2θ), and approximately 28.1°(2θ).

[0136] In some embodiments, hydrobromide exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 84°C and approximately 235°C. In some embodiments, hydrobromide exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 84°C. In some embodiments, hydrobromide exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 235°C. In some embodiments, hydrobromide has a DSC thermogram substantially shown in Figure 18. In some embodiments, hydrobromide has a TGA thermogram substantially shown in Figure 19.

[0137] In some embodiments, the hydrobromide of compound 1 has at least one characteristic XRPD peak selected from about 7.3, about 9.3, about 13.9, about 14.5, and about 16.1, and this hydrobromide exhibits a DSC thermogram with endothermic peaks at temperatures of about 84°C and about 235°C.

[0138] In some embodiments, the hydrobromide salt of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0139] Fumarate The fumarate of compound 1 can be prepared by any suitable method for preparing fumarate addition salts. For example, compound 1 can be mixed with fumaric acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of fumaric acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of fumaric acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of fumaric acid.

[0140] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0141] In some embodiments, the crystallization solvent is methanol.

[0142] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0143] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0144] In some embodiments, the precipitation and / or crystallization of the fumarate is carried out by filtering the salt from the solution.

[0145] The crystalline fumarate form of compound 1 can be identified by its distinctive signature (e.g., related to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0146] In some embodiments, crystalline fumarates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 21.

[0147] In some embodiments, the fumarate of compound 1 has at least one characteristic XRPD peak selected from about 6.3°(2θ), about 7.1°(2θ), about 7.8°(2θ), and about 12.7°(2θ).

[0148] In some embodiments, the fumarate of compound 1 has at least two characteristic XRPD peaks selected from about 6.3°(2θ), about 7.1°(2θ), about 7.8°(2θ), and about 12.7°(2θ).

[0149] In some embodiments, the fumarate of compound 1 has at least three characteristic XRPD peaks selected from about 6.3°(2θ), about 7.1°(2θ), about 7.8°(2θ), and about 12.7°(2θ).

[0150] In some embodiments, the fumarate of compound 1 has at least one characteristic XRPD peak selected from approximately 6.3°(2θ), approximately 7.1°(2θ), approximately 7.8°(2θ), approximately 12.7°(2θ), approximately 16.5°(2θ), approximately 18.8°(2θ), approximately 21.2°(2θ), approximately 21.8°(2θ), approximately 22.6°(2θ), approximately 23.5°(2θ), approximately 25.1°(2θ), approximately 25.5°(2θ), and approximately 25.9°(2θ).

[0151] In some embodiments, the fumarate of compound 1 has at least two characteristic XRPD peaks selected from approximately 6.3°(2θ), approximately 7.1°(2θ), approximately 7.8°(2θ), approximately 12.7°(2θ), approximately 16.5°(2θ), approximately 18.8°(2θ), approximately 21.2°(2θ), approximately 21.8°(2θ), approximately 22.6°(2θ), approximately 23.5°(2θ), approximately 25.1°(2θ), approximately 25.5°(2θ), and approximately 25.9°(2θ).

[0152] In some embodiments, the fumarate of compound 1 has at least three characteristic XRPD peaks selected from approximately 6.3°(2θ), approximately 7.1°(2θ), approximately 7.8°(2θ), approximately 12.7°(2θ), approximately 16.5°(2θ), approximately 18.8°(2θ), approximately 21.2°(2θ), approximately 21.8°(2θ), approximately 22.6°(2θ), approximately 23.5°(2θ), approximately 25.1°(2θ), approximately 25.5°(2θ), and approximately 25.9°(2θ).

[0153] In some embodiments, the fumarate exhibits a DSC thermogram with an endothermic peak at a temperature of approximately 214°C. In some embodiments, the fumarate has a DSC thermogram substantially shown in Figure 22. In some embodiments, the fumarate has a TGA thermogram substantially shown in Figure 23.

[0154] In some embodiments, the fumarate of compound 1 has at least one characteristic XRPD peak selected from about 6.3, about 7.1, about 7.8, and about 12.7, and this fumarate exhibits a DSC thermogram with an endothermic peak at a temperature of about 214°C.

[0155] In some embodiments, the fumarate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0156] Phosphate The phosphate of compound 1 can be prepared by any suitable method for preparing a phosphate addition salt. For example, compound 1 can be mixed with phosphoric acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of phosphoric acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of phosphoric acid.

[0157] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0158] In some embodiments, the crystallization solvent is methanol.

[0159] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0160] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0161] In some embodiments, phosphate precipitation and / or crystallization is carried out by filtering the salt from the solution.

[0162] The crystalline phosphate form of compound 1 can be identified by its distinctive signature (e.g., relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR). In some embodiments, the crystalline phosphate can be characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in Figure 25.

[0163] In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak selected from about 3.9°(2θ), about 7.7°(2θ), about 10.4°(2θ), and about 12.6°(2θ).

[0164] In some embodiments, the phosphate of compound 1 has at least two characteristic XRPD peaks selected from about 3.9°(2θ), about 7.7°(2θ), about 10.4°(2θ), and about 12.6°(2θ).

[0165] In some embodiments, the phosphate of compound 1 has at least three characteristic XRPD peaks selected from about 3.9°(2θ), about 7.7°(2θ), about 10.4°(2θ), and about 12.6°(2θ).

[0166] In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak selected from about 3.9°(2θ), about 7.7°(2θ), about 10.4°(2θ), about 12.6°(2θ), about 14.3°(2θ), about 16.9°(2θ), about 19.7°(2θ), about 20.8°(2θ), about 23.2°(2θ), about 25.1°(2θ), about 27.2°(2θ), about 28.6°(2θ), and about 30.0°(2θ).

[0167] In some embodiments, the phosphate of compound 1 has at least two characteristic XRPD peaks selected from approximately 3.9°(2θ), approximately 7.7°(2θ), approximately 10.4°(2θ), approximately 12.6°(2θ), approximately 14.3°(2θ), approximately 16.9°(2θ), approximately 19.7°(2θ), approximately 20.8°(2θ), approximately 23.2°(2θ), approximately 25.1°(2θ), approximately 27.2°(2θ), approximately 28.6°(2θ), and approximately 30.0°(2θ).

[0168] In some embodiments, the phosphate of compound 1 has at least three characteristic XRPD peaks selected from approximately 3.9°(2θ), approximately 7.7°(2θ), approximately 10.4°(2θ), approximately 12.6°(2θ), approximately 14.3°(2θ), approximately 16.9°(2θ), approximately 19.7°(2θ), approximately 20.8°(2θ), approximately 23.2°(2θ), approximately 25.1°(2θ), approximately 27.2°(2θ), approximately 28.6°(2θ), and approximately 30.0°(2θ).

[0169] In some embodiments, the phosphate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 215°C and approximately 221°C. In some embodiments, the phosphate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 215°C. In some embodiments, the phosphate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 221°C. In some embodiments, the phosphate has a DSC thermogram substantially shown in Figure 26. In some embodiments, the phosphate has a TGA thermogram substantially shown in Figure 27.

[0170] In some embodiments, the phosphate of compound 1 has at least one characteristic XRPD peak selected from about 3.9, about 7.7, about 10.4, and about 12.6, and this phosphate exhibits a DSC thermogram with endothermic peaks at temperatures of about 215°C and about 221°C.

[0171] In some embodiments, the phosphate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0172] Benzenesulfonate The benzenesulfonate of compound 1 can be prepared by any suitable method for preparing benzenesulfonic acid addition salts. For example, compound 1 can be mixed with benzenesulfonic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of benzenesulfonic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of benzenesulfonic acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of benzenesulfonic acid.

[0173] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0174] In some embodiments, the crystallization solvent is methanol.

[0175] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0176] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0177] In some embodiments, the precipitation and / or crystallization of the benzenesulfonate is carried out by filtering the salt from the solution.

[0178] The crystalline benzenesulfonate form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0179] In some embodiments, crystalline benzenesulfonates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 29.

[0180] In some embodiments, the benzenesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 3.8°(2θ), about 6.7°(2θ), about 7.4°(2θ), about 9.8°(2θ), about 11.0°(2θ), and about 13.0°(2θ).

[0181] In some embodiments, the benzenesulfonate of compound 1 has at least two characteristic XRPD peaks selected from about 3.8°(2θ), about 6.7°(2θ), about 7.4°(2θ), about 9.8°(2θ), about 11.0°(2θ), and about 13.0°(2θ).

[0182] In some embodiments, the benzenesulfonate of compound 1 has at least three characteristic XRPD peaks selected from about 3.8°(2θ), about 6.7°(2θ), about 7.4°(2θ), about 9.8°(2θ), about 11.0°(2θ), and about 13.0°(2θ).

[0183] In some embodiments, the benzenesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 3.8°(2θ), about 6.7°(2θ), about 7.4°(2θ), about 9.8°(2θ), about 11.0°(2θ), about 13.0°(2θ), about 13.4°(2θ), about 15.1°(2θ), about 16.0°(2θ), about 16.9°(2θ), about 19.4°(2θ), about 20.6°(2θ), about 21.0°(2θ), about 22.3°(2θ), about 23.6°(2θ), about 25.6°(2θ), about 26.1°(2θ), and about 30.1°(2θ).

[0184] In some embodiments, the benzenesulfonate of compound 1 has at least two characteristic XRPD peaks selected from approximately 3.8°(2θ), approximately 6.7°(2θ), approximately 7.4°(2θ), approximately 9.8°(2θ), approximately 11.0°(2θ), approximately 13.0°(2θ), approximately 13.4°(2θ), approximately 15.1°(2θ), approximately 16.0°(2θ), approximately 16.9°(2θ), approximately 19.4°(2θ), approximately 20.6°(2θ), approximately 21.0°(2θ), approximately 22.3°(2θ), approximately 23.6°(2θ), approximately 25.6°(2θ), approximately 26.1°(2θ), and approximately 30.1°(2θ).

[0185] In some embodiments, the benzenesulfonate of compound 1 has at least three characteristic XRPD peaks selected from approximately 3.8°(2θ), approximately 6.7°(2θ), approximately 7.4°(2θ), approximately 9.8°(2θ), approximately 11.0°(2θ), approximately 13.0°(2θ), approximately 13.4°(2θ), approximately 15.1°(2θ), approximately 16.0°(2θ), approximately 16.9°(2θ), approximately 19.4°(2θ), approximately 20.6°(2θ), approximately 21.0°(2θ), approximately 22.3°(2θ), approximately 23.6°(2θ), approximately 25.6°(2θ), approximately 26.1°(2θ), and approximately 30.1°(2θ).

[0186] In some embodiments, benzenesulfonates exhibit DSC thermograms with endothermic peaks at temperatures of approximately 105°C, 190°C, 222°C, and 241°C. In some embodiments, benzenesulfonates exhibit DSC thermograms with endothermic peaks at temperatures of approximately 105°C. In some embodiments, benzenesulfonates exhibit DSC thermograms with endothermic peaks at temperatures of approximately 190°C. In some embodiments, benzenesulfonates exhibit DSC thermograms with endothermic peaks at temperatures of approximately 222°C. In some embodiments, benzenesulfonates exhibit DSC thermograms with endothermic peaks at temperatures of approximately 241°C. In some embodiments, benzenesulfonates have a DSC thermogram substantially shown in Figure 30. In some embodiments, benzenesulfonates have a TGA thermogram substantially shown in Figure 31.

[0187] In some embodiments, the benzenesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 3.8, about 6.7, about 7.4, about 9.8, about 11.0, and about 13.0, and this benzenesulfonate exhibits a DSC thermogram with endothermic peaks at temperatures of about 105°C, about 190°C, about 222°C, and about 241°C.

[0188] In some embodiments, the benzenesulfonate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0189] Ethanolate The ethanesulfonate of compound 1 can be prepared by any suitable method for preparing ethanesulfonic acid addition salts. For example, compound 1 can be mixed with ethanesulfonic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of ethanesulfonic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of ethanesulfonic acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of ethanesulfonic acid.

[0190] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane. In some embodiments, the crystallization solvent includes isopropanol.

[0191] In some embodiments, the crystallization solvent is methanol. In some embodiments, the crystallization solvent is a mixture of methanol and isopropanol.

[0192] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0193] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0194] In some embodiments, the precipitation and / or crystallization of the ethanesulfonate is carried out by filtering the salt from the solution.

[0195] The crystalline ethanesulfonate form of compound 1 can be identified by its distinctive signature (e.g., those relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0196] In some embodiments, crystalline ethanesulfonates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 33.

[0197] In some embodiments, the ethanesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 4.5°(2θ), about 7.3°(2θ), about 9.0°(2θ), about 14.7°(2θ), and about 15.9°(2θ).

[0198] In some embodiments, the ethanesulfonate of compound 1 has at least two characteristic XRPD peaks selected from about 4.5°(2θ), about 7.3°(2θ), about 9.0°(2θ), about 14.7°(2θ), and about 15.9°(2θ).

[0199] In some embodiments, the ethanesulfonate of compound 1 has at least three characteristic XRPD peaks selected from about 4.5°(2θ), about 7.3°(2θ), about 9.0°(2θ), about 14.7°(2θ), and about 15.9°(2θ).

[0200] In some embodiments, the ethanesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 4.5°(2θ), about 7.3°(2θ), about 9.0°(2θ), about 14.7°(2θ), about 15.9°(2θ), about 18.0°(2θ), about 18.9°(2θ), about 19.4°(2θ), about 21.4°(2θ), about 22.1°(2θ), about 25.3°(2θ), about 27.7°(2θ), and about 31.6°(2θ).

[0201] In some embodiments, the ethanesulfonate of compound 1 has at least two characteristic XRPD peaks selected from approximately 4.5°(2θ), approximately 7.3°(2θ), approximately 9.0°(2θ), approximately 14.7°(2θ), approximately 15.9°(2θ), approximately 18.0°(2θ), approximately 18.9°(2θ), approximately 19.4°(2θ), approximately 21.4°(2θ), approximately 22.1°(2θ), approximately 25.3°(2θ), approximately 27.7°(2θ), and approximately 31.6°(2θ).

[0202] In some embodiments, the ethanesulfonate of compound 1 has at least three characteristic XRPD peaks selected from approximately 4.5°(2θ), approximately 7.3°(2θ), approximately 9.0°(2θ), approximately 14.7°(2θ), approximately 15.9°(2θ), approximately 18.0°(2θ), approximately 18.9°(2θ), approximately 19.4°(2θ), approximately 21.4°(2θ), approximately 22.1°(2θ), approximately 25.3°(2θ), approximately 27.7°(2θ), and approximately 31.6°(2θ).

[0203] In some embodiments, ethanesulfonates exhibit a DSC thermogram with an endothermic peak at a temperature of approximately 227°C. In some embodiments, ethanesulfonates have a DSC thermogram substantially shown in Figure 34. In some embodiments, ethanesulfonates have a TGA thermogram substantially shown in Figure 35.

[0204] In some embodiments, the ethanesulfonate of compound 1 has at least one characteristic XRPD peak selected from about 4.5, about 7.3, about 9.0, about 14.7, and about 15.9, and this ethanesulfonate exhibits a DSC thermogram with an endothermic peak at a temperature of about 227°C.

[0205] In some embodiments, the ethanesulfonate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0206] maleate The maleate of compound 1 can be prepared by any suitable method for preparing maleic acid addition salts. For example, compound 1 can be mixed with maleic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering it from the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of maleic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of maleic acid. In certain embodiments, compound 1 is mixed with about 1.2 molar equivalents of maleic acid.

[0207] The crystallization solvent may include any solvent or solvent mixture capable of at least partially dissolving compound 1. In some embodiments, the crystallization solvent includes alcohols. Suitable alcohols include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, isopropanol (isopropyl alcohol, 2-propanol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-pentanol, 2-pentanol, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. In some embodiments, the crystallization solvent includes dichloromethane, methanol, ethanol, 1-propanol, or isopropanol. In some embodiments, the crystallization solvent includes dichloromethane.

[0208] In some embodiments, the crystallization solvent is methanol.

[0209] In some embodiments, the crystallization solvent is heated to a temperature of about 50°C. In some embodiments, temperatures of about 50°C to about 80°C are used. In some embodiments, temperatures of about 40°C to about 60°C are used. In some embodiments, temperatures of about 45°C to about 55°C are used. In some embodiments, temperatures of about 45°C, about 50°C, about 55°C, about 60°C, about 65°C, about 70°C, about 75°C, or about 80°C are used.

[0210] In some embodiments, the crystallization solvent is heated to a temperature that can induce crystallization at a practical rate. In some embodiments, crystallization is completed within about 12 to about 24 hours, but this time can be extended or shortened depending on the choice of crystallization solvent and temperature.

[0211] In some embodiments, the precipitation and / or crystallization of the maleate is carried out by filtering the salt from the solution.

[0212] The crystalline maleate form of compound 1 can be identified by its distinctive signature (e.g., related to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR).

[0213] In some embodiments, crystalline maleates can be characterized by powder X-ray diffraction (XRPD) patterns substantially shown in Figure 37.

[0214] In some embodiments, the maleate of compound 1 has at least one characteristic XRPD peak selected from about 6.6°(2θ), about 8.4°(2θ), about 8.9°(2θ), about 13.1°(2θ), and about 13.5°(2θ).

[0215] In some embodiments, the maleate of compound 1 has at least two characteristic XRPD peaks selected from about 6.6°(2θ), about 8.4°(2θ), about 8.9°(2θ), about 13.1°(2θ), and about 13.5°(2θ).

[0216] In some embodiments, the maleate of compound 1 has at least three characteristic XRPD peaks selected from about 6.6°(2θ), about 8.4°(2θ), about 8.9°(2θ), about 13.1°(2θ), and about 13.5°(2θ).

[0217] In some embodiments, the maleate of compound 1 has at least one characteristic XRPD peak selected from approximately 6.6°(2θ), approximately 8.4°(2θ), approximately 8.9°(2θ), approximately 12.7°(2θ), approximately 13.1°(2θ), approximately 13.5°(2θ), approximately 14.6°(2θ), approximately 15.3°(2θ), approximately 19.7°(2θ), approximately 21.2°(2θ), approximately 25.7°(2θ), approximately 26.4°(2θ), and approximately 26.8°(2θ).

[0218] In some embodiments, the maleate of compound 1 has at least two characteristic XRPD peaks selected from approximately 6.6°(2θ), approximately 8.4°(2θ), approximately 8.9°(2θ), approximately 12.7°(2θ), approximately 13.1°(2θ), approximately 13.5°(2θ), approximately 14.6°(2θ), approximately 15.3°(2θ), approximately 19.7°(2θ), approximately 21.2°(2θ), approximately 25.7°(2θ), approximately 26.4°(2θ), and approximately 26.8°(2θ).

[0219] In some embodiments, the maleate of compound 1 has at least three characteristic XRPD peaks selected from approximately 6.6°(2θ), approximately 8.4°(2θ), approximately 8.9°(2θ), approximately 12.7°(2θ), approximately 13.1°(2θ), approximately 13.5°(2θ), approximately 14.6°(2θ), approximately 15.3°(2θ), approximately 19.7°(2θ), approximately 21.2°(2θ), approximately 25.7°(2θ), approximately 26.4°(2θ), and approximately 26.8°(2θ).

[0220] In some embodiments, the maleate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 205°C and approximately 280°C. In some embodiments, the maleate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 205°C. In some embodiments, the maleate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 280°C. In some embodiments, the maleate has a DSC thermogram substantially shown in Figure 38. In some embodiments, the maleate has a TGA thermogram substantially shown in Figure 39. In some embodiments, the maleate of compound 1 has at least one characteristic XRPD peak selected from approximately 6.6, approximately 8.4, approximately 8.9, approximately 13.1, and approximately 13.5, and this maleate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 205°C and approximately 280°C.

[0221] In some embodiments, the maleate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0222] Adipine salt The adipic salt of compound 1 can be prepared by any suitable method for preparing an adipic acid addition salt. For example, compound 1 can be mixed with adipic acid (e.g., about 1.0 molar equivalent or more) in a crystallization solvent, and the resulting salt can be isolated by filtering the solution. In certain embodiments, compound 1 is mixed with about 1 to about 2 molar equivalents of adipic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.5 molar equivalents of adipic acid. In certain embodiments, compound 1 is mixed with about 1 to about 1.25 molar equivalents of adipic acid.

[0223] The crystalline adipicate form of compound 1 can be identified by its distinctive signature (e.g., relating to powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid-state NMR). In some embodiments, the crystalline adipicate can be characterized by the powder X-ray diffraction (XRPD) pattern substantially shown in Figure 40.

[0224] In some embodiments, the adipine salt of compound 1 has at least one characteristic XRPD peak selected from about 6.7°(2θ), about 8.9°(2θ), about 16.2°(2θ), and about 17.8°(2θ).

[0225] In some embodiments, the adipine salt of compound 1 has at least two characteristic XRPD peaks selected from about 6.7°(2θ), about 8.9°(2θ), about 16.2°(2θ), and about 17.8°(2θ).

[0226] In some embodiments, the adipine salt of compound 1 has at least three characteristic XRPD peaks selected from about 6.7°(2θ), about 8.9°(2θ), about 16.2°(2θ), and about 17.8°(2θ).

[0227] In some embodiments, the adipinate of compound 1 has at least one characteristic XRPD peak selected from approximately 6.7°(2θ), approximately 8.9°(2θ), approximately 16.2°(2θ), approximately 17.8°(2θ), approximately 19.9°(2θ), approximately 21.4°(2θ), approximately 22.0°(2θ), approximately 22.5°(2θ), approximately 23.9°(2θ), approximately 24.4°(2θ), and approximately 25.6°(2θ).

[0228] In some embodiments, the adipinate of compound 1 has at least two characteristic XRPD peaks selected from approximately 6.7°(2θ), approximately 8.9°(2θ), approximately 16.2°(2θ), approximately 17.8°(2θ), approximately 19.9°(2θ), approximately 21.4°(2θ), approximately 22.0°(2θ), approximately 22.5°(2θ), approximately 23.9°(2θ), approximately 24.4°(2θ), and approximately 25.6°(2θ).

[0229] In some embodiments, the adipinate of compound 1 has at least three characteristic XRPD peaks selected from approximately 6.7°(2θ), approximately 8.9°(2θ), approximately 16.2°(2θ), approximately 17.8°(2θ), approximately 19.9°(2θ), approximately 21.4°(2θ), approximately 22.0°(2θ), approximately 22.5°(2θ), approximately 23.9°(2θ), approximately 24.4°(2θ), and approximately 25.6°(2θ).

[0230] In some embodiments, the adipinate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 62°C and approximately 271°C. In some embodiments, the adipinate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 62°C. In some embodiments, the adipinate exhibits a DSC thermogram with endothermic peaks at temperatures of approximately 271°C. In some embodiments, the adipinate has a DSC thermogram substantially shown in Figure 41.

[0231] In some embodiments, the adipinate of compound 1 has at least one characteristic XRPD peak selected from about 6.7, about 8.9, about 16.2, and about 17.8, and this adipinate exhibits a DSC thermogram with endothermic peaks at temperatures of about 62°C and about 271°C.

[0232] In some embodiments, the adipinate of compound 1 is substantially crystalline. In some embodiments, the salt is crystalline. In some embodiments, the salt is a hydrate. In some embodiments, the salt is a solvate.

[0233] How to use Compound 1 and the salts described herein can inhibit the activity of FGFR enzymes. For example, Compound 1 may be used to inhibit the activity of FGFR enzymes in cells, individuals, or patients where such inhibition is required, by administering Compound 1 in an inhibitory dose to such cells, individuals, or patients.

[0234] Compound 1 and its salts are useful as FGFR inhibitors in the treatment of various diseases associated with abnormal expression or activity of FGFR enzymes or FGFR ligands. Compounds that inhibit FGFR are useful in providing means of inhibiting tumor growth or inducing tumor apoptosis, specifically by inhibiting angiogenesis. Therefore, Compound 1 and its salts are expected to prove useful in the treatment or prevention of proliferative disorders (such as cancer). Certain tumors containing activating mutants of receptor tyrosine kinases, or certain tumors in which receptor tyrosine kinases are upregulated, may be particularly sensitive to these inhibitors.

[0235] In certain embodiments, the present disclosure provides a method for treating an FGFR-mediated disorder in a patient requiring treatment, the method comprising the step of administering a salt of compound 1 or a pharmaceutical composition thereof to the patient.

[0236] For example, compound 1, its salts, and their solid forms are useful in the treatment of cancer. Examples of cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., larynx, hypopharynx, nasopharynx, oropharynx, lip, and mouth cancers, head and neck squamous cell carcinoma), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma). Examples include bronchial cancer, bronchial adenoma, pleuroblastoma, 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, skin cancer (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma), and brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0237] Further examples of cancer 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 lymphoma or non-Hodgkin lymphoma, myeloproliferative neoplasms (e.g., 8p11 myeloproliferative syndrome, polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenström macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-associated lymphoma, and Burkitt lymphoma.

[0238] In certain embodiments, a method for treating cancer is provided herein, which comprises administering to a patient in need of it a therapeutically effective amount of compound 1, its salts, and their solid forms. In certain embodiments, 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 lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, myeloproliferative neoplasm, chronic myeloid lymphoma, acute lymphoblastic lymphoma, hairy cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma. In certain embodiments, cancer is bladder cancer. In certain embodiments, liver cancer is cholangiocarcinoma.

[0239] Other cancers that can be treated with compound 1, its salts, or their solid forms include tumors of the eye, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0240] Compound 1, its salts, or their solid forms may also be useful in suppressing tumor metastasis.

[0241] In some embodiments, Compound 1 or the solid form described herein may be used for the treatment of Alzheimer's disease, HIV, or tuberculosis.

[0242] As used herein, the term “8p11 myeloproliferative syndrome” is intended to refer to myeloid / lymphoid neoplasms associated with eosinophilia and FGFR1 abnormalities.

[0243] As used herein, the term “cells” is intended to refer to in vitro, ex vivo, or in vivo cells. In some embodiments, ex vivo cells may be part of a tissue sample excised from an organism (such as a mammal). In some embodiments, in vitro cells may be cells in a cell culture. In some embodiments, in vivo cells may be living cells in an organism (such as a mammal).

[0244] As used herein, the term “contact” refers to bringing a specified part together in an in vitro or in vivo system. For example, “contact” an FGFR enzyme with a compound described herein (e.g., a salt of compound 1) includes administering the compound described herein to an individual or patient (such as a human) having FGFR, and introducing the compound described herein (e.g., a salt of compound 1) into a sample, for example, a cell preparation or purified preparation containing an FGFR enzyme.

[0245] As used herein, the terms “individual” or “patient” are interchangeable and refer to any animal, including mammals, which are preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0246] As used herein, the term “therapeutably effective amount” refers to the amount of an active compound or pharmaceutical product (such as any amount of the solid form or salt thereof disclosed herein) that elicits a biological or pharmacological response in a tissue, system, animal, individual, or human being being sought by a researcher, veterinarian, physician, or other clinician. An appropriate “effective” amount in any individual case may be determined using methods known to those skilled in the art.

[0247] The term "pharmaceutically acceptable" is used herein to mean that a compound, material, composition, and / or dosage form is suitable for use in contact with human and animal tissues within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and that the benefit / risk ratio is reasonable.

[0248] As used herein, the term “pharmaceutically acceptable carrier or pharmaceutical additive” refers to a pharmaceutically acceptable material, composition, or medium (such as a liquid or solid excipient, diluent, solvent, or encapsulating material). Pharmaceutical additives or carriers are generally safe, non-toxic, and non-biologically or otherwise harmless, and such pharmaceutical additives or carriers include those acceptable for veterinary use and for pharmaceutically acceptable use in humans. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005, Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009, Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007, Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0249] As used herein, the terms “to treat” or “to treat” mean either suppressing a disease (e.g., suppressing a disease, condition, or disorder in an individual who has or is exhibiting the pathology or overall symptoms of a disease, condition, or disorder (i.e., preventing further progression of the pathology and / or overall symptoms)) or alleviating a disease (e.g., alleviating a disease, condition, or disorder in an individual who has or is exhibiting the pathology or overall symptoms of a disease, condition, or disorder (i.e., improving the pathology and / or overall symptoms) (such as reducing the severity of the disease)).

[0250] Certain features of the present invention are described in relation to individual embodiments for clarity, but it should be understood that they may also be provided in combination in a single embodiment (whereas such embodiments are intended to be combined as if they were multiplicative). Conversely, various features of the present invention are described in relation to a single embodiment for simplification, but may also be provided separately or in any suitable partial combination.

[0251] Combination therapy To treat diseases, disorders, or conditions associated with FGFR, or any of the diseases or conditions described herein, one or more additional pharmaceuticals or therapeutic methods (e.g., antiviral agents, chemotherapeutic agents or other anticancer agents, immunostimulants, immunosuppressants, radiation, antitumor vaccines and antiviral vaccines, cytokine therapies (e.g., IL-2, GM-CSF, etc.), and / or tyrosine kinase inhibitors) may be used in combination with Compound 1 or a salt thereof. Such agents may be used in combination with the compound of the present invention in a single dosage form, or they may be administered concurrently or sequentially in separate dosage forms.

[0252] The salts of the FGFR inhibitor (Compound 1) described in this specification can be used in combination with one or more other kinase inhibitors for treating diseases (such as cancer) affected by multiple signal transduction pathways. For example, the combination can include one or more inhibitors of the following kinases for treating 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 / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. Further, the salts of the FGFR inhibitor described in this specification can be used in combination with inhibitors of kinases (such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinase, etc.) associated with the PIK3 / Akt / mTOR signal transduction pathway.

[0253] In some embodiments, the salts of Compound 1 described in this specification 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, etc.) for treating diseases and disorders. Examples of diseases and disorders include cancer, infectious diseases, inflammation, and neurodegenerative disorders.

[0254] In some embodiments, salts of compound 1 described herein may be used in combination with therapeutic agents that target epigenetic regulators. Examples of epigenetic regulators include bromodomain inhibitors, histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, for example, vorinostat.

[0255] For the treatment of cancer and other proliferative disorders, salts of Compound 1 described herein may be used in combination with targeted therapeutic agents. Such targeted therapeutic agents include JAK kinase inhibitors (ruxolitinib, used as an addendum, JAK1 / 2 selective and JAK1 selective baricitinib or INCB39110), Pim kinase inhibitors (e.g., INCB53914), PI3 kinase inhibitors (PI3K-delta selective inhibitors and broad-spectrum PI3K inhibitors (e.g., INCB50465 and INCB54707), PI3K-gamma inhibitors (e.g., PI3K-gamma 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, BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (bortezomib, carfilzomib), HDAC inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, BET (bromo These include inhibitors of members of the family (and extra terminal) (e.g., bromodomain inhibitors, or BET inhibitors such as INCB54329 or INCB57643), LSD1 inhibitors (INCB59872 or INCB60003), arginase inhibitors (INCB1158), indoleamine 2,3-dioxygenase inhibitors (epacadostat, NLG919, or BMS-986205), and PARP inhibitors (e.g., olaparib or lucaparib).

[0256] For the treatment of cancer and other proliferative disorders, salts of Compound 1 described herein may be used in combination with chemotherapeutic agents, nuclear receptor agonists or antagonists, or other antiproliferative agents. Salts of Compound 1 may also be used in combination with medical treatments (such as surgery or radiotherapy (e.g., gamma irradiation, neutron radiotherapy, electron radiotherapy, proton therapy, brachytherapy, and systemic radioisotope therapy)). Examples of suitable chemotherapeutic agents include: avalerix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, baricitinib, bendamustine, bevacizumab, bexarotene, bleomycin, bortezomib, intravenous busulfan, oral busulfan Carsterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin difutitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, Erlotinib, Estramustine, Etoposide Phosphate, Etoposide, Exemestane, Fentanyl Citrate, Filgrastim, Phloxuridine, Fludarabine, Fluorouracil, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab Ozogamicin, Goserelin Acetate, Histrelin Acetate, Ibritumomab Tiuxetan, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Irinotecan, Ditosylate Lapatinib, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechloretamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone fenpropionate, nelarabine, niraparib, nofetumomab, olaparib, oxaliplatin, paclitaxel, pamidronic acid, panobinostat, panitumumab,Pegasparagase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobromane, pricamycin, procarbazine, quinacrine, rasburicase, rituximab, rucaparib, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malate, tamoxifen, temozolomide, teniposide, testactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, barrubicin, vinblastine, vincristine, vinorelbine, vorinostat, beriparib, talazoparib, and zoledronate.

[0257] In some embodiments, salts of compound 1 described herein may be used in combination with immune checkpoint inhibitors. Examples of immune checkpoint inhibitors include inhibitors against immune checkpoint molecules, such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is an irritant checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of the disclosure provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0258] In some embodiments, the compounds provided herein may be used in combination with one or more agonists of immune checkpoint molecules (e.g., OX40, CD27, GITR, and CD137 (also known as 4-1BB)).

[0259] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0260] In some embodiments, the inhibitor of the immune checkpoint molecule is a small molecule PD-L1 inhibitor. In some embodiments, the IC50 of the small molecule PD-L1 inhibitor is less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM when tested in the PD-L1 assay described in U.S. Patent Publications US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260 (each of these publications is incorporated in whole by reference for any purpose).

[0261] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor (e.g., an anti-PD-1 monoclonal antibody). In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. 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. Other anticancer drugs (multiple options are possible) include antibody drugs (such as those targeting 4-1BB, e.g., urelumab, utomirumab).

[0262] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0263] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor (e.g., an anti-PD-1 monoclonal antibody). In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®), pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. 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. Other anticancer drugs (multiple options are possible) include antibody drugs (such as those targeting 4-1BB, e.g., urelumab, utomirumab).

[0264] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor (e.g., 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.

[0265] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1 (e.g., an anti-PD-1 / PD-L1 monoclonal antibody). In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0266] In some embodiments, the inhibitor is MCLA-145.

[0267] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4 (e.g., an anti-CTLA-4 antibody). In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0268] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3 (e.g., an anti-LAG3 antibody). In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

[0269] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3 (e.g., an anti-TIM3 antibody). In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0270] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR (e.g., an anti-GITR antibody). In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, or MEDI1873.

[0271] In some embodiments, the inhibitor of the immune checkpoint molecule is an OX40 agonist (e.g., an OX40 agonist antibody or an OX40L fusion protein). In some embodiments, the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0272] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor (e.g., an anti-CD20 antibody). In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0273] The compounds of this disclosure may be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor. In some embodiments, the compounds of this disclosure may be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitors are inhibitors of IDO1, TDO, or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0274] As described throughout, these additional compounds, inhibitors, and agents may be used in combination with the compounds of the present invention in a single or sequential dosage form, or administered simultaneously or sequentially as separate dosage forms. In some embodiments, salts of Compound 1 described herein may be used in combination with one or more agents for treating a disease (such as cancer). In some embodiments, the agents are alkylating agents, proteasome inhibitors, corticosteroids, or immunomodulators. 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).

[0275] Suitable antiviral agents intended for use in combination with compound 1 or a salt thereof may include nucleoside and nucleotide-based reverse transcriptase inhibitors (NRTIs), non-nucleoside-based reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0276] Examples of suitable NRTIs include zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir (BMS-180194), BCH-10652, emtricitabine [(-)-FTC], beta-L-FD4 (also called beta-L-D4C, the name being beta-L-2’,3’-dideoxy-5-fluorocytidine), DAPD, ((-)-beta-D-2,6,-diaminopurine dioxolane), and rodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587), delavirdine (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 (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0277] Suitable agents for use in combination with compound 1 or its salts for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiotherapy. Compound 1 and its salts may be effective in combination with antihormone agents for the treatment of breast cancer and other tumors. Suitable examples include anti-estrogen agents (including, but not limited to, tamoxifen and toremifene), aromatase inhibitors (including, but not limited to, letrozole, anastrozole, and exemestane), corticosteroids (e.g., prednisone), progestins (e.g., megastrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormone agents used for the treatment of prostate cancer and other cancers may also be used in combination with compound 1 and its salts. These antihormone agents include antiandrogens (including, but not limited to, flutamide, bicalutamide, and nilutamide), luteinizing hormone-releasing hormone (LHRH) analogues (including leuprolide, goserelin, triptorelin, and histrelin), LHRH antagonists (e.g., degarelix), androgen receptor blockers (e.g., enzalutamide), and agents that suppress androgen production (e.g., abiraterone).

[0278] Compound 1 and its salts may be used in combination with or in succession with other agents against membrane receptor kinases, particularly in patients who have pre-existing or acquired resistance to targeted therapy. Such agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, as well as inhibitors or antibodies against cancer-associated fusion protein kinases (such as Bcr-Abl and EML4-Alk). EGFR inhibitors include gefitinib and erlotinib, while EGFR / Her2 inhibitors include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and nesitumumab. c-Met inhibitors may be used in combination with FGFR inhibitors. These c-Met inhibitors include onartumzumab, tivantinib, and INC-280. Drugs for Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, while drugs for Alk (or EML4-ALK) include crizotinib.

[0279] Angiogenesis inhibitors, when used in combination with FGFR inhibitors, may be effective in some tumors. These angiogenesis inhibitors include antibodies against VEGF or VEGFR, or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenic inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0280] In cancer, intracellular signaling pathways are frequently activated, and drugs that target components of these pathways are used in combination with drugs that target receptors to enhance efficacy and reduce resistance. Examples of drugs that can be used in combination with compound 1 or its salts include inhibitors of the PI3K-AKT-mTOR pathway, the Raf-MAPK pathway, the JAK-STAT pathway, as well as protein chaperones and cell cycle progression inhibitors.

[0281] Drugs targeting PI3 kinase include, but are not limited to, piralalisib, idelalisib, and buparisib. mTOR inhibitors (such as rapamycin, sirolimus, temsirolimus, and everolimus) may be used in combination with FGFR inhibitors. Other appropriate examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors), as well as trametinib, selumetinib, and GDC-0973 (MEK inhibitors). Inhibitors against one or more JAKs (e.g., ruxolitinib, baricitinib, tofacitinib), inhibitors against one or more Hsp90s (e.g., tanespimycin), inhibitors against one or more cyclin-dependent kinases (e.g., palbociclib), inhibitors against one or more HDACs (e.g., panobinostat), inhibitors against one or more PARPs (e.g., olaparib), and inhibitors against one or more proteasomes (e.g., bortezomib, carfilzomib) may also be used in combination with compound 1 or a salt thereof. In some embodiments, the JAK inhibitor is selective for JAK1 compared to JAK2 and JAK3.

[0282] Other agents suitable for use in combination with compound 1 or its salts include combination chemotherapy used in lung cancer and other solid tumors (platinum-based dual combination therapies such as cisplatin or carboplatin + gemcitabine, cisplatin or carboplatin + docetaxel, cisplatin or carboplatin + paclitaxel, cisplatin or carboplatin + pemetrexed, or gemcitabine + paclitaxel-bound particles (Abraxane®)).

[0283] Appropriate chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosourea, and triazenes), such alkylating agents include uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobromane, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0284] Other agents suitable for use in combination with compound 1 or its salts include dacarbazine (DTIC) (optionally used in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin); the "Dartmouth regimen" (consisting of DTIC, BCNU, cisplatin, and tamoxifen); a combination of cisplatin, vinblastine, and DTIC; or temozolomide. Compound 1 can also be used in combination with immunotherapeutic agents, such as cytokines (interferon alpha, interleukin-2, and tumor necrosis factor (TNF)).

[0285] Appropriate chemotherapeutic agents 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, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0286] Appropriate chemotherapeutic agents or other anticancer agents further include 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®), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0287] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0288] Suitable treatments include epidophyllotoxin, anti-cancer enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum-coordinated complexes (such as cisplatin and carboplatin), biological response modifiers, proliferation inhibitors, anti-hormone therapies, leucovorin, tegafur, and cytotoxic agents such as hematopoietic growth factors.

[0289] Other anticancer drugs include antibody drugs, such as trastuzumab (Herceptin), antibodies against costimulatory molecules (CTLA-4 antibody, 4-1BB antibody, PD-L1 antibody, and PD-1 antibody, etc.), or antibodies against cytokines (IL-10, TGF-β, etc.).

[0290] Other anticancer drugs include those that block the migration of immune cells (such as antagonists targeting chemokine receptors, including CCR2 and CCR4).

[0291] Other anticancer drugs include those that enhance the immune system (such as adjuvants or adoptive T-cell transplantation).

[0292] Cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0293] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, the administration of such agents is also 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), and the disclosures of that document are incorporated herein by reference as well as shown in their entirety.

[0294] Formulation, dosage form, and administration When used as a pharmaceutical, the salts of the present invention as described herein may be administered in the form of a pharmaceutical composition (meaning a combination of a salt of Compound 1 as described herein and at least one pharmaceutically acceptable carrier). Such compositions may be prepared in manner well known in the pharmaceutical field and may be administered by various routes of administration depending on whether the desired treatment is topical or systemic, and the area of ​​treatment. Administration may be topical (including transocular administration and administration to mucous membranes (including intranasal, intravaginal, and intrarectal delivery)), intrapulmonary administration (e.g., administration by inhalation or blowing of powder or aerosol (including by nebulizer), intratracheal administration, intranasal administration, subcutaneous administration, and transdermal administration), ophthalmic administration, oral administration, or parenteral administration. Methods for transocular delivery may include topical administration (ophthalmic administration), subconjunctival injection, periorbital injection, or intravitreal injection, or introduction by a balloon catheter or intraocular implant surgically placed in the conjunctival sac. Parenteral administration includes injection or infusion into the vein, artery, subcutaneous, peritoneal, or intramuscular space, or administration into the intracranial space (e.g., subarachnoid or ventricle). Parenteral administration may be in the form of a single bolus dose or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous bases, powder bases, or oily bases, thickeners, and the like may be required or desirable.

[0295] This disclosure also includes pharmaceutical compositions comprising a salt of compound 1 as an active ingredient in combination with one or more pharmaceutically acceptable carriers. In the preparation of the compositions described herein, the active ingredient is typically mixed with a pharmaceutical additive, diluted with a pharmaceutical additive, or encapsulated in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the pharmaceutical additive acts as a diluent, such pharmaceutical additive may be a solid, semi-solid, or liquid material, and such material acts as a medium, carrier, or intermediary for the active ingredient. Accordingly, the compositions may take the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments (for example, containing up to 10% by weight of the active compound), soft gelatin capsules and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaging powders.

[0296] In the preparation of a formulation, the active compound may be pulverized to an appropriate particle size before being mixed with other components. If the active compound is substantially insoluble, it may be pulverized to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by pulverization (e.g., to about 40 mesh) to distribute the active compound substantially uniformly in the formulation.

[0297] Some examples of suitable pharmaceutical additives include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may further contain lubricants (such as talc, magnesium stearate, and mineral oil), humectants, emulsifiers and suspending agents, preservatives (such as methyl hydroxybenzoate and propyl hydroxybenzoate), sweeteners, and flavoring agents. The compositions described herein may be formulated to accelerate, prolong, or delay the release of the active ingredient after administration to a patient using procedures known in the art.

[0298] The composition can be formulated in unit dosage forms, each dose containing approximately 5 to 100 mg of the active ingredient, more typically 10 to 30 mg. The term "unit dosage form" refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect when combined with appropriate pharmaceutical excipients.

[0299] Active compounds can be effective over a wide dose range and are generally administered in pharmaceutically effective amounts. However, it should be understood that the actual amount of compound administered will usually be determined by the physician in accordance with the relevant circumstances, including the condition to be treated, the route of administration chosen, the compound actually administered, the individual patient's age, weight, and response, the severity of the patient's symptoms, and similar factors.

[0300] For the preparation of solid compositions (such as tablets), a solid pre-formulation composition containing a homogeneous mixture of salts of compound 1 is formed by mixing the main active ingredient with pharmaceutical additives. When such a pre-formulation composition is referred to as homogeneous, it typically means that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms (such as tablets, pills, and capsules). This pre-formulation solid is then subdivided into unit dosage forms of the above type (for example, containing 0.1 to about 500 mg of the active ingredient of this disclosure).

[0301] The tablets or pills of this disclosure may be coated or otherwise treated to obtain a dosage form that offers the advantage of extended action. For example, the tablets or pills may contain an internal dose component and an external dose component, the external dose component taking the form of an outer coating that surrounds the internal dose component. These two components may be separated by an enteric coating that works to resist disintegration in the stomach and allows the internal component to reach the duodenum intact or delays its release. A variety of materials may be used for such enteric coatings or enteric layers, including several polymer acids, as well as mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0302] Liquid forms in which a salt of Compound 1 described herein, or a composition thereof, may be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, emulsions flavored with edible oils (such as cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical media.

[0303] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain the aforementioned appropriate pharmaceutically acceptable pharmaceutical additives. In some embodiments, compositions are administered orally or via nasal respiratory routes to obtain topical or systemic effects. Compositions may be sprayed using an inert gas. The sprayed solution may be directly inhaled from a spraying device, or the spraying device may be attached to a face mask tent or intermittent positive pressure respirator. Solution compositions, suspension compositions, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0304] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, the mode of administration, and similar factors. For therapeutic purposes, a composition may be administered to a patient already suffering from a disease in an amount sufficient to cure, or at least partially suppress, the symptoms of that disease and its complications. The effective dose will depend on the medical condition being treated, as well as the judgment of the attending physician, taking into account several factors (e.g., the severity of the disease, the patient's age, weight, and overall health, and similar factors).

[0305] The compositions administered to patients may take the form of the pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization methods or by filtration sterilization. Aqueous solutions may be packaged for immediate use or lyophilized; the lyophilized preparations may be mixed with a sterile aqueous carrier before administration. The pH of the compound preparations is typically 3–11, more preferably 5–9, and most preferably 7–8. It will be understood that the use of the aforementioned pharmaceutical additives, carriers, or stabilizers may result in the formation of pharmaceutical salts.

[0306] The therapeutic dose of a salt of compound 1 may vary depending on, for example, the specific use in which the treatment is performed, the mode of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The proportion or concentration of a salt of compound 1 in a pharmaceutical composition may vary depending on several factors, including the dose, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, a salt of compound 1 may be provided for parenteral administration in an aqueous physiological buffer containing the compound at approximately 0.1 to approximately 10% w / v. Some typical dose ranges are approximately 1 μg / kg body weight / day to approximately 1 g / kg body weight / day. In some embodiments, the dose range is approximately 0.01 mg / kg body weight / day to approximately 100 mg / kg body weight / day. The dose may depend on variables such as the type and progression of the disease or disorder, the overall health status of a particular patient, the relative biological potency of the compound selected, the formulation of the pharmaceutical excipients, and its route of administration. The effective dose may be extrapolated from dose-response curves obtained from in vitro or animal model test systems.

[0307] Salts of compound 1 may also be formulated in combination with one or more additional active ingredients, which may include any pharmaceutical product (such as antivirals, vaccines, antibodies, immunostimulants, immunosuppressants, anti-inflammatory agents, and the like). [Examples]

[0308] Example 1 Experimental method In the following experiment, powder X-ray diffraction analysis was performed using a Rigaku MiniFlex X-ray Powder Diffractometer (XRPD) instrument. The general experimental procedure for XRPD is as follows: (1) X-ray irradiation is performed using copper as the X-ray source (wavelength 1.054056 Å, K β (2) X-ray output 30KV, 15mA, and (3) sample powder is scattered on a non-reflective sample holder. Typical XRPD measurement conditions are as follows: start angle 3°; end angle 45°; sampling 0.02°; scanning speed 2° / min.

[0309] Differential scanning calorimetry (DSC) was performed using a TA Instruments Differential Scanning Calorimetry, Model Q200 (with autosampler). The DSC instrument conditions were as follows: 30-300°C at 10°C / min; Tzero aluminum sample pan and lid; nitrogen gas flow rate of 50 mL / min.

[0310] Thermogravimetric analysis (TGA) was performed using a TA Instrument Thermogravimetric Analyzer, Model Q500. The general experimental conditions for TGA were as follows: heating range 20°C to 600°C (20°C / min); nitrogen purging (performed at a gas flow rate of 40 mL / min, and the balance side was also purged at this flow rate); sample purging flow rate of 60 mL / min; platinum sample pan.

[0311] Example 2 Preparation of D-(-)-tartrate A solution containing compound 1 (94.55 mg, 0.194 mmol) in a 1:1 (v / v) mixture of methanol and dichloromethane (2.4 mL) was prepared by adding D-(-)-tartaric acid (32.55 mg, 0.217 mmol, 1.12 equivalents). The reaction mixture was stirred to obtain a viscous slurry. This slurry was stirred at 50°C for 1.5 hours, then cooled to room temperature and stirred overnight. The slurry was filtered, and the solid was dried under reduced pressure at 36-40°C overnight (16 hours) to obtain compound 1 D-(-)-tartrate (104.6 mg, yield 84%).

[0312] The stoichiometric ratio of compound 1 to D-(-)-tartaric acid is 1 The ratio was determined to be 1:1 by 1H NMR (Figure 1). The crystallinity of compound 1 D-(-)-tartrate was confirmed by XRPD (Figure 2) and further confirmed by DSC (Figure 3) and TGA (Figure 4). The analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This DSC thermogram of DSC shows an endothermic peak at a temperature of approximately 276°C. [Table 1]

[0313] Example 3 Preparation of L-(+)-tartrate To a solution containing compound 1 (85.01 mg, 0.174 mmol) in a 1:1 mixture of methanol and dichloromethane (2.4 mL), L-(-)-tartaric acid (32.85 mg, 0.218 mmol, 1.25 equivalents) was added. The reaction mixture was stirred to obtain a slurry. This slurry was stirred at 50°C for 50 minutes, then cooled to room temperature and stirred overnight. The slurry was filtered, the solid was washed with methyl t-butyl ether, and dried under reduced pressure at 36-40°C overnight (16 hours) to obtain compound 1 L-(-)-tartrate (104.6 mg, yield 84%).

[0314] The stoichiometric ratio of compound 1 to L-(+)-tartaric acid is 1 The ratio was determined to be 1:1 by 1H NMR (Figure 5). The crystallinity of compound 1 L-(+)-tartrate was confirmed by XRPD (Figure 6) and further confirmed by DSC (Figure 7). The TGA of this salt is shown in Figure 8. The analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This L-(+)-tartrate shows a DSC thermogram with endothermic peaks at temperatures of approximately 90°C, approximately 211°C, and approximately 266°C. [Table 2]

[0315] Example 4 Preparation of salicylates A solution containing compound 1 (94.42 mg, 0.193 mmol) in a mixture of dichloromethane (1.5 mL) and methanol (1.0 mL) was prepared by adding salicylic acid (33.8 mg, 0.245 mmol, 1.26 equivalents). The reaction mixture was stirred to obtain a clear solution. This solution was evaporated to remove the dichloromethane, yielding a slurry. This slurry was stirred at 50°C for 50 minutes, then cooled to room temperature and stirred overnight. The slurry was filtered, and the solid was washed with methyl t-butyl ether. The solid was dried under reduced pressure at 36-40°C overnight (16 hours) to obtain compound 1 salicylate (111.7 mg, 92% yield).

[0316] The stoichiometric ratio of compound 1 to salicylic acid 1 The ratio was determined to be 1:1 by 1H NMR (Figure 9). The crystallinity of compound 1 salicylate was confirmed by XRPD (Figure 10) and further confirmed by DSC (Figure 11). The TGA of this salicylate is shown in Figure 12. The analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This salicylate shows a DSC thermogram with an endothermic peak at a temperature of approximately 212°C. [Table 3-1] [Table 3-2]

[0317] Example 5 Preparation of hydrochloride A solution containing compound 1 (94.49 mg, 0.194 mmol) in a mixture of dichloromethane (1.5 mL) and methanol (1.0 mL) was prepared by adding hydrochloric acid (0.25 mL, 2-propanol / 1 M in water, 0.25 mmol, 1.25 equivalents). The reaction mixture was stirred to obtain a clear solution. This solution was evaporated to remove the dichloromethane, yielding a slurry. This slurry was stirred at 50°C for 50 minutes, then cooled to room temperature and stirred overnight. The slurry was filtered, and the solid was washed with methyl t-butyl ether. The solid was dried under reduced pressure at 36-40°C overnight (16 hours) to obtain compound 1 hydrochloride (88.2 mg, yield 87%).

[0318] The crystallinity of compound 1 hydrochloride was confirmed by XRPD (Figure 13) and further confirmed by DSC (Figure 14). Figure 15 shows the TGA results. The analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This hydrochloride shows a DSC thermogram with endothermic peaks at temperatures of approximately 120°C, approximately 189°C, and approximately 274°C. [Table 4]

[0319] Example 6 Preparation of hydrobromide A solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL) was prepared, to which hydrobromic acid (48% in water, 0.084 mL, 1.2 equivalents) was added. This reaction mixture was heated to 50°C, and dichloromethane was removed by distillation. The mixture was stirred at 50°C for about 1 hour. The mixture was cooled to room temperature and stirred for a further 1.5 hours. The reaction mixture was filtered, and the solid was washed with methyl t-butyl ether (1.5 mL). The solid was dried under reduced pressure at 40°C overnight to obtain compound 1 hydrobromide (0.32 g, yield 91.4%).

[0320] Figure 16 shows the hydrobromide of compound 1. 1The 1H NMR spectrum is shown. The crystallinity of compound 1 hydrobromide was confirmed by XRPD (Figure 17). Figure 18 shows the DSC thermogram of compound 1 hydrobromide. Figure 19 shows the TGA thermogram of compound 1 hydrobromide. The analytical data collected for this product, including characterization by XRPD and DSC, were obtained as described in Example 1. This hydrobromide shows a DSC thermogram with endothermic peaks at temperatures of approximately 84°C and approximately 235°C. [Table 5]

[0321] Example 7 Preparation of fumarate To a solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL), fumaric acid (0.086 g, 1.2 equivalents) was added. This reaction mixture was heated to 50°C and distilled to remove the dichloromethane. The mixture was stirred at 50°C for about 1 hour. The mixture was cooled to room temperature and stirred for a further 1.5 hours. The reaction mixture was filtered, and the solid was washed with methyl t-butyl ether (1.5 mL). The solid was dried under reduced pressure at 40°C overnight to obtain compound 1 fumarate (0.34 g, yield 91.6%).

[0322] Figure 20 shows the compound 1 fumarate. 1 Figure 21 shows the 1H NMR spectrum. Figure 22 shows the XRPD pattern of compound 1 fumarate. Figure 23 shows the DSC thermogram of compound 1 fumarate. Figure 23 shows the TGA thermogram of compound 1 fumarate. The analytical data collected for this product, including characterization by XRPD and DSC, were obtained as described in Example 1. This fumarate shows a DSC thermogram with an endothermic peak at a temperature of approximately 214°C. [Table 6]

[0323] Example 8 Preparation of phosphates To a solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL), phosphoric acid (85% in water, 0.051 mL, 1.2 equivalents) was added. The reaction solution was heated to 50 °C and distilled to remove dichloromethane. The mixture was stirred at 50 °C for about 1 hour. The mixture was cooled to room temperature and further stirred for 1.5 hours. The reaction solution was filtered and the solid was washed with methyl t-butyl ether (1.5 mL). The solid was dried under reduced pressure at 40 °C overnight to obtain compound 1 phosphate (0.35 g, yield 97.2%).

[0324] Figure 24 shows the 1 1H NMR of compound 1 phosphate. Figure 25 shows the XRPD pattern of compound 1 phosphate. Figure 26 shows the DSC thermogram of compound 1 phosphate. Figure 27 shows the TGA thermogram of compound 1 phosphate. Analytical data collected for this product, including characterization by XRPD and DSC, was obtained as described in Example 1. This phosphate shows a DSC thermogram with endothermic peaks at temperatures of about 215 °C and about 221 °C. [Table 7]

[0325] Example 9 Preparation of benzenesulfonate To a solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL), benzenesulfonic acid (94%, 0.124 g, 1.2 equivalents) was added. The reaction solution was heated to 50 °C and distilled to remove dichloromethane. The mixture was stirred at 50 °C for about 1 hour. The mixture was cooled to room temperature and further stirred for 1.5 hours. The reaction solution was filtered and the solid was washed with methyl t-butyl ether (1.5 mL). The solid was dried under reduced pressure at 40 °C overnight to obtain compound 1 benzenesulfonate (0.28 g, yield 70.5%).

[0326] Figure 28 shows the 1Figure 29 shows the 1H NMR spectrum. Figure 30 shows the XRPD pattern of the solid state of compound 1 benzenesulfonate. Figure 31 shows the DSC thermogram of the solid state of compound 1 benzenesulfonate. Figure 31 shows the TGA thermogram of the solid state of compound 1 benzenesulfonate. Analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This benzenesulfonate shows a DSC thermogram with endothermic peaks at temperatures of approximately 105°C, 190°C, 222°C, and 241°C. [Table 8]

[0327] Example 10 Preparation of ethanesulfonates To a solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL), ethanesulfonic acid (95%, 0.063 mL, 1.2 equivalents) was added. This reaction mixture was heated to 50°C and dichloromethane was removed by distillation. Isopropyl alcohol (3 mL) was added. This mixture was stirred at 50°C for about 1 hour. This mixture was cooled to room temperature and stirred for a further 1.5 hours. This reaction mixture was filtered and the solid was washed with methyl t-butyl ether (1.5 mL). This solid was dried under reduced pressure at 40°C overnight to obtain compound 1 ethanesulfonate (0.27 g, yield 73.4%).

[0328] Figure 32 shows compound 1 ethanesulfonate. 1 Figure 33 shows the 1H NMR spectrum. Figure 34 shows the XRPD pattern of compound 1 ethanesulfonate. Figure 35 shows the DSC thermogram of compound 1 ethanesulfonate in solid form. Figure 35 shows the TGA thermogram of compound 1 ethanesulfonate in solid form. Analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This ethanesulfonate shows a DSC thermogram with an endothermic peak at a temperature of approximately 227°C. [Table 9]

[0329] Example 11 Preparation of maleate A solution containing compound 1 (0.3 g) in a mixture of dichloromethane (3.6 mL) and methanol (4.0 mL) was prepared, to which maleic acid (0.086 g, 1.2 equivalents) was added. This reaction mixture was heated to 50°C and distilled to remove the dichloromethane. The mixture was stirred at 50°C for about 1 hour. The mixture was cooled to room temperature and stirred for a further 1.5 hours. The reaction mixture was filtered, and the solid was washed with methyl t-butyl ether (1.5 mL). The solid was dried under reduced pressure at 40°C overnight to obtain compound 1 maleate (0.38 g, yield 102.7% [the product may contain residual solvent]).

[0330] Figure 36 shows the maleate of compound 1. 1 Figure 37 shows the 1H NMR spectrum. Figure 38 shows the XRPD pattern of compound 1 maleate. Figure 39 shows the DSC thermogram of compound 1 maleate. Figure 39 shows the TGA thermogram of compound 1 maleate. The analytical data collected for this product, including characterization by XRPD, DSC, and TGA, were obtained as described in Example 1. This maleate shows a DSC thermogram with endothermic peaks at temperatures of approximately 205°C and approximately 280°C. [Table 10]

[0331] Example 12 Preparation of adipine salts Compound 1 was reacted with adipic acid to obtain the corresponding adipine salt. The analytical data collected for this product were obtained as described in Example 1. Figure 26 shows the XRPD pattern of the solid form of compound 1 adipine salt. Figure 27 shows the DSC thermogram of the solid form of compound 1 adipine salt. [Table 11]

[0332] Example A FGFR enzyme assay The inhibitory efficacy of compound 1 was measured in an enzyme assay that detects product formation by measuring peptide phosphorylation using FRET assay. Compound 1 was serially diluted with DMSO, and 0.5 μL volumes were transferred to the wells of a 384-well plate. For FGFR3, 10 μL of FGFR3 enzyme (Millipore), diluted in assay buffer (50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 0.01% Tween-20, 5 mM DTT, pH 7.5), was added to the plate and incubated for 5–10 minutes beforehand. Appropriate controls (enzyme blank and enzyme without inhibitor) were included in the plate. The assay was initiated by adding 10 μL of a solution containing biotinylated EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1) and ATP (final concentrations of 500 nM and 140 μM, respectively) in assay buffer to the wells. The plate was incubated at 25°C for 1 hour. The reaction was stopped by adding 10 μL / well of a reaction stop solution (50 mM Tris, 150 mM NaCl, 0.5 mg / mL BSA, pH 7.8; 30 mM EDTA containing Perkin Elmer Lance Reagent (Eu-antibody PY20 (3.75 nM) and APC-streptavidin (180 nM))). After equilibrating the plate for approximately 1 hour, the wells were scanned using a PheraStar plate reader (BMG Labtech).

[0333] For the measurement of FGFR1 and FGFR2, the enzyme and ATP concentrations were modified (FGFR1 was changed to 0.02 nM and 210 μM, respectively, and FGFR2 was changed to 0.01 nM and 100 μM, respectively) and performed under equivalent conditions. These enzymes were purchased from Millipore or Invitrogen.

[0334] GraphPad prism3 was used for data analysis. 50The values ​​were derived by fitting the data to the equation for a sigmoid dose-response with a variable gradient. Y = minimum value + (maximum value - minimum value) / (1 + 10^((LogIC) 50 -X) * Hill gradient)) (where X is the logarithm of the concentration and Y is the reaction). IC 50 Compounds with a concentration of 1 μM or less are considered to be active.

[0335] Compound 1 of the present invention was found to be an inhibitor of one or more of FGFR1, FGFR2, and FGFR3 according to the above assay. 50 This is shown in Table 12 below. The "+" symbol indicates IC 50 The symbol "++" indicates that the current is less than 100 nM. 50 This indicates that the value is between 100 and 500 nM. [Table 12]

[0336] Example B FGFR cell proliferation / survival assay The ability of exemplary compounds to inhibit the proliferation of cells whose survival depends on FGFR signaling was measured using a viability determination assay. Recombinant cell lines overexpressing human FGFR3 were created by stably transfecting mouse Pro B Ba / F3 cells (obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen) with a plasmid encoding full-length human FGFR3. Cells resistant to puromycin and proliferating in the presence of heparin and FGF1 were sequentially selected. Single cell clones were isolated and characterized for functional expression of FGFR3. These Ba / F3-FGFR3 clones were used in cell proliferation assays, and compounds were screened for their ability to inhibit cell proliferation / survival. These Ba / F3-FGFR3 cells were seeded at 3500 cells / well in 96-well black cell culture plates containing RPMI1640 medium with 2% FBS, 20 μg / mL heparin, and 5 ng / mL FGF1. Cells were treated with 10 μL of a 10× concentration compound, serially diluted (from 5 mM DSMO solution to serum-free medium), to a final volume of 100 μL / well. After 72 hours of incubation, 100 μL of Cell Titer Glo® reagent (Promega Corporation) was added to each well to measure the ATP levels of the cells. After incubation for 20 minutes with shaking, luminescence was read using a plate reader. The luminescence readings were converted to inhibition percentages relative to the DMSO-treated control wells, and IC was calculated using GraphPad Prism software by fitting the data to an equation for a sigmoid dose-response with a variable gradient. 50 The value is calculated. IC 50Compounds with an IC5 concentration of 10 μM or less are considered to be active. 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, FGFR1 gene amplification)) are used in similar proliferation assays. In some experiments, MTS reagent (Cell Titer 96® AQueous One Solution Reagent (Promega Corporation)) was added at a final concentration of 333 μg / mL instead of Cell Titer Glo, and readings were made at 490 / 650 nm using a plate reader. IC5 50 Compounds with a concentration of 5 μM or less are considered to be active.

[0337] Experiment C Cell-based FGFR phosphorylation assay The inhibitory effect of compounds on FGFR phosphorylation in related cell lines (Ba / F3-FGFR3 cancer cell line, KMS-11 cancer cell line, RT112 cancer cell line, KatoIII cancer cell line, H-1581 cancer cell line, and HUVEC cell line) can be evaluated using FGFR phosphorylation-specific immunoassays. Cells are starved for 4 to 18 hours in low serum concentration (0.5%) medium without FGF1, depending on the cell line, and then treated with individual inhibitors at various concentrations for 1 to 4 hours. For some cell lines (Ba / F3-FGFR3 and KMS-11, etc.), cells are stimulated with heparin (20 μg / mL) and FGF1 (10 ng / mL) for 10 minutes. A whole cell protein extract is prepared by incubation at 4°C in a lysis buffer containing protease inhibitors and phosphatase inhibitors [50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgCl2, 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)]. The protein extract is clarified by removing cell debris by centrifugation at 14,000 × g for 10 minutes and quantified using BCA (bicinchoninic acid) microplate assay reagent (Thermo Scientific).

[0338] Phosphorylation of the FGFR receptor in protein extracts was determined using immunoassays (including Western blotting, enzyme-linked immunosorbent assay (ELISA), or bead-based immunoassay (Luminex)). For the detection of phosphorylated FGFR2, a commercially available ELISA kit (DuoSet IC Human Phospho-FGF R2α ELISA assay (R&D Systems, Minneapolis, MN)) can be used. For this assay, Kato III cells, contained in Iskov medium supplemented with 0.2% FBS, are seeded (50,000 cells / well / 100 μL) in 96-well flat-bottom tissue culture-treated plates (Corning, Corning, NY) and incubated for 4 hours at 37°C in a 5% CO2 atmosphere, either in or out of a range of test compounds. The assay is stopped by adding 200 μL of chilled PBS and centrifugation. Washed cells were lysed on wet ice for 30 minutes in cell lysis buffer (Cell Signaling, no. 9803) containing a protease inhibitor (Calbiochem, no. 535140) and PMSF (Sigma, no. P7626). The cell solubilization solution was frozen at -80°C until a certain volume was tested using the DuoSet IC Human Phospho-FGF R2α ELISA assay kit. GraphPad prism3 was used for data analysis. 50 The values ​​were derived by fitting the data to an equation for a sigmoid dose-response with a variable gradient.

[0339] For the detection of phosphorylated FGFR3, a bead-based immunoassay was developed. Anti-human FGFR3 mouse mAb (R&D Systems, catalog number MAB7661) was conjugated to Luminex MAGplex microspheres (bead region 20) and used as a capture antibody. RT-112 cells were seeded in multi-well tissue culture plates and cultured until 70% confluence was reached. The cells were washed with PBS and starved for 18 hours in RPMI containing 0.5% FBS. The cells were treated for 1 hour at 37°C under a 5% CO2 atmosphere with 10 μL of serially diluted 10× concentration compounds, and then stimulated for 10 minutes with 10 ng / mL human FGF1 and 20 μg / mL heparin. The cells were washed with chilled PBS, lysed with Cell Extraction Buffer (Invitrogen), and centrifuged. The clarified supernatant was frozen at -80°C until analysis.

[0340] For this assay, the cell solubilator is diluted 1:10 with the assay diluent and incubated with the capture antibody-conjugated beads in a 96-well filter plate on a plate shaker for 2 hours at room temperature. The plate is washed three times using a vacuum manifold and incubated with anti-phospho-FGF R1-4 (Y653 / Y654) rabbit polyclonal antibody (R&D Systems catalog no. AF3285) with shaking at room temperature for 1 hour. The plate is washed three times. Diluted reporter antibody (goat anti-rabbit-RPE conjugated antibody (Invitrogen catalog no. LHB0002)) is added and incubated with shaking for 30 minutes. The plate is washed three times. The beads are suspended in wash buffer with shaking at room temperature for 5 minutes and then read on a Luminex 200 instrument (gate setting 7500-13500) set to count 50 events per sample. Data are presented as mean fluorescence intensity (MFI). The inhibition percentage is determined by dividing the MFI derived from the sample treated with the compound by the MFI value derived from the DMSO control, and IC is performed using GraphPad Prism software. 50 The value is calculated. IC 50Compounds with a concentration of 1 μM or less are considered to be active.

[0341] Example D Cell-based FGFR signaling assay When FGFR is activated, the Erk protein is phosphorylated. Detection of pErk is monitored using the Cellu'Erk HTRF (Uniform Time-Resolved Fluorescence) assay (CisBio) according to the manufacturer's protocol. KMS-11 cells are seeded at 40,000 cells / well in a 96-well plate containing RPMI medium with 0.25% FBS and left under starvation conditions for 2 days. This medium is aspirated and the cells are treated with 30 μL of 1× concentration compound, serially diluted (diluted from 5 mM DSMO solution to serum-free medium) to a final volume of 30 μL / well, and incubated at room temperature for 45 minutes. Cells are stimulated by adding 10 μL of a solution containing heparin (100 μg / mL) and FGF1 (50 ng / mL) to each well and incubated at room temperature for 10 minutes. After lysis, a fixed volume of cell extract is transferred to a 384-well low-volume plate, 4 μL of detection reagent is added, and the plate is incubated at room temperature for 3 minutes. Plate readings are performed on the PheraStar instrument with HTRF settings configured. Normalized fluorescence readings are converted to inhibition percentages relative to the DMSO-treated control well, and ICs are calculated using GraphPad Prism software. 50 The value is calculated. IC 50 Compounds with a concentration of 1 μM or less are considered to be active.

[0342] Example E VEGFR2 kinase assay The enzymatic reaction is carried out in a black 384-well polystyrene plate with 40 μL of solution at 25°C for 1 hour. DMSO (0.8 μL) containing the test compound is added to each well. The assay buffer contains 50 mM Tris (pH 7.5), 0.01% Tween-20, 10 mM MgCl2, 1 mM EGTA, 5 mM DTT, 0.5 μM biotin-labeled EQEDEPEGDYFEWLE peptide substrate (SEQ ID NO: 1), 1 mM ATP, and 0.1 nM enzyme (Millipore catalog number 14-630). Reaction termination is performed by adding 20 μL of a stop buffer (50 mM Tris (pH=7.8), 150 mM NaCl, 0.5 mg / mL BSA, 45 mM EDTA) containing 225 nM LANCE Streptavidin Surelight® APC (PerkinElmer catalog no. CR130-100) and 4.5 nM LANCE Eu-W1024 antiphosphorylated tyrosine (PY20) antibody (PerkinElmer catalog no. AD0067). After incubation at room temperature for 20 minutes, the plate is read using a PheraStar FS plate reader (BMG Labtech). IC50 is performed using GraphPad Prism by fitting the data to the equation for a sigmoid dose-response with a variable gradient. 50 The value can be calculated. IC 50 Compounds with a concentration of 1 μM or less are considered to be active.

[0343] 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 be included in the appended claims. All references cited herein, including patents, patent applications, and publications, are incorporated herein by reference in their entirety. This application also includes the following aspects. [Aspect 1] Structure below: [ka] A salt that is an acidic salt of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, or a hydrate or solvate thereof. [Aspect 2] The salt according to embodiment 1, wherein the salt is substantially crystalline. [Aspect 3] The salt according to embodiment 1, wherein the salt is crystalline. [Aspect 4] The salt according to any one of embodiments 1 to 3, wherein the acid is selected from L-(+)-tartaric acid, D-(-)-tartaric acid, salicylic acid, fumaric acid, benzenesulfonic acid, ethanesulfonic acid, hydrochloric acid, hydrobromic acid, and phosphoric acid. [Aspect 5] A hydrated salt as described in any one of embodiments 1 to 4. [Aspect 6] A solvate of the salt described in any one of embodiments 1 to 4. [Aspect 7] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one L-(+)-tartrate. [Aspect 8] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one D-(-)-tartrate. [Aspect 9] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one salicylate. [Aspect 10] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one fumarate. [Aspect 11] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one besylate. [Aspect 12] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one ethanesulfonate. [Aspect 13] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one hydrochloride. [Aspect 14] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one hydrobromide. [Aspect 15] The salt according to any one of embodiments 1 to 6, wherein the salt is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one phosphate. [Aspect 16] The salt according to embodiment 7, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 6. [Aspect 17] The salt according to embodiment 8, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 2. [Aspect 18] The salt according to embodiment 9, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 10. [Aspect 19] The salt according to embodiment 10, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 21. [Aspect 20] The salt according to embodiment 11, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 29. [Aspect 21] The salt according to embodiment 12, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 33. [Aspect 22] The salt according to embodiment 13, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 13. [Aspect 23] The salt according to embodiment 14, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 17. [Aspect 24] The salt according to embodiment 15, having a powder X-ray diffraction pattern with characteristic peaks substantially shown in Figure 25. [Pattern 25] A pharmaceutical composition comprising a salt according to any one of embodiments 1 to 24 and a pharmaceutically acceptable carrier or pharmaceutical additive. [Aspect 26] A solid oral dosage form comprising the pharmaceutical composition described in Embodiment 25. [Aspect 27] A method for inhibiting FGFR, wherein the method comprises contacting the FGFR with a salt according to any one of embodiments 1 to 24. [Aspect 28] A method for treating cancer, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of the salt described in any one of embodiments 1 to 24. [Aspect 29] The method according to embodiment 28, wherein 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 lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, myeloproliferative neoplasm, chronic myeloid lymphoma, acute lymphoblastic lymphoma, hairy cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma. [Aspect 30] The method according to embodiment 29, wherein the cancer is bladder cancer. [Aspect 31] The method according to embodiment 29, wherein the liver cancer is cholangiocarcinoma. [Aspect 32] The method according to embodiment 29, wherein the myeloproliferative neoplasm is 8p11 myeloproliferative syndrome.

Claims

1. Structure below: 【Chemistry 1】 A salt of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholine-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3-d]pyrimidine-2-one, which is a salicylate, or a hydrate or solvate thereof, wherein the salt is crystalline, The salt has at least one characteristic XRPD peak selected from 10.4°±0.2°(2θ), 11.8°±0.2°(2θ), 12.1°±0.2°(2θ), 13.4°±0.2°(2θ), and 13.9°±0.2°(2θ). The aforementioned salt, or its hydrate or solvate.

2. The salt according to claim 1, having at least two characteristic XRPD peaks selected from 10.4°±0.2°(2θ), 11.8°±0.2°(2θ), 12.1°±0.2°(2θ), 13.4°±0.2°(2θ), and 13.9°±0.2°(2θ).

3. The salt according to claim 1, having at least three characteristic XRPD peaks selected from 10.4°±0.2°(2θ), 11.8°±0.2°(2θ), 12.1°±0.2°(2θ), 13.4°±0.2°(2θ), and 13.9°±0.2°(2θ).

4. The salt according to claim 1, having characteristic XRPD peaks at 10.4°±0.2°(2θ), 11.8°±0.2°(2θ), 12.1°±0.2°(2θ), 13.4°±0.2°(2θ), and 13.9°±0.2°(2θ).

5. Figure 10: The salt according to claim 1, having a powder X-ray diffraction pattern with characteristic peaks shown.

6. The salt according to any one of claims 1 to 5, which exhibits a DSC thermogram having an endothermic peak at a temperature of approximately 212°C.

7. Figure 11: A salt according to any one of claims 1 to 5, having a DSC thermogram substantially shown therein.

8. A pharmaceutical composition comprising a salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier or pharmaceutical additive.

9. A solid oral dosage form comprising the pharmaceutical composition described in claim 8.

10. A pharmaceutical agent for inhibiting FGFR, comprising a salt according to any one of claims 1 to 7.

11. A pharmaceutical for the treatment of cancer, comprising the salt described in any one of claims 1 to 7.

12. The pharmaceutical product according to claim 11, wherein 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 lymphoma or non-Hodgkin lymphoma, Waldenström macroglobulinemia, myeloproliferative neoplasm, chronic myeloid lymphoma, acute lymphoblastic lymphoma, hairy cell lymphoma, Burkitt lymphoma, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

13. The pharmaceutical product according to claim 11, wherein the cancer is bladder cancer.

14. The pharmaceutical product according to claim 12, wherein the liver cancer is cholangiocarcinoma.

15. The pharmaceutical product according to claim 12, wherein the myeloproliferative neoplasm is 8p11 myeloproliferative syndrome.

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