Crystalline forms of JAK2 inhibitors

Abstract

The present disclosure provides crystalline forms of JAK2 inhibitors, compositions thereof, and methods of treating JAK2-mediated disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 804,332, filed on February 12, 2019, the entirety of which is hereby incorporated by reference. Field of the Invention

[0003] The present invention provides compounds and compositions thereof that are useful as protein kinase inhibitors. Background of the Invention

[0005] In recent years, the search for new therapeutic agents has been greatly aided by a better understanding of the structure of enzymes and other biomolecules involved in disease. One important class of enzymes that has been the subject of extensive research is the protein kinases.

[0006] Protein kinases constitute a large family of structurally related enzymes that are responsible for controlling a variety of signal transduction processes within cells. Due to the conservation of structure and catalytic function, protein kinases are believed to have evolved from a common ancestral gene. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into families based on the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0007] In general, protein kinase mediates intracellular signal transduction by affecting the phosphoryl transfer from nucleoside triphosphates to the protein receptors involved in the signal transduction pathway. These phosphorylation events serve as molecular on / off switches that can regulate or control the biological functions of target proteins. These phosphorylation events ultimately respond to multiple extracellular and other stimulations and trigger. Examples of such stimulations include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins and H2O2), cytokines (e.g., interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α)) and growth factors (e.g., granulocyte macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimulation can affect one or more cell responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control and cell cycle regulation.

[0008] As described above, many diseases are associated with abnormal cellular responses triggered by events mediated by protein kinases. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Therefore, there remains a need to find protein kinase inhibitors that can be used as therapeutic agents. Summary of the invention

[0009] In some embodiments, the present disclosure provides one or more crystalline forms of Compound 1:

[0010]

[0011] In some embodiments, the present disclosure provides one or more complex forms comprising Compound 1 and coformer X,

[0012] in:

[0013] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0014] In some embodiments, Compound 1 or its crystalline form or complex can be used to treat a myeloproliferative disorder. In some embodiments, the myeloproliferative disorder is selected from myelofibrosis, polycythemia vera, and essential thrombocythemia. In some embodiments, myelofibrosis is selected from primary myelofibrosis or secondary myelofibrosis. In some embodiments, secondary myelofibrosis is selected from post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

[0015] In some embodiments, the present disclosure provides a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with Compound 1 or a crystalline form or complex thereof or a composition thereof.

[0016] According to another embodiment, the present disclosure relates to a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering compound 1 or its crystalline form or complex or a composition thereof to the patient. In other embodiments, the present disclosure provides a method of treating a JAK2-mediated disease or condition in a patient in need thereof, the method comprising the step of administering compound 1 or its crystalline form or complex or a composition thereof to the patient. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 An X-ray powder diffraction (XRPD) pattern of Form A of Compound 1 is depicted.

[0018] Figure 2A A thermogravimetric analysis (TGA) pattern of Form A of Compound 1 is depicted. Figure 2B Depicted is a differential scanning calorimetry (DSC) pattern of Form A of Compound 1.

[0019] Figure 2C A dynamic vapor sorption (DVS) isotherm of Form A of Compound 1 is depicted.

[0020] Figure 3 The XRPD pattern of Form B of Compound 1 is depicted.

[0021] Figure 4A The TGA pattern of Form B of Compound 1 is depicted. Figure 4B The DSC pattern of Form B of Compound 1 is depicted.

[0022] Figure 5 The XRPD pattern of Form C of Compound 1 is depicted.

[0023] Fig. 6A The TGA pattern of Form C of Compound 1 is depicted. Figure 6B The DSC pattern of Form C of Compound 1 is depicted.

[0024] Figure 7 The DVS isotherm of Form C of Compound 1 is depicted.

[0025] Figure 8 The XRPD pattern of Form D of Compound 1 is depicted.

[0026] Fig. 9A The TGA pattern of Form D of Compound 1 is depicted. Fig. 9B The DSC pattern of Form D of Compound 1 is depicted.

[0027] Fig.10 Depicted is the FT-Raman spectrum of Compound 1 Form A hydrobromide salt.

[0028] Fig.11 Depicted is the XRPD pattern of Form A hydrobromide salt of Compound 1.

[0029] Fig.12 Depicted are a TGA pattern of the Form A hydrobromide salt of Compound 1 (12A) and a DSC pattern of the Form A hydrobromide salt of Compound 1 (12B).

[0030] Fig.13 Depicted is the FT-Raman spectrum of Form B hydrobromide salt of Compound 1.

[0031] Fig.14 Depicted is the XRPD pattern of Form B hydrobromide salt of Compound 1.

[0032] Fig.15 Depicted are a TGA pattern of the Form B hydrobromide salt of Compound 1 (15A) and a DSC pattern of the Form B hydrobromide salt of Compound 1 (15B).

[0033] Fig.16 Depicted is the dynamic vapor sorption (DVS) isotherm of Form B hydrobromide salt of Compound 1.

[0034] Fig.17 Depicted is the XRPD pattern of Form B hydrobromide salt of Compound 1 after DVS.

[0035] Fig.18 Depicted is the FT-Raman spectrum of Form A sulfate salt of Compound 1.

[0036] Fig.19 Depicted is the XRPD pattern of Form A sulfate salt of Compound 1.

[0037] Fig. 20 Depicted are a TGA pattern of Form A sulfate salt of Compound 1 (20A) and a DSC pattern of Form A sulfate salt of Compound 1 (20B).

[0038] Fig.21 Depicted is the FT-Raman spectrum of Form B sulfate salt of Compound 1.

[0039] Fig. 22 Depicted is the XRPD pattern of Form B sulfate salt of Compound 1.

[0040] Fig.23 Depicted are a TGA pattern of Form B sulfate of Compound 1 (23A) and a DSC pattern of Form B sulfate of Compound 1 (23B).

[0041] Fig.24 Depicted is the FT-Raman spectrum of Form C sulfate salt of Compound 1.

[0042] Fig.25 Depicted is the XRPD pattern of Form C sulfate salt of Compound 1.

[0043] Fig.26 Depicted is the DSC trace of Form C sulfate salt of Compound 1.

[0044] Fig. 27 Depicted is the FT-Raman spectrum of Form D sulfate salt of Compound 1.

[0045] Fig.28 Depicted is the XRPD pattern of Form D sulfate salt of Compound 1.

[0046] Fig.29 Depicted are a TGA pattern of Form D sulfate salt of Compound 1 (29A) and a DSC pattern of Form D sulfate salt of Compound 1 (29B).

[0047] Fig.30 Depicted is the XRPD pattern of Form A tosylate salt of Compound 1.

[0048] Fig.31 Depicted are a TGA pattern of a Form A tosylate salt of Compound 1 (31A) and a DSC pattern of a Form A tosylate salt of Compound 1 (31B).

[0049] Fig.32 Depicted is the XRPD pattern of Form B tosylate salt of Compound 1.

[0050] Fig.33 Depicted are a TGA pattern of Form B tosylate salt of Compound 1 (33A) and a DSC pattern of Form B tosylate salt of Compound 1 (33B).

[0051] Fig.34 Depicted is the FT-Raman spectrum of Compound 1 Form C tosylate salt.

[0052] Fig.35 Depicted is the XRPD pattern of Form C tosylate salt of Compound 1.

[0053] Fig.36 Depicted are a TGA pattern of Form C tosylate salt of Compound 1 (36A) and a DSC pattern of Form C tosylate salt of Compound 1 (36B).

[0054] Fig.37 The DVS isotherm of Compound 1 Form C tosylate salt is depicted.

[0055] Fig.38 Depicted is the XRPD pattern of Form C tosylate salt of Compound 1 after DVS.

[0056] Fig.39 Depicted is the Form C tosylate of Compound 1 1 H-NMR spectrum.

[0057] Fig.40 Depicted is the FT-Raman spectrum of Compound 1 Form A mesylate salt.

[0058] Fig.41 Depicted is the XRPD pattern of Form A mesylate salt of Compound 1.

[0059] Fig.42Depicted are a TGA pattern (42A) of a dried sample of Form A mesylate salt of Compound 1 and a DSC pattern (42B) of a dried sample of Form A mesylate salt of Compound 1.

[0060] Fig.43 Depicted is Form A mesylate salt of Compound 1 1 H-NMR spectrum.

[0061] Fig.44 Depicted is the XRPD pattern of Form B mesylate salt of Compound 1.

[0062] Fig.45 Depicted is the XRPD pattern of Form C mesylate salt of Compound 1.

[0063] Fig.46 Depicted are the DSC trace of Form A mesylate salt of Compound 1 (46A), the DSC trace of Form B mesylate salt of Compound 1 (46B), and the DSC trace of Form C mesylate salt of Compound 1 (46C).

[0064] Fig.47 Depicted is the FT-Raman spectrum of Compound 1 Form A 2-naphthalenesulfonate salt.

[0065] Fig.48 Depicted is the XRPD pattern of Form A 2-naphthalenesulfonate salt of Compound 1.

[0066] Fig.49 Depicted is an XRPD pattern of a mixture of Form A and Form B 2-naphthalenesulfonate salts of Compound 1.

[0067] Fig.50 Depicted are a TGA pattern of Compound 1 Form A 2-naphthalenesulfonate salt (50A) and a DSC pattern of Compound 1 Form A 2-naphthalenesulfonate salt (50B).

[0068] Fig.51 Depicted is a mixture of Form A and Form B 2-naphthalenesulfonate salts of Compound 1. 1 H NMR.

[0069] Fig.52 Depicted is the XRPD pattern of Form A phosphate salt of Compound 1.

[0070] Fig.53 Depicted is the XRPD pattern of Form B phosphate salt of Compound 1.

[0071] Fig.54 Depicted is the XRPD pattern of Form C phosphate salt of Compound 1.

[0072] Fig.55Depicted is the XRPD pattern of Form D phosphate salt of Compound 1.

[0073] Fig.56 Depicted are the DSC pattern of Form A phosphate of Compound 1 (56A), the DSC pattern of Form B phosphate of Compound 1 (56B), the DSC pattern of Form C phosphate of Compound 1 (56C), and the DSC pattern of Form D phosphate of Compound 1 (56D).

[0074] Fig.57 Depicted is the FT-Raman spectrum of Form E phosphate salt of Compound 1.

[0075] Fig.58 The XRPD pattern of Form E phosphate salt of Compound 1 is depicted.

[0076] Fig.59 Depicted are a TGA pattern of the Form E phosphate salt of Compound 1 (59A) and a DSC pattern of the Form E phosphate salt of Compound 1 (59B).

[0077] Fig.60 Depicted is the FT-Raman spectrum of Compound 1 Form A DL-tartrate salt.

[0078] Fig.61 Depicted is the XRPD pattern of Compound 1 Form A DL-tartrate salt.

[0079] Fig.62 Depicted are a TGA pattern of Compound 1 Form A DL-tartrate salt (62A) and a DSC pattern of Compound 1 Form A DL-tartrate salt (62B).

[0080] Fig.63 The DVS isotherm of Compound 1 Form A DL-tartrate salt is depicted.

[0081] Fig.64 Depicted is Form A DL-tartrate of Compound 1 1 H-NMR spectrum.

[0082] Fig.65 Depicted is the XRPD pattern of Form B DL-tartrate salt of Compound 1.

[0083] Fig.66 Depicted are a TGA pattern of Compound 1 Form B DL-tartrate salt (66A) and a DSC pattern of Compound 1 Form B DL-tartrate salt (66B).

[0084] Fig.67 Depicted is the XRPD pattern of Form A succinate salt of Compound 1.

[0085] Fig.68 Depicted are a TGA pattern of Compound 1 Form A succinate salt (68A) and a DSC pattern of Compound 1 Form A succinate salt (68B).

[0086] Fig.69 Depicted is the FT-Raman spectrum of Compound 1 Form B succinate salt.

[0087] Fig.70 Depicted is the XRPD pattern of Form B succinate salt of Compound 1.

[0088] Fig.71 Depicted are a TGA pattern of Compound 1 Form B succinate salt (71A) and a DSC pattern of Compound 1 Form B succinate salt (71B).

[0089] Fig.72 Depicted is Form B succinate salt of Compound 1 1 H-NMR spectrum.

[0090] Fig.73 Depicted is the FT-Raman spectrum of Form A gentisate of Compound 1.

[0091] Fig.74 Depicted is the XRPD pattern of Form A gentisate salt of Compound 1.

[0092] Fig.75 Depicted are a TGA pattern of Form A gentisate of Compound 1 (75A) and a DSC pattern of Form A gentisate of Compound 1 (75B).

[0093] Fig.76 Depicted is the Form A gentisate of Compound 1 1 H-NMR spectrum.

[0094] Fig.77 Depicted is the FT-Raman spectrum of Compound 1 Form A hippurate salt.

[0095] Fig.78 Depicted is the XRPD pattern of Form A hippurate salt of Compound 1.

[0096] Fig.79 Depicted are a TGA pattern of Form A hippurate salt of Compound 1 (79A) and a DSC pattern of Form A hippurate salt of Compound 1 (79B).

[0097] Fig.80 Depicted is Form A hippurate of Compound 1 1 H-NMR spectrum.

[0098] Fig.81 Depicted is the XRPD pattern of Form A adipate salt of Compound 1.

[0099] Fig.82 Depicted are a TGA pattern of Compound 1 Form A adipate salt (82A) and a DSC pattern of Compound 1 Form A adipate salt (82B).

[0100] Fig.83 Depicted is the FT-Raman spectrum of Compound 1 Form C adipate salt.

[0101] Fig.84 Depicted is the XRPD pattern of Compound 1 Form C adipate salt.

[0102] Fig.85 Depicted are a TGA pattern of Compound 1 Form C adipate salt (85A) and a DSC pattern of Compound 1 Form C adipate salt (85B).

[0103] Fig.86 Depicted is the Form C adipate salt of Compound 1 1 H-NMR spectrum.

[0104] Fig.87 Depicted is the FT-Raman spectrum of Compound 1 Form A galactarate salt.

[0105] Fig.88 Depicted is the XRPD pattern of Form A galactarate salt of Compound 1.

[0106] Fig.89 Depicted are a TGA pattern of Form A galactarate salt of Compound 1 (89A) and a DSC pattern of Form A galactarate salt of Compound 1 (89B).

[0107] Fig.90 Depicted is Form A galactamate salt of Compound 1 1 H-NMR spectrum.

[0108] Fig.91 Depicted is the XRPD pattern of Form A napsylate salt of Compound 1.

[0109] Fig.92 Depicted is the XRPD pattern of Form B napsylate salt of Compound 1.

[0110] Fig.93 Depicted is the XRPD pattern of Form C napsylate salt of Compound 1.

[0111] Fig.94 Depicted are the DSC trace of Form A naphalene disulfonate salt of Compound 1 (94A), the DSC trace of Form B naphalene disulfonate salt of Compound 1 (94B), and the DSC trace of Form C naphalene disulfonate salt of Compound 1 (94C).

[0112] Fig.95 Depicted is the FT-Raman spectrum of Form A (S)-camsylate salt of Compound 1.

[0113] Fig.96 Depicted is the XRPD pattern of Form A (S)-camsylate salt of Compound 1.

[0114] Fig.97 Depicted are a TGA pattern of Form A (S)-camsylate salt of Compound 1 (97A) and a DSC pattern of Form A (S)-camsylate salt of Compound 1 (97B).

[0115] Fig.98 Depicted is the FT-Raman spectrum of Form B (S)-camsylate salt of Compound 1.

[0116] Fig.99 Depicted is the XRPD pattern of Form B (S)-camsylate salt of Compound 1.

[0117] Fig.100 Depicted are a TGA pattern of Form B (S)-camsylate salt of Compound 1 (100A) and a DSC pattern of Form B (S)-camsylate salt of Compound 1 (100B).

[0118] Fig.101 Depicted is the XRPD pattern of Form A edisylate salt of Compound 1.

[0119] Fig.102 Depicted is the XRPD pattern of Form B edisylate salt of Compound 1.

[0120] Fig.103 Depicted is the XRPD pattern of Form C edisylate salt of Compound 1.

[0121] Fig.104 Depicted is the XRPD pattern of Compound 1 Form D edisylate salt.

[0122] Fig.105 Depicted are a TGA pattern (105A) of Compound 1 Form A edisylate salt and a DSC pattern (105B) of Compound 1 Form A edisylate salt.

[0123] Fig.106 Depicted are the DSC pattern of Form C edisylate of Compound 1 (106A), the DSC pattern of Form B edisylate of Compound 1 (106B), the DSC pattern of Form D edisylate of Compound 1 (106C), and the DSC pattern of Form A edisylate of Compound 1 (106D).

[0124] Fig.107Depicted is the XRPD pattern of Form A ethanesulfonate salt of Compound 1.

[0125] Fig.108 Depicted is the XRPD pattern of Form B ethanesulfonate salt of Compound 1.

[0126] Fig.109 Depicted are a TGA pattern of Form A ethanesulfonate salt of Compound 1 (109A) and a DSC pattern of Form A ethanesulfonate salt of Compound 1 (109B).

[0127] Fig.110 Depicted are a TGA pattern of Form B ethanesulfonate salt of Compound 1 (110A) and a DSC pattern of Form B ethanesulfonate salt of Compound 1 (110B).

[0128] Fig.111 Depicted is the XRPD pattern of Form A besylate salt of Compound 1.

[0129] Fig.112 Depicted is the XRPD pattern of Form B besylate salt of Compound 1.

[0130] Fig.113 Depicted is the XRPD pattern of Form C besylate salt of Compound 1.

[0131] Fig.114 Depicted is the XRPD pattern of Form D besylate salt of Compound 1.

[0132] Fig.115 Depicted are the DSC pattern of Form A benzenesulfonate of Compound 1 (115A), the DSC pattern of Form B benzenesulfonate of Compound 1 (115B), the DSC pattern of Form C benzenesulfonate of Compound 1 (115C), and the DSC pattern of Form D benzenesulfonate of Compound 1 (115D).

[0133] Fig.116 Depicted are a TGA pattern of Form D besylate salt of Compound 1 (116A) and a DSC pattern of Form D besylate salt of Compound 1 (116B).

[0134] Fig.117 Depicted is the XRPD pattern of Form A oxalate salt of Compound 1.

[0135] Fig.118 Depicted is the XRPD pattern of Form B oxalate salt of Compound 1.

[0136] Fig.119 Depicted are a TGA pattern of Form A oxalate salt of Compound 1 (119A) and a DSC pattern of Form A oxalate salt of Compound 1 (119B).

[0137] Fig.120Depicted are a TGA pattern of Form B oxalate salt of Compound 1 (120A) and a DSC pattern of Form B oxalate salt of Compound 1 (120B).

[0138] Fig.121 Depicted is the XRPD pattern of Form A maleate salt of Compound 1.

[0139] Fig.122 Depicted are a TGA pattern of Compound 1 Form A maleate salt (122A) and a DSC pattern of Compound 1 Form A maleate salt (122B).

[0140] Fig.123 Depicted is the XRPD pattern of Compound 1 Form A pamoate salt.

[0141] Fig.124 Depicted are a TGA pattern of Compound 1 Form A pamoate salt (124A) and a DSC pattern of Compound 1 Form A pamoate salt (124B).

[0142] Fig.125 Depicted is the XRPD pattern of Compound 1 Form A 1-hydroxy-2-naphthoate salt.

[0143] Fig.126 Depicted is the DSC pattern of Compound 1 Form A 1-hydroxy-2-naphthoate salt.

[0144] Fig.127 Depicted is the XRPD pattern of Form A malonate salt of Compound 1.

[0145] Fig.128 Depicted are a TGA pattern of Form A malonate salt of Compound 1 (128A) and a DSC pattern of Form A malonate salt of Compound 1 (128B).

[0146] Fig.129 Depicted is the XRPD pattern of Form B malonate salt of Compound 1.

[0147] Fig.130 Depicted are a TGA pattern of Form B malonate salt of Compound 1 (130A) and a DSC pattern of Form B malonate salt of Compound 1 (130B).

[0148] Fig.131 Depicted is the XRPD pattern of Form C malonate salt of Compound 1.

[0149] Fig.132 Depicted is the DSC pattern of Form C malonate salt of Compound 1.

[0150] Fig.133 Depicted is the XRPD pattern of Compound 1 Form A L-tartrate salt.

[0151] Fig.134 Depicted are a TGA pattern of Compound 1 Form A L-tartrate salt (134A) and a DSC pattern of Compound 1 Form A L-tartrate salt (134B).

[0152] Fig.135 Depicted is the XRPD pattern of Form B L-tartrate salt of Compound 1.

[0153] Fig.136 Depicted is the DSC pattern of Compound 1 Form B L-tartrate salt.

[0154] Fig.137 Depicted is the XRPD pattern of Compound 1 Form C L-tartrate salt.

[0155] Fig.138 Depicted are the TGA pattern of Compound 1 Form CL-tartrate salt (138A) and the DSC pattern of Compound 1 Form CL-tartrate salt (138B).

[0156] Fig.139 Depicted is the XRPD pattern of Form D L-tartrate salt of Compound 1.

[0157] Fig.140 Depicted are a TGA pattern of Compound 1 Form D L-tartrate salt (140A) and a DSC pattern of Compound 1 Form DL-tartrate salt (140B).

[0158] Fig.141 Depicted is the XRPD pattern of Form A fumarate salt of Compound 1.

[0159] Fig.142 Depicted are a TGA pattern of Form A fumarate salt of Compound 1 (142A) and a DSC pattern of Form A fumarate salt of Compound 1 (142B).

[0160] Fig.143 Depicted is the XRPD pattern of Form B fumarate salt of Compound 1.

[0161] Fig.144 Depicted is the DSC pattern of Form B fumarate salt of Compound 1.

[0162] Fig.145 Depicted is the XRPD pattern of Form C fumarate salt of Compound 1.

[0163] Fig.146 Depicted are a TGA pattern of Form C fumarate salt of Compound 1 (146A) and a DSC pattern of Form C fumarate salt of Compound 1 (146B).

[0164] Fig.147 Depicted is the XRPD pattern of Form D fumarate salt of Compound 1.

[0165] Fig.148 Depicted are a TGA pattern of Form D fumarate salt of Compound 1 (148A) and a DSC pattern of Form D fumarate salt of Compound 1 (148B).

[0166] Fig.149 Depicted is the XRPD pattern of Form A citrate salt of Compound 1.

[0167] Fig.150 Depicted are a TGA pattern of Compound 1 Form A citrate salt (150A) and a DSC pattern of Compound 1 Form A citrate salt (150B).

[0168] Fig.151 Depicted is the XRPD pattern of Compound 1 Form A L-lactate salt.

[0169] Fig.152 Depicted are a TGA pattern of Compound 1 Form A L-lactate (152A) and a DSC pattern of Compound 1 Form A L-lactate (152B).

[0170] Fig.153 Depicted is the XRPD pattern of Form A acetate salt of Compound 1.

[0171] Fig.154 Depicted are a TGA pattern of Form A acetate salt of Compound 1 (154A) and a DSC pattern of Form A acetate salt of Compound 1 (154B).

[0172] Fig.155 Depicted is the XRPD pattern of Form B acetate salt of Compound 1.

[0173] Fig.156 Depicted are a TGA pattern (156A) of the Form B acetate salt of Compound 1 and a DSC pattern (156B) of the Form B acetate salt of Compound 1.

[0174] Fig.157 Depicted is the XRPD pattern of Form A propionate salt of Compound 1.

[0175] Fig.158 Depicted are a TGA pattern of Form A propionate salt of Compound 1 (158A) and a DSC pattern of Form A propionate salt of Compound 1 (158B).

[0176] Fig.159 Depicted is the XRPD pattern of Form A DL-lactate salt of Compound 1.

[0177] Fig.160 Depicted are a TGA pattern of Compound 1 Form A DL-lactate salt (160A) and a DSC pattern of Compound 1 Form A DL-lactate salt (160B).

[0178] Fig.161 Depicted is the XRPD pattern of Form A D-gluconate salt of Compound 1.

[0179] Fig.162 Depicted is the DSC pattern of Form A D-gluconate salt of Compound 1.

[0180] Fig.163 Depicted is the XRPD pattern of Compound 1 Form A DL-malate salt.

[0181] Fig.164 Depicted are a TGA pattern of Compound 1 Form A DL-malate salt (164A) and a DSC pattern of Compound 1 Form A DL-malate salt (164B).

[0182] Fig.165 Depicted is the XRPD pattern of Form B DL-malate salt of Compound 1.

[0183] Fig.166 Depicted are a TGA pattern of Compound 1 Form B DL-malate salt (166A) and a DSC pattern of Compound 1 Form B DL-malate salt (166B).

[0184] Fig.167 Depicted is the XRPD pattern of Form A glycolic acid salt of Compound 1.

[0185] Fig.168 Depicted are a TGA pattern of Form A glycolic acid salt of Compound 1 (168A) and a DSC pattern of Form A glycolic acid salt of Compound 1 (168B).

[0186] Fig.169 Depicted is the XRPD pattern of Compound 1 Form A glutarate salt.

[0187] Fig.170 Depicted are a TGA pattern (170A) of Compound 1 Form A glutarate salt and a DSC pattern (170B) of Compound 1 Form A glutarate salt.

[0188] Fig.171 Depicted is the XRPD pattern of Form B glutarate salt of Compound 1.

[0189] Fig.172 Depicted are a TGA pattern (172A) of Compound 1 Form B glutarate salt and a DSC pattern (172B) of Compound 1 Form B glutarate salt.

[0190] Fig.173 Depicted is the XRPD pattern of Compound 1 Form A L-malate salt.

[0191] Fig.174 Depicted are a TGA pattern of Compound 1 Form A L-malate salt (174A) and a DSC pattern of Compound 1 Form A L-malate salt (174B).

[0192] Fig.175 Depicted is the XRPD pattern of Form A camphorate salt of Compound 1.

[0193] Fig.176 Depicted are a TGA pattern of Form A camphorate salt of Compound 1 (176A) and a DSC pattern of Form A camphorate salt of Compound 1 (176B).

[0194] Fig.177 Depicted is the XRPD pattern of Form B camphorate salt of Compound 1.

[0195] Fig.178 Depicted are a TGA pattern of Form B camphorate salt of Compound 1 (178A) and a DSC pattern of Form B camphorate salt of Compound 1 (178B).

[0196] Fig.179 Depicted is the XRPD pattern of Form C camphorate salt of Compound 1.

[0197] Fig.180 Depicted are a TGA pattern (180A) of Compound 1 Form C camphorate and a DSC pattern (180B) of Compound 1 Form C camphorate.

[0198] Fig.181 Depicted is the XRPD pattern of Form D camphorate salt of Compound 1.

[0199] Fig.182 Depicted are a TGA pattern of Form D camphorate salt of Compound 1 (182A) and a DSC pattern of Form D camphorate salt of Compound 1 (182B).

[0200] Fig.183 Depicted is the XRPD pattern of Compound 1 Form A DL-mandelate salt.

[0201] Fig.184 Depicted are a TGA pattern of Compound 1 Form A DL-mandelate salt (184A) and a DSC pattern of Compound 1 Form A DL-mandelate salt (184B).

[0202] Fig.185Depicted is the XRPD pattern of Form B DL-mandelate salt of Compound 1.

[0203] Fig.186 Depicted are the TGA pattern of Compound 1 Form B DL-mandelate salt (186A) and the DSC pattern of Compound 1 Form B DL-mandelate salt (186B).

[0204] Fig.187 Depicted is the XRPD pattern of Compound 1 Form C DL-mandelate salt.

[0205] Fig.188 Depicted are the TGA pattern of Compound 1 Form C DL-mandelate salt (188A) and the DSC pattern of Compound 1 Form C DL-mandelate salt (188B).

[0206] Fig.189 Depicted is the FT-Raman spectrum of Compound 1 Form A saccharin cocrystal.

[0207] Fig.190 Depicted is the XRPD pattern of Form A saccharin cocrystal of Compound 1.

[0208] Fig.191 Depicted are a TGA pattern of Compound 1 Form A saccharin cocrystal (191A) and a DSC pattern of Compound 1 Form A saccharin cocrystal (191B).

[0209] Fig.192 Depicted is Form A saccharin cocrystal of Compound 1 1 H-NMR spectrum.

[0210] Fig.193 Depicted is the FT-Raman spectrum of Compound 1 Form A nicotinate.

[0211] Fig.194 Depicted is the XRPD pattern of Compound 1 Form A nicotinate salt.

[0212] Fig.195 Depicted are a TGA pattern of Compound 1 Form A Nicotinate (195A) and a DSC pattern of Compound 1 Form A Nicotinate (195B).

[0213] Fig.196 Depicted is the Form A nicotinate of Compound 1 1 H-NMR spectrum.

[0214] Fig.197 Depicted is the XRPD pattern of Form B nicotinate salt of Compound 1.

[0215] Fig.198 The TGA pattern of Form B nicotinate salt of Compound 1 is depicted. Fig.198 B depicts the DSC pattern of Compound 1 Form B nicotinate.

[0216] Fig.199 Depicted is the XRPD pattern of Form C nicotinate salt of Compound 1.

[0217] Fig.200 Depicted are a TGA pattern (200A) of the Form C Nicotinate Salt of Compound 1 and a DSC pattern (200B) of the Form C Nicotinate Salt of Compound 1.

[0218] Fig.201 Depicted is the FT-Raman spectrum of Compound 1 Form A ascorbate salt.

[0219] Fig.202 Depicted is the XRPD pattern of Form A ascorbate salt of Compound 1.

[0220] Fig.203 Depicted are a TGA pattern of Form A ascorbate salt of Compound 1 (203A) and a DSC pattern of Form A ascorbate salt of Compound 1 (203B).

[0221] Fig.204 Depicted is the Form A ascorbate of Compound 1 1 H-NMR spectrum.

[0222] Fig.205 Depicted is the FT-Raman spectrum of Compound 1 Form A gallic acid salt.

[0223] Fig.206 Depicted is the XRPD pattern of Form A gallic acid salt of Compound 1.

[0224] Fig.207 Depicted are a TGA pattern (207A) of Compound 1 Form A gallic acid salt and a DSC pattern (207B) of Compound 1 Form A gallic acid salt.

[0225] Fig.208 Depicted is the Form A gallate of Compound 1 1 H-NMR spectrum.

[0226] Fig.209 Depicted is the FT-Raman spectrum of Compound 1 Form A salicylate salt.

[0227] Fig.210 Depicted is the XRPD pattern of Form A salicylate salt of Compound 1.

[0228] Fig.211 Depicted are a TGA pattern of Form A salicylate salt of Compound 1 (211A) and a DSC pattern of Form A salicylate salt of Compound 1 (211B).

[0229] Fig.212 Depicted is Form A salicylate of Compound 1 1 H-NMR spectrum.

[0230] Fig.213 Depicted is the XRPD pattern of Compound 1 Form A orotate.

[0231] Fig.214 Depicted are a TGA pattern of Compound 1 Form A orotate (214A) and a DSC pattern of Compound 1 Form A orotate (214B).

[0232] Fig.215 Depicted is an XRPD pattern of a mixture of Form B and Form E orotate salts of Compound 1.

[0233] Fig.216 Depicted is an XRPD pattern of a mixture of Form C and Form E orotate salts of Compound 1.

[0234] Fig.217 Depicted is the XRPD pattern of Form D orotate salt of Compound 1.

[0235] Fig.218 Depicted are a TGA pattern of Compound 1 Form D orotate (218A) and a DSC pattern of Compound 1 Form D orotate (218B).

[0236] Fig.219 Depicted is the XRPD pattern of Form E orotate of Compound 1.

[0237] Fig.220 Depicted are a TGA pattern of Compound 1 Form E orotate (220A) and a DSC pattern of Compound 1 Form E orotate (220B).

[0238] Fig.221 Depicted is the XRPD pattern of Form G orotate salt of Compound 1.

[0239] Fig.222 Depicted is the FT-Raman spectrum of Compound 1 Form F orotate.

[0240] Fig.223 Depicted is the XRPD pattern of Form F orotate salt of Compound 1.

[0241] Fig.224 Depicted are a TGA pattern of Compound 1 Form F orotate (224A) and a DSC pattern of Compound 1 Form F orotate (224B).

[0242] Fig.225Depicted is Form F orotate of Compound 1 1 H-NMR spectrum.

[0243] Fig.226 Depicted is the FT-Raman spectrum of Compound 1 Form H orotate.

[0244] Fig.227 Depicted is the XRPD pattern of Compound 1 Form H orotate.

[0245] Fig.228 Depicted are a TGA pattern of Compound 1 Form H orotate (228A) and a DSC pattern of Compound 1 Form H orotate (228B).

[0246] Fig.229 Depicted is the Form H orotate of Compound 1 1 H-NMR spectrum.

[0247] Fig.230 Depicted are XRPD patterns of Form A of Compound 1, Form A of Compound 1 isonicotinamide cocrystals, and a mixture of isonicotinamide coformers.

[0248] Fig.231 Depicted is an XRPD pattern of Form A pyrogallol cocrystal of Compound 1, possibly admixed with one or more forms of Compound 1 free base.

[0249] Fig.232 Depicted are a TGA pattern (232A) of Form A pyrogallol co-crystal of Compound 1 that may be mixed with one or more forms of Compound 1 free base, and a DSC pattern (232B) of a mixture of Form A pyrogallol co-crystals of Compound 1 that may be mixed with one or more forms of Compound 1 free base.

[0250] Fig.233 Depicted is an XRPD pattern of Form A xylitol cocrystal of Compound 1, possibly admixed with one or more forms of Compound 1 free base and a xylitol coformer.

[0251] Fig.234 Depicted is the XRPD pattern of Form B ascorbate salt of Compound 1.

[0252] Fig.235 Depicted are a TGA pattern of Compound 1 Form B ascorbate salt (235A) and a DSC pattern of Compound 1 Form B ascorbate salt (235B).

[0253] Fig.236 Depicted is an XRPD pattern of a mixture of Compound 1 Form A gallic acid salt and Compound 1 Form B gallic acid salt.

[0254] Fig.237 Depicted is the XRPD pattern of Form B salicylate salt of Compound 1.

[0255] Fig.238 Depicted are a TGA pattern of Form B salicylate salt of Compound 1 (238A) and a DSC pattern of Form B salicylate salt of Compound 1 (238B).

[0256] Fig.239 Depicted is the XRPD pattern of Form B acetylsalicylate of Compound 1.

[0257] Fig.240 Depicted are a TGA pattern of Form B acetylsalicylate of Compound 1 (240A) and a DSC pattern of Form B acetylsalicylate of Compound 1 (240B). DETAILED DESCRIPTION

[0258] General Description of Certain Aspects of the Invention

[0259] U.S. Pat. No. 7,528,143, issued May 5, 2009 (the "'143 patent"), which is hereby incorporated by reference herein, describes certain 2,4-disubstituted pyrimidine compounds that are useful for treating myeloproliferative diseases, including polycythemia vera, essential thrombocythemia, and myelofibrosis (e.g., primary myelofibrosis and secondary myelofibrosis, such as post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis). Such compounds include Compound 1:

[0260]

[0261] Compound 1, N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide, is designated Compound No. LVII, and the synthesis of Compound 1 is described in detail in Example 90 of the '143 patent.

[0262] Compound 1 is active in a variety of assays and therapeutic models demonstrating inhibition of Janus kinase 2 (JAK2). Therefore, Compound 1 or a crystalline form or complex thereof may be used to treat one or more disorders associated with JAK2 activity.

[0263] Crystalline form of compound 1

[0264] In some embodiments, the present disclosure provides a crystalline form of Compound 1. It should be understood that the crystalline form of Compound 1 can exist in a pure or unsolvated form, a hydrated form, and / or a solvated form. In some embodiments, the crystalline form of Compound 1 is a pure or unsolvated crystalline form, and thus there is no water or solvent incorporated into the crystal structure. In some embodiments, the crystalline form of Compound 1 is a hydrated or solvated form. In some embodiments, the crystalline form of Compound 1 is a hydrate / solvate form (also referred to herein as a "heterosolvate").

[0265] Thus, in some embodiments, the present disclosure provides one or more crystalline anhydrous forms of Compound 1:

[0266]

[0267] In some embodiments, the present disclosure provides one or more crystalline hydrate forms of Compound 1:

[0268]

[0269] In some embodiments, the present disclosure provides one or more crystalline solvate forms of Compound 1:

[0270]

[0271] In some embodiments, the present disclosure provides a sample comprising a crystalline form of compound 1, wherein the sample is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the sample does not contain a significant amount of foreign matter. In some embodiments, the sample comprising a crystalline form of compound 1 is substantially free of amorphous compound 1. In certain embodiments, the sample comprises at least about 90% by weight of the crystalline form of compound 1. In certain embodiments, the sample comprises at least about 95% by weight of the crystalline form of compound 1. In other embodiments, the sample comprises at least about 99% by weight of the crystalline form of compound 1.

[0272] According to some embodiments, the sample comprises at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent (wt%) of the crystalline form of compound 1, wherein the percentage is based on the total weight of the sample. According to some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 5.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 3.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 1.5% total organic impurities. In some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 1.0% total organic impurities. In some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 0.6% total organic impurities. In some embodiments, the sample comprising the crystalline form of compound 1 comprises no more than about 0.5% total organic impurities. In some embodiments, the percentage of total organic impurities is measured by HPLC.

[0273] It has been discovered that Compound 1 can exist in at least four different crystalline forms or polymorphs.

[0274] In some embodiments, the present disclosure provides an anhydrous form of Compound 1. In some embodiments, the anhydrous form of Compound 1 is a crystalline anhydrous form of Compound 1. In some embodiments, the crystalline anhydrous form of Compound 1 is characterized by one or more peaks selected from 9.7, 14.6, 19.5, 24.3, and 25.6 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the crystalline anhydrous form of Compound 1 is Form A.

[0275] In some embodiments, Form A of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern:

[0276]

[0277]

[0278] In some embodiments, Form A of Compound 1 is characterized by Figure 1 The x-ray powder diffraction (XRPD) pattern depicted in .

[0279] In some embodiments, Form A of Compound 1 is characterized by Figure 2A Thermogravimetric analysis (TGA) patterns depicted in .

[0280] In some embodiments, Form A of Compound 1 is characterized by Figure 2B Differential Scanning Calorimetry (DSC) pattern depicted in .

[0281] In some embodiments, Form A of Compound 1 is characterized by Figure 2C The dynamic vapor sorption (DVS) isotherm depicted in .

[0282] In some embodiments, the present disclosure provides a solvate form of Compound 1. In some such embodiments, the solvate form of Compound 1 is a 2-methyl-tetrahydrofuran solvate. In some embodiments, the 2-methyl-tetrahydrofuran solvate form of Compound 1 is a crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1. In some embodiments, the crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1 is characterized by one or more peaks selected from 12.5, 18.3, 18.9, 20.1 and 23.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the crystalline 2-methyl-tetrahydrofuran solvate form of Compound 1 is Form B.

[0283] In some embodiments, Form B of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern:

[0284]

[0285]

[0286] In some embodiments, Form B of Compound 1 is characterized by Figure 3 The x-ray powder diffraction (XRPD) pattern depicted in .

[0287] In some embodiments, Form B of Compound 1 is characterized by Figure 4A Thermogravimetric analysis (TGA) patterns depicted in .

[0288] In some embodiments, Form B of Compound 1 is characterized by Figure 4B Differential Scanning Calorimetry (DSC) pattern depicted in .

[0289] In some embodiments, the present disclosure provides a hydrate form of Compound 1. In some embodiments, the hydrate form of Compound 1 is a crystalline hydrate form of Compound 1. In some embodiments, the crystalline hydrate form of Compound 1 is a monohydrate. In some embodiments, the crystalline monohydrate form of Compound 1 is characterized by one or more peaks selected from 8.7, 15.2, 17.3, 18.0, and 19.4 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the crystalline monohydrate form of Compound 1 is Form C.

[0290] In some embodiments, Form C of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern:

[0291]

[0292] In some embodiments, Form C of Compound 1 is characterized by Figure 5 The x-ray powder diffraction (XRPD) pattern depicted in .

[0293] In some embodiments, Form C of Compound 1 is characterized by Fig. 6A Thermogravimetric analysis (TGA) patterns depicted in .

[0294] In some embodiments, Form C of Compound 1 is characterized by Figure 6B Differential Scanning Calorimetry (DSC) pattern depicted in .

[0295] In some embodiments, Form C of Compound 1 is characterized by Figure 7 The dynamic vapor sorption (DVS) isotherm depicted in .

[0296] In some embodiments, the crystalline hydrate form of Compound 1 is a tetrahydrate. In some embodiments, the crystalline tetrahydrate form of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.4, 18.5, 19.3, 20.3, and 23.6 ± 0.2 degrees 2θ. In some such embodiments, the crystalline tetrahydrate form of Compound 1 is Form D.

[0297] In some embodiments, Form D of Compound 1 is characterized by the following peaks in its X-ray powder diffraction pattern:

[0298]

[0299] In some embodiments, Form D of Compound 1 is characterized by Figure 8 The x-ray powder diffraction (XRPD) pattern depicted in .

[0300] In some embodiments, Form D of Compound 1 is characterized by Fig. 9A Thermogravimetric analysis (TGA) patterns depicted in .

[0301] In some embodiments, Form D of Compound 1 is characterized by Fig. 9B Differential Scanning Calorimetry (DSC) pattern depicted in .

[0302] In some embodiments, it will be desirable to provide a form of Compound 1 that confers characteristics such as improved aqueous solubility, stability, and ease of formulation compared to Compound 1. Accordingly, the present invention provides complexes of Compound 1.

[0303] Complex form of compound 1

[0304] In some embodiments, the present disclosure provides a complex comprising Compound 1:

[0305]

[0306] and coformer X;

[0307] in:

[0308] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0309] It should be understood that the complex comprising Compound 1 and coformer X can exist in a pure or unsolvated form, a hydrated form, a solvated form, and / or a heterosolvated form. In some embodiments, the complex comprising Compound 1 and coformer X is a pure or unsolvated crystalline form, and thus no water or solvent is incorporated into the crystal structure. In some embodiments, the complex comprising Compound 1 and coformer X is a hydrated or solvated form. In some embodiments, the complex comprising Compound 1 and coformer X is in a hydrate / solvate form (also referred to herein as a "heterosolvate"). In some embodiments, the present disclosure provides an anhydrous form of a complex comprising Compound 1:

[0310]

[0311]

[0312] and coformer X;

[0313] in:

[0314] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0315] In some embodiments, the present disclosure provides a hydrate form of a complex comprising Compound 1:

[0316]

[0317] and coformer X;

[0318] in:

[0319] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0320] In some embodiments, the present disclosure provides a solvate form of a complex comprising Compound 1:

[0321]

[0322] and coformer X;

[0323] in:

[0324] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0325] In some embodiments, the present disclosure provides a heterosolvate form of a complex comprising Compound 1:

[0326]

[0327] and coformer X;

[0328] in:

[0329] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[0330] In some embodiments, the term "complex" is used herein to refer to a form comprising Compound 1 non-covalently associated with a coformer. Such non-covalent associations include, for example, ionic interactions, dipole-dipole interactions, π-stacking interactions, hydrogen bonding interactions, and the like.

[0331] It is to be understood that the term "complex" encompasses salt forms resulting from ionic interactions between Compound 1 and acids or bases as well as non-ionic associations between Compound 1 and neutral species.

[0332] In some embodiments, the term "complex" is used herein to refer to a form comprising Compound 1 associated with a coformer ion. Thus, in some such embodiments, the term "complex" is used herein to refer to a salt comprising Compound 1 and an acid or base.

[0333] In some embodiments, the "complex" is an inclusion complex, a salt form, a cocrystal, a clathrate, or a hydrate and / or solvate thereof, etc. In some embodiments, the term "complex" is used to refer to a 1:1 (i.e., stoichiometric) ratio of Compound 1 and a coformer. In some embodiments, the term "complex" does not necessarily indicate any particular ratio of Compound 1 and a coformer. In some embodiments, the complex is a salt form or a hydrate or solvate thereof. In some embodiments, the complex is a cocrystal form or a hydrate or solvate thereof. In some embodiments, the complex is an inclusion complex or a hydrate or solvate thereof. In some embodiments, the complex is a clathrate or a hydrate or solvate thereof.

[0334] In some embodiments, coformer X and compound 1 are ionically associated. In some embodiments, compound 1 and coformer X are non-covalently associated.

[0335] The complex form of compound 1 can exist in a variety of physical forms. For example, the complex form of compound 1 can be in solution, suspension or in solid form. In some embodiments, the complex form of compound 1 is in solution form. In certain embodiments, the complex form of compound 1 is in solid form. When the complex of compound 1 is in solid form, the compound can be amorphous, crystalline or a mixture thereof. In some embodiments, the complex form of compound 1 is an amorphous solid. In some embodiments, the complex form of compound 1 is a crystalline solid. Exemplary complex forms of compound 1 are described in more detail below.

[0336] It is understood that a complex comprising Compound 1 and coformer X may comprise 1 equivalent of X. Thus, in some embodiments, the complexes described herein comprise Compound 1 and 1 equivalent of X. In some embodiments, the complexes described herein comprise Compound 1 and 2 equivalents of X. In some embodiments, the complexes described herein comprise Compound 1 and 3 equivalents of X. In some embodiments, the complexes described herein comprise Compound 1 and 0.5-2.5 equivalents of X (e.g., 0.5, 0.9, 1.2, 1.5, etc. equivalents of X).

[0337] In some embodiments, the present invention provides a sample comprising a complex form of Compound 1, wherein the sample is substantially free of impurities. In some embodiments, the sample comprising the complex form of Compound 1 is substantially free of any excess coformer X, excess Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of the complex form of Compound 1. In certain embodiments, the sample comprises at least about 90% by weight of the complex form of Compound 1. In certain embodiments, the sample comprises at least about 95% by weight of the complex form of Compound 1. In other embodiments, the sample comprises at least about 99% by weight of the complex form of Compound 1.

[0338] According to some embodiments, the sample comprises at least about 95, 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent (wt%) of the complex form of compound 1, wherein the percentage is based on the total weight of the sample. According to some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 5.0% of total organic impurities. In some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 3.0% of total organic impurities. In some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 1.5% of total organic impurities. In some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 1.0% of total organic impurities. In some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 0.6% of total organic impurities. In some embodiments, the sample comprising the complex form of compound 1 comprises no more than about 0.5% of total organic impurities. In some embodiments, the percentage of total organic impurities is measured by HPLC.

[0339] The structures depicted for the complex forms of Compound 1 include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a structure having the present invention but with the replacement of hydrogen by deuterium or tritium or with the replacement of carbon by 13 C or 14 C-enriched carbon-substituted compounds are within the scope of the present invention.

[0340] In some embodiments, the complex form of Compound 1 is crystalline, wherein X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glycolic acid, L-malic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

[0341] In some embodiments, X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glutamic acid, glycolic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

[0342] In some embodiments, X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glycolic acid, L-malic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

[0343] In some embodiments of the complex form of Compound 1, X is hydrobromic acid. In some such embodiments, the complex form of Compound 1 is a hydrobromide salt. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of hydrobromic acid. In some embodiments, the hydrobromide salt of Compound 1 is a crystalline hydrobromide salt. In some embodiments, the crystalline hydrobromide salt of Compound 1 is characterized by one or more peaks selected from 9.3, 13.9, 16.6, 19.0, and 20.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A hydrobromide salt.

[0344] In some embodiments, the Form A hydrobromide salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0345]

[0346]

[0347] In some embodiments, the Form A hydrobromide salt is characterized by Fig.10 FT-Raman spectra depicted in .

[0348] In some embodiments, the Form A hydrobromide salt is characterized by Fig.11 The x-ray powder diffraction (XRPD) pattern depicted in .

[0349] In some embodiments, the Form A hydrobromide salt is characterized by Fig.12 Thermogravimetric analysis (TGA) pattern depicted by trace 12A.

[0350] In some embodiments, the Form A hydrobromide salt is characterized by Fig.12 The differential scanning calorimetry (DSC) pattern is depicted in trace 12B.

[0351] In some embodiments, the complex form of Compound 1 comprises 2 equivalents of hydrobromic acid. In some embodiments, the hydrobromide salt of Compound 1 is a hydrate. In some embodiments, the hydrate form of the hydrobromide salt of Compound 1 is a crystalline hydrate form of the hydrobromide salt. In some embodiments, the crystalline hydrate form of the hydrobromide salt of Compound 1 is characterized by one or more peaks selected from 8.4, 9.8, 18.4 and 25.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form B hydrobromide.

[0352] In some embodiments, the Form B hydrobromide salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0353]

[0354] In some embodiments, the Form B hydrobromide salt is characterized by Fig.13 FT-Raman spectra depicted in .

[0355] In some embodiments, the Form B hydrobromide salt is characterized by Fig.14 The x-ray powder diffraction (XRPD) pattern depicted in .

[0356] In some embodiments, the Form B hydrobromide salt is characterized by Fig.15 Thermogravimetric analysis (TGA) pattern depicted by trace 15A.

[0357] In some embodiments, the Form B hydrobromide salt is characterized by Fig.15 The differential scanning calorimetry (DSC) pattern is depicted in trace 15B.

[0358] In some embodiments, the Form B hydrobromide salt is characterized by Fig.16 The dynamic vapor sorption (DVS) isotherm depicted in .

[0359] In some embodiments of the complex form of Compound 1, X is sulfuric acid. In some such embodiments, the complex form of Compound 1 is a sulfate salt. In some embodiments, the sulfate salt of Compound 1 is a crystalline sulfate salt.

[0360] In some embodiments, the sulfate salt of Compound 1 is a hydrate. In some embodiments, the hydrate form of the sulfate salt of Compound 1 is a crystalline hydrate form of the sulfate salt. In some embodiments, the crystalline hydrate form of the sulfate salt of Compound 1 is characterized by one or more peaks selected from 5.9, 7.4, 10.8, 11.8, 15.7, 17.1, and 17.7 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A sulfate.

[0361] In some embodiments, the Form A sulfate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0362]

[0363] In some embodiments, Form A sulfate is characterized by Fig.18 FT-Raman spectra depicted in .

[0364] In some embodiments, Form A sulfate is characterized by Fig.19 The x-ray powder diffraction (XRPD) pattern depicted in .

[0365] In some embodiments, Form A sulfate is characterized by Fig. 20 Thermogravimetric analysis (TGA) pattern depicted by trace 20A.

[0366] In some embodiments, Form A sulfate is characterized by Fig. 20 The differential scanning calorimetry (DSC) pattern is depicted in trace 20B.

[0367] In some embodiments, the sulfate salt of Compound 1 is a heterosolvate. In some such embodiments, the heterosolvate form of the sulfate salt of Compound 1 is a water:tetrahydrofuran heterosolvate. In some embodiments, the water:tetrahydrofuran heterosolvate form of the sulfate salt of Compound 1 is a crystalline water:tetrahydrofuran heterosolvate form of the sulfate salt. In some embodiments, the crystalline water:tetrahydrofuran heterosolvate form of the sulfate salt of Compound 1 is characterized by one or more peaks selected from 5.3, 6.9, 7.5, 10.5, 18.1 and 18.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form B sulfate.

[0368] In some embodiments, the Form B sulfate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0369]

[0370] In some embodiments, Form B sulfate is characterized by Fig.21 FT-Raman spectra depicted in .

[0371] In some embodiments, Form B sulfate is characterized by Fig. 22 The x-ray powder diffraction (XRPD) pattern depicted in .

[0372] In some embodiments, Form B sulfate is characterized by Fig.23 Thermogravimetric analysis (TGA) pattern depicted by trace 23A.

[0373] In some embodiments, Form B sulfate is characterized by Fig.23 The differential scanning calorimetry (DSC) pattern is depicted in trace 23B.

[0374] In some embodiments, the crystalline sulfate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.1, 6.5, and 7.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C sulfate.

[0375] In some embodiments, the Form C sulfate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0376]

[0377] In some embodiments, Form C sulfate is characterized by Fig.24 FT-Raman spectra depicted in .

[0378] In some embodiments, Form C sulfate is characterized by Fig.25 The x-ray powder diffraction (XRPD) pattern depicted in .

[0379] In some embodiments, Form C sulfate is characterized by Fig.26 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0380] In some embodiments, the complex form of Compound 1 comprises 0.5 equivalents of sulfuric acid. In some embodiments, the sulfate of Compound 1 is a solvate. In some embodiments, the solvate form of the sulfate of Compound 1 is an acetone solvate. In some such embodiments, the solvate form of the sulfate of Compound 1 is a diacetone solvate. In some embodiments, the diacetone solvate form of the sulfate of Compound 1 is a crystalline diacetone solvate form of the sulfate. In some embodiments, the crystalline diacetone solvate form of the sulfate of Compound 1 is characterized by one or more peaks selected from 6.9, 11.6, 12.1, 16.4, 16.9 and 18.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form D sulfate.

[0381] In some embodiments, the Form D sulfate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0382]

[0383] In some embodiments, Form D sulfate is characterized by Fig. 27 FT-Raman spectra depicted in .

[0384] In some embodiments, Form D sulfate is characterized by Fig.28 The x-ray powder diffraction (XRPD) pattern depicted in .

[0385] In some embodiments, Form D sulfate is characterized by Fig.29 Thermogravimetric analysis (TGA) pattern depicted by trace 29A.

[0386] In some embodiments, Form D sulfate is characterized by Fig.29 The differential scanning calorimetry (DSC) pattern is depicted in trace 29B.

[0387] In some embodiments of the complex form of Compound 1, X is p-toluenesulfonic acid. In some such embodiments, the complex form of Compound 1 is a p-toluenesulfonic acid salt (also referred to as a "tosylate salt"). In some embodiments, the tosylate salt of Compound 1 is a crystalline tosylate salt.

[0388] In some embodiments, the crystalline tosylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.3, 7.1, 8.6, 9.3, 17.2, and 17.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A tosylate salt.

[0389] In some embodiments, the Form A tosylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0390]

[0391]

[0392] In some embodiments, Form A tosylate salt is characterized by Fig.30 The x-ray powder diffraction (XRPD) pattern depicted in .

[0393] In some embodiments, Form A tosylate salt is characterized by Fig.31 Thermogravimetric analysis (TGA) pattern depicted by trace 31A.

[0394] In some embodiments, Form A tosylate salt is characterized by Fig.31 The differential scanning calorimetry (DSC) pattern is depicted by trace 31B.

[0395] In some embodiments, the crystalline tosylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.5, 9.3, 11.0, 15.2, 15.7, and 16.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B tosylate.

[0396] In some embodiments, the Form B tosylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0397]

[0398] In some embodiments, Form B tosylate salt is characterized by Fig.32 The x-ray powder diffraction (XRPD) pattern depicted in .

[0399] In some embodiments, Form B tosylate salt is characterized by Fig.33 Thermogravimetric analysis (TGA) pattern depicted by trace 33A.

[0400] In some embodiments, Form B tosylate salt is characterized by Fig.33 The differential scanning calorimetry (DSC) pattern is depicted in trace 33B.

[0401] In some embodiments, the complex form of Compound 1 comprises 1 equivalent of p-toluenesulfonic acid. In some embodiments, the crystalline tosylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.6, 12.0, 15.9, 17.9, and 19.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C tosylate.

[0402] In some embodiments, the Form C tosylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0403]

[0404] In some embodiments, Form C tosylate is characterized by Fig.34 FT-Raman spectra depicted in .

[0405] In some embodiments, Form C tosylate is characterized by Fig.35 The x-ray powder diffraction (XRPD) pattern depicted in .

[0406] In some embodiments, Form C tosylate is characterized by Fig.36 Thermogravimetric analysis (TGA) pattern depicted by trace 36A.

[0407] In some embodiments, Form C tosylate is characterized by Fig.36 The differential scanning calorimetry (DSC) pattern is depicted by trace 36B.

[0408] In some embodiments, Form C tosylate is characterized by Fig.37 The dynamic vapor sorption (DVS) isotherm depicted in .

[0409] In some embodiments, Form C tosylate is characterized by Fig.38 Post-DVS x-ray powder diffraction (XRPD) pattern depicted in .

[0410] In some embodiments, Form C tosylate is characterized by Fig.39 Depicted in 1 H NMR.

[0411] In some embodiments of the complex form of Compound 1, X is methanesulfonic acid. In some such embodiments, the complex form of Compound 1 is a methanesulfonate salt (also referred to as a "mesylate salt"). In some embodiments, the complex form of Compound 1 comprises 1.2 equivalents of methanesulfonic acid. In some embodiments, the mesylate salt of Compound 1 is a crystalline mesylate salt.

[0412] In some embodiments, the crystalline mesylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.2, 12.6, 13.2, and 18.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A mesylate.

[0413] In some embodiments, the Form A mesylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0414]

[0415] In some embodiments, Form A mesylate salt is characterized by Fig.40 FT-Raman spectra depicted in .

[0416] In some embodiments, Form A mesylate salt is characterized by Fig.41 The x-ray powder diffraction (XRPD) pattern depicted in .

[0417] In some embodiments, Form A mesylate salt is characterized by Fig.42 Thermogravimetric analysis (TGA) pattern depicted by trace 42A.

[0418] In some embodiments, Form A mesylate salt is characterized by Fig.42 The differential scanning calorimetry (DSC) pattern is depicted by trace 42B.

[0419] In some embodiments, Form A mesylate salt is characterized by Fig.43 Depicted in 1 H NMR.

[0420] In some embodiments, the crystalline mesylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 13.4, 13.6, 14.0, and 18.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B mesylate.

[0421] In some embodiments, the Form B mesylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0422]

[0423] In some embodiments, Form B mesylate salt is characterized by Fig.44 The x-ray powder diffraction (XRPD) pattern depicted in .

[0424] In some embodiments, Form B mesylate salt is characterized by Fig.46 The differential scanning calorimetry (DSC) pattern is depicted by trace 46B.

[0425] In some embodiments, the crystalline mesylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.6, 8.9, 9.1, 13.0, 13.3, 13.6, 17.8, and 18.2 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C mesylate.

[0426] In some embodiments, the Form C mesylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0427]

[0428] In some embodiments, Form C mesylate is characterized by Fig.45 The x-ray powder diffraction (XRPD) pattern depicted in .

[0429] In some embodiments, Form C mesylate is characterized by Fig.46 The differential scanning calorimetry (DSC) pattern is depicted by trace 46C.

[0430] In some embodiments of the complex form of Compound 1, X is 2-naphthalenesulfonic acid. In some such embodiments, the complex form of Compound 1 is a 2-naphthalenesulfonate salt. In some embodiments, the 2-naphthalenesulfonate salt of Compound 1 is a crystalline 2-naphthalenesulfonate salt.

[0431] In some embodiments, the complex form of Compound 1 comprises 1.5 equivalents of 2-naphthalenesulfonic acid. In some embodiments, the 2-naphthalenesulfonate salt of Compound 1 is a hemisolvate. In some such embodiments, the hemisolvate form of the 2-naphthalenesulfonate salt of Compound 1 is a hemi-acetone solvate. In some embodiments, the hemi-acetone solvate form of the 2-naphthalenesulfonate salt of Compound 1 is a crystalline hemi-acetone solvate form of the 2-naphthalenesulfonate salt.

[0432] In some embodiments, the crystalline hemiacetone solvate form of the 2-naphthalenesulfonate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.6, 10.5, 10.9, 11.1, 12.6, 16.8, and 17.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A 2-naphthalenesulfonate salt.

[0433] In some embodiments, the Form A 2-naphthalenesulfonate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0434]

[0435] In some embodiments, Form A 2-naphthalenesulfonate is characterized by Fig.47 FT-Raman spectra depicted in .

[0436] In some embodiments, Form A 2-naphthalenesulfonate is characterized by Fig.48 The x-ray powder diffraction (XRPD) pattern depicted in .

[0437] In some embodiments, Form A 2-naphthalenesulfonate is characterized by Fig.50 Thermogravimetric analysis (TGA) pattern depicted by trace 50A.

[0438] In some embodiments, Form A 2-naphthalenesulfonate is characterized by Fig.50 The differential scanning calorimetry (DSC) pattern is depicted by trace 50B.

[0439] In some embodiments of the complex form of Compound 1, X is phosphoric acid. In some such embodiments, the complex form of Compound 1 is a phosphate salt. In some embodiments, the phosphate salt of Compound 1 is a crystalline phosphate salt.

[0440] In some embodiments, the crystalline phosphate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.2, 10.9, 13.5, 15.0, and 16.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A phosphate salt.

[0441] In some embodiments, the Form A phosphate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0442]

[0443] In some embodiments, Form A phosphate is characterized by Fig.52 The x-ray powder diffraction (XRPD) pattern depicted in .

[0444] In some embodiments, Form A phosphate is characterized by Fig.56 The differential scanning calorimetry (DSC) pattern is depicted by trace 56A.

[0445] In some embodiments, the crystalline phosphate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.9, 8.3, 9.8, 11.0, 17.2, and 19.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B phosphate.

[0446] In some embodiments, the Form B phosphate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0447]

[0448] In some embodiments, Form B phosphate is characterized by Fig.53 The x-ray powder diffraction (XRPD) pattern depicted in .

[0449] In some embodiments, Form B phosphate is characterized by Fig.56 The differential scanning calorimetry (DSC) pattern is depicted by trace 56B.

[0450] In some embodiments, the crystalline phosphate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 9.9, 10.4, 12.3, and 14.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C phosphate.

[0451] In some embodiments, the Form C phosphate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0452]

[0453] In some embodiments, Form C phosphate is characterized by Fig.54 The x-ray powder diffraction (XRPD) pattern depicted in .

[0454] In some embodiments, Form C phosphate is characterized by Fig.56 The differential scanning calorimetry (DSC) pattern is depicted by trace 56C.

[0455] In some embodiments, the crystalline phosphate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.1, 11.1, 14.2, 16.9, and 22.3 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D phosphate.

[0456] In some embodiments, the Form D phosphate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0457]

[0458] In some embodiments, Form D phosphate is characterized by Fig.55 The x-ray powder diffraction (XRPD) pattern depicted in .

[0459] In some embodiments, Form D phosphate is characterized by Fig.56The differential scanning calorimetry (DSC) pattern is depicted by trace 56D.

[0460] In some embodiments, the complex form of Compound 1 comprises 1 equivalent of phosphoric acid. In some embodiments, the phosphate salt of Compound 1 is a solvate. In some embodiments, the solvate form of the phosphate salt of Compound 1 is a methanol solvate. In some embodiments, the methanol solvate form of the phosphate salt of Compound 1 is a crystalline methanol solvate. In some embodiments, the crystalline methanol solvate form of the phosphate salt of Compound 1 is characterized by one or more peaks selected from 8.2, 10.1, 10.9, 14.5, 14.8, 18.0 and 19.5 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form E phosphate.

[0461] In some embodiments, the Form E phosphate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0462]

[0463] In some embodiments, the Form E phosphate salt is characterized by Fig.57 FT-Raman spectra depicted in .

[0464] In some embodiments, the Form E phosphate salt is characterized by Fig.58 The x-ray powder diffraction (XRPD) pattern depicted in .

[0465] In some embodiments, the Form E phosphate salt is characterized by Fig.59 Thermogravimetric analysis (TGA) pattern depicted by trace 59A.

[0466] In some embodiments, the Form E phosphate salt is characterized by Fig.59 The differential scanning calorimetry (DSC) pattern is depicted in trace 59B.

[0467] In some embodiments of the complex form of Compound 1, X is DL-tartaric acid. In some such embodiments, the complex form of Compound 1 is a DL-tartrate salt. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of DL-tartaric acid. In some embodiments, the DL-tartrate salt of Compound 1 is a crystalline DL-tartrate salt.

[0468] In some embodiments, the DL-tartrate salt of Compound 1 is a hydrate. In some embodiments, the hydrated form of the DL-tartrate salt of Compound 1 is a crystalline hydrated form of the DL-tartrate salt. In some embodiments, the crystalline hydrated form of the DL-tartrate salt of Compound 1 is characterized by one or more peaks selected from 4.7, 7.4, 9.3, 11.0 and 13.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A DL-tartrate.

[0469] In some embodiments, Form A DL-tartrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0470]

[0471] In some embodiments, Form A DL-tartrate is characterized by Fig.60 FT-Raman spectra depicted in .

[0472] In some embodiments, Form A DL-tartrate is characterized by Fig.61 The x-ray powder diffraction (XRPD) pattern depicted in .

[0473] In some embodiments, Form A DL-tartrate is characterized by Fig.62 Thermogravimetric analysis (TGA) pattern depicted by trace 62A.

[0474] In some embodiments, Form A DL-tartrate is characterized by Fig.62 The differential scanning calorimetry (DSC) pattern is depicted by trace 62B.

[0475] In some embodiments, Form A DL-tartrate is characterized by Fig.63 Dynamic vapor sorption (DVS) isotherm plotted in .

[0476] In some embodiments, Form A DL-tartrate is characterized by Fig.64 Depicted in 1 H NMR.

[0477] In some embodiments, the crystalline DL-tartrate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.9, 9.7, 13.1, 13.4, 16.9, and 17.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B DL-tartrate salt.

[0478] In some embodiments, Form B DL-tartrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0479]

[0480] In some embodiments, Form B DL-tartrate is characterized by Fig.65 The x-ray powder diffraction (XRPD) pattern depicted in .

[0481] In some embodiments, Form B DL-tartrate is characterized by Fig.66 Thermogravimetric analysis (TGA) pattern depicted by trace 66A.

[0482] In some embodiments, Form B DL-tartrate is characterized by Fig.66 The differential scanning calorimetry (DSC) pattern is depicted by trace 66B.

[0483] In some embodiments of the complex form of Compound 1, X is succinic acid. In some such embodiments, the complex form of Compound 1 is a succinate salt. In some embodiments, the succinate salt of Compound 1 is a crystalline succinate salt. In some embodiments, the crystalline succinate salt of Compound 1 is characterized by one or more peaks selected from 5.0, 5.4, 6.0, 6.4, 6.8, and 16.7 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A succinate salt.

[0484] In some embodiments, the Form A succinate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0485]

[0486] In some embodiments, Form A succinate salt is characterized by Fig.67 The x-ray powder diffraction (XRPD) pattern depicted in .

[0487] In some embodiments, Form A succinate salt is characterized by Fig.68 Thermogravimetric analysis (TGA) pattern depicted by trace 68A.

[0488] In some embodiments, Form A succinate salt is characterized by Fig.68 The differential scanning calorimetry (DSC) pattern is depicted by trace 68B.

[0489] In some embodiments, the complex form of Compound 1 comprises 1 equivalent of succinic acid. In some embodiments, the crystalline succinate salt of Compound 1 is characterized by one or more peaks selected from 4.7, 5.8, 6.2, 6.7, 9.4, and 10.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form B succinate.

[0490] In some embodiments, the Form B succinate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0491]

[0492] In some embodiments, Form B succinate salt is characterized by Fig.69 FT-Raman spectra depicted in .

[0493] In some embodiments, Form B succinate salt is characterized by Fig.70 The x-ray powder diffraction (XRPD) pattern depicted in .

[0494] In some embodiments, Form B succinate salt is characterized by Fig.71 Thermogravimetric analysis (TGA) pattern depicted by trace 71A.

[0495] In some embodiments, Form B succinate salt is characterized by Fig.71 The differential scanning calorimetry (DSC) pattern is depicted by trace 71B.

[0496] In some embodiments, Form B succinate salt is characterized by Fig.72 Depicted in 1 H NMR.

[0497] In some embodiments of the complex form of Compound 1, X is gentisic acid. In some such embodiments, the complex form of Compound 1 is gentisate. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of gentisic acid. In some embodiments, the gentisate of Compound 1 is crystalline gentisate. In some embodiments, the crystalline gentisate of Compound 1 is characterized by one or more peaks selected from 3.9, 7.9, 11.9, 15.8 and 17.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A gentisate.

[0498] In some embodiments, Form A gentisate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0499]

[0500]

[0501] In some embodiments, Form A gentisate is characterized by Fig.73 FT-Raman spectra depicted in .

[0502] In some embodiments, Form A gentisate is characterized by Fig.74 The x-ray powder diffraction (XRPD) pattern depicted in .

[0503] In some embodiments, Form A gentisate is characterized by Fig.75 Thermogravimetric analysis (TGA) pattern depicted by trace 75A.

[0504] In some embodiments, Form A gentisate is characterized by Fig.75 The differential scanning calorimetry (DSC) pattern is depicted by trace 75B.

[0505] In some embodiments, Form A gentisate is characterized by Fig.76 Depicted in 1 H NMR.

[0506] In some embodiments of the complex form of Compound 1, X is hippuric acid. In some such embodiments, the complex form of Compound 1 is hippurate. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of hippuric acid. In some embodiments, the hippurate of Compound 1 is a crystalline hippurate. In some embodiments, the crystalline hippurate of Compound 1 is characterized by one or more peaks selected from 7.6, 9.7, 11.4, 15.2, and 18.6 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A hippurate.

[0507] In some embodiments, the Form A hippurate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0508]

[0509] In some embodiments, Form A hippurate is characterized by Fig.77 FT-Raman spectra depicted in .

[0510] In some embodiments, Form A hippurate is characterized by Fig.78 The x-ray powder diffraction (XRPD) pattern depicted in .

[0511] In some embodiments, Form A hippurate is characterized by Fig.79Thermogravimetric analysis (TGA) pattern depicted by trace 79A.

[0512] In some embodiments, Form A hippurate is characterized by Fig.79 The differential scanning calorimetry (DSC) pattern is depicted in trace 79B.

[0513] In some embodiments, Form A hippurate is characterized by Fig.80 Depicted in 1 H NMR.

[0514] In some embodiments of the complex form of Compound 1, X is adipic acid. In some such embodiments, the complex form of Compound 1 is an adipate salt. In some embodiments, the complex form of Compound 1 comprises 0.9 equivalents of adipic acid. In some embodiments, the adipate salt of Compound 1 is a crystalline adipate salt. In some embodiments, the crystalline adipate salt of Compound 1 is characterized by one or more peaks selected from 8.0, 8.6, 9.5, 12.0, 12.6, 13.0, 15.4, and 16.1 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A adipate salt.

[0515] In some embodiments, the Form A adipate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0516]

[0517] In some embodiments, the Form A adipate salt is characterized by Fig.81 The x-ray powder diffraction (XRPD) pattern depicted in .

[0518] In some embodiments, the Form A adipate salt is characterized by Fig.82 Thermogravimetric analysis (TGA) pattern depicted by trace 82A.

[0519] In some embodiments, the Form A adipate salt is characterized by Fig.82 The differential scanning calorimetry (DSC) pattern is depicted by trace 82B.

[0520] In some embodiments, the crystalline adipate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.1, 9.5, 12.1, 15.7, 16.1, 20.2, and 20.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C adipate salt.

[0521] In some embodiments, the Form C adipate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0522]

[0523] In some embodiments, Form C adipate salt is characterized by Fig.83 FT-Raman spectra depicted in .

[0524] In some embodiments, Form C adipate salt is characterized by Fig.84 The x-ray powder diffraction (XRPD) pattern depicted in .

[0525] In some embodiments, Form C adipate salt is characterized by Fig.85 Thermogravimetric analysis (TGA) pattern depicted by trace 85A.

[0526] In some embodiments, Form C adipate salt is characterized by Fig.85 The differential scanning calorimetry (DSC) pattern is depicted in trace 85B.

[0527] In some embodiments, Form C adipate salt is characterized by Fig.86 Depicted in 1 H NMR.

[0528] In some embodiments of the complex form of Compound 1, X is galactaric acid. In some such embodiments, the complex form of Compound 1 is a galactaric acid salt. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of galactaric acid. In some embodiments, the galactaric acid salt of Compound 1 is a crystalline galactaric acid salt. In some embodiments, the crystalline galactaric acid salt of Compound 1 is characterized by one or more peaks selected from 9.3, 12.1, 12.5, 15.2, 16.6, and 17.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A galactaric acid salt.

[0529] In some embodiments, the Form A galactarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0530]

[0531] In some embodiments, Form A galactamate is characterized by Fig.87 The x-ray powder diffraction (XRPD) pattern depicted in .

[0532] In some embodiments, Form A galactamate is characterized by Fig.89 Thermogravimetric analysis (TGA) pattern depicted by trace 89A.

[0533] In some embodiments, Form A galactamate is characterized by Fig.89 The differential scanning calorimetry (DSC) pattern is depicted in trace 89B.

[0534] In some embodiments, Form A galactamate is characterized by Fig.90 Depicted in 1 H NMR.

[0535] In some embodiments of the complex form of Compound 1, X is 1,5-naphthalene disulfonic acid. In some such embodiments, the complex form of Compound 1 is a 1,5-naphthalene disulfonic acid salt (also referred to as a "naphthalene disulfonate"). In some embodiments, the naphthalene disulfonate salt of Compound 1 is a crystalline naphthalene disulfonate salt. In some embodiments, the crystalline naphthalene disulfonate salt of Compound 1 is characterized by one or more peaks selected from 3.8, 6.5, and 7.5 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A naphthalene disulfonate.

[0536] In some embodiments, the Form A napsylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0537]

[0538] In some embodiments, Form A naphthalene disulfonate is characterized by Fig.91 The x-ray powder diffraction (XRPD) pattern depicted in .

[0539] In some embodiments, Form A naphthalene disulfonate is characterized by Fig.94 The differential scanning calorimetry (DSC) pattern is depicted by trace 94A.

[0540] In some embodiments, the crystalline naphthalene disulfonate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.0, 7.9, and 11.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B naphthalene disulfonate salt.

[0541] In some embodiments, the Form B napsylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0542]

[0543] In some embodiments, Form B naphthalene disulfonate is characterized by Fig.92 The x-ray powder diffraction (XRPD) pattern depicted in .

[0544] In some embodiments, Form B naphthalene disulfonate is characterized by Fig.94 The differential scanning calorimetry (DSC) pattern is depicted by trace 94B.

[0545] In some embodiments, the crystalline naphthalene disulfonate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.6, 13.4, and 14.4 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C naphthalene disulfonate salt.

[0546] In some embodiments, the Form C napsylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0547]

[0548] In some embodiments, Form C naphthalene disulfonate is characterized by Fig.93 The x-ray powder diffraction (XRPD) pattern depicted in .

[0549] In some embodiments, Form C naphthalene disulfonate is characterized by Fig.94 The differential scanning calorimetry (DSC) pattern is depicted by trace 94C.

[0550] In some embodiments of the complex form of Compound 1, X is (S)-camphorsulfonic acid. In some such embodiments, the complex form of Compound 1 is a (S)-camphorsulfonate salt. In some embodiments, the (S)-camphorsulfonate salt of Compound 1 is a crystalline (S)-camphorsulfonate salt. In some embodiments, the crystalline (S)-camphorsulfonate salt of Compound 1 is characterized by one or more peaks selected from 5.0, 9.9, 10.4, 11.1, and 14.3 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A (S)-camphorsulfonate salt.

[0551] In some embodiments, Form A (S)-camsylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0552]

[0553] In some embodiments, Form A (S)-camsylate is characterized by Fig.95 FT-Raman spectra depicted in .

[0554] In some embodiments, Form A (S)-camsylate is characterized by Fig.96 The x-ray powder diffraction (XRPD) pattern depicted in .

[0555] In some embodiments, Form A (S)-camsylate salt is characterized by Fig.97 Thermogravimetric analysis (TGA) pattern depicted by trace 97A.

[0556] In some embodiments, Form A (S)-camsylate salt is characterized by Fig.97 The differential scanning calorimetry (DSC) pattern is depicted in trace 97B.

[0557] In some embodiments, the crystalline (S)-camsylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.9, 10.2, 11.4, and 12.4 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B (S)-camsylate salt.

[0558] In some embodiments, Form B (S)-camsylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0559]

[0560] In some embodiments, Form B (S)-camsylate is characterized by Fig.98 FT-Raman spectra depicted in .

[0561] In some embodiments, Form B (S)-camsylate is characterized by Fig.99 The x-ray powder diffraction (XRPD) pattern depicted in .

[0562] In some embodiments, Form B (S)-camsylate is characterized by Fig.100 Thermogravimetric analysis (TGA) pattern depicted by trace 100A.

[0563] In some embodiments, Form B (S)-camsylate is characterized by Fig.100 The differential scanning calorimetry (DSC) pattern is depicted by trace 100B.

[0564] In some embodiments of the complex form of Compound 1, X is 1,2-ethanedisulfonic acid. In some such embodiments, the complex form of Compound 1 is a 1,2-ethanedisulfonic acid salt (also referred to as "ethanedisulfonic acid salt"). In some embodiments, the ethanedisulfonic acid salt of Compound 1 is a crystalline ethanedisulfonic acid salt. In some embodiments, the ethanedisulfonic acid salt is a hydrate. In some embodiments, the hydrate form of the ethanedisulfonic acid salt of Compound 1 is a crystalline hydrate form of the ethanedisulfonic acid salt. In some embodiments, the crystalline hydrate form of the ethanedisulfonic acid salt of Compound 1 is characterized by one or more peaks selected from 9.1, 10.7, 11.1, 14.0, 14.7, 18.2, and 19.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A ethanedisulfonic acid salt.

[0565] In some embodiments, the Form A edisylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0566]

[0567] In some embodiments, Form A edisylate salt is characterized by Fig.101 The x-ray powder diffraction (XRPD) pattern depicted in .

[0568] In some embodiments, Form A edisylate salt is characterized by Fig.105 Thermogravimetric analysis (TGA) pattern depicted by trace 105A.

[0569] In some embodiments, Form A edisylate salt is characterized by Fig.105 The differential scanning calorimetry (DSC) pattern is depicted by trace 105B.

[0570] In some embodiments, the crystalline edisylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.8, 10.9, 13.1, 13.6, and 19.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B edisylate salt.

[0571] In some embodiments, the Form B edisylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0572]

[0573] In some embodiments, Form B edisylate salt is characterized by Fig.102 The x-ray powder diffraction (XRPD) pattern depicted in .

[0574] In some embodiments, Form B edisylate salt is characterized by Fig.106 The differential scanning calorimetry (DSC) pattern is depicted by trace 106B.

[0575] In some embodiments, the crystalline edisylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.0, 12.8, 13.3, 13.7, and 16.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C edisylate salt.

[0576] In some embodiments, the Form C edisylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0577]

[0578] In some embodiments, Form C edisylate salt is characterized by Fig.103 The x-ray powder diffraction (XRPD) pattern depicted in .

[0579] In some embodiments, Form C edisylate salt is characterized by Fig.106 The differential scanning calorimetry (DSC) pattern is depicted by trace 106A.

[0580] In some embodiments, the crystalline edisylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.1, 10.2, 10.4, 12.5, 15.8, 16.0, and 17.0 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D edisylate salt.

[0581] In some embodiments, Form D edisylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0582]

[0583] In some embodiments, Form D edisylate is characterized by Fig.104 The x-ray powder diffraction (XRPD) pattern depicted in .

[0584] In some embodiments, Form D edisylate is characterized by Fig.106 The differential scanning calorimetry (DSC) pattern is depicted by trace 106C.

[0585] In some embodiments of the complex form of Compound 1, X is ethanesulfonic acid. In some such embodiments, the complex form of Compound 1 is an ethanesulfonate. In some embodiments, the ethanesulfonate salt of Compound 1 is a crystalline ethanesulfonate salt. In some embodiments, the crystalline ethanesulfonate salt of Compound 1 is characterized by one or more peaks selected from 8.4, 17.0, 17.4, 18.2, 18.7, and 25.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A ethanesulfonate.

[0586] In some embodiments, the Form A esylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0587]

[0588] In some embodiments, Form A ethanesulfonate is characterized by Fig.107 The x-ray powder diffraction (XRPD) pattern depicted in .

[0589] In some embodiments, Form A ethanesulfonate is characterized by Fig.109 Thermogravimetric analysis (TGA) pattern depicted by trace 109A.

[0590] In some embodiments, Form A ethanesulfonate is characterized by Fig.109 The differential scanning calorimetry (DSC) pattern is depicted by trace 109B.

[0591] In some embodiments, the crystalline esylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.5, 9.8, 12.5, 12.9, and 14.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B esylate salt.

[0592] In some embodiments, the Form B esylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0593]

[0594] In some embodiments, Form B esylate salt is characterized by Fig.108 The x-ray powder diffraction (XRPD) pattern depicted in .

[0595] In some embodiments, Form B esylate salt is characterized by Fig.110 Thermogravimetric analysis (TGA) pattern depicted by trace 110A.

[0596] In some embodiments, Form B esylate salt is characterized by Fig.110The differential scanning calorimetry (DSC) pattern depicted by trace 110B.

[0597] In some embodiments of the complex form of Compound 1, X is benzenesulfonic acid. In some such embodiments, the complex form of Compound 1 is a benzenesulfonate salt (also referred to as "besylate"). In some embodiments, the besylate salt of Compound 1 is a crystalline besylate salt. In some embodiments, the crystalline besylate salt of Compound 1 is characterized by one or more peaks selected from 5.5, 7.5, 10.4, 11.0, 12.8, 14.3, and 14.9 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A besylate.

[0598] In some embodiments, the Form A besylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0599]

[0600] In some embodiments, Form A besylate salt is characterized by Fig.111 The x-ray powder diffraction (XRPD) pattern depicted in .

[0601] In some embodiments, Form A besylate salt is characterized by Fig.115 The differential scanning calorimetry (DSC) pattern is depicted by trace 115A.

[0602] In some embodiments, the crystalline besylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.5, 9.2, 11.1, 12.1, 14.1, and 15.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B besylate.

[0603] In some embodiments, the Form B besylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0604]

[0605] In some embodiments, Form B besylate is characterized by Fig.112 The x-ray powder diffraction (XRPD) pattern depicted in .

[0606] In some embodiments, Form B besylate is characterized by Fig.115 The differential scanning calorimetry (DSC) pattern is depicted by trace 115B.

[0607] In some embodiments, the crystalline besylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.1, 8.2, 12.3, 16.4, and 20.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C besylate.

[0608] In some embodiments, the Form C besylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0609]

[0610]

[0611] In some embodiments, Form C besylate is characterized by Fig.113 The x-ray powder diffraction (XRPD) pattern depicted in .

[0612] In some embodiments, Form C besylate is characterized by Fig.115 The differential scanning calorimetry (DSC) pattern is depicted by trace 115C.

[0613] In some embodiments, the benzenesulfonate salt of Compound 1 is a hydrate. In some embodiments, the hydrate form of the benzenesulfonate salt of Compound 1 is a crystalline hydrate form of the benzenesulfonate salt. In some embodiments, the crystalline hydrate form of the benzenesulfonate salt of Compound 1 is characterized by one or more peaks selected from 6.1, 7.2, 11.5, 12.1, 12.6 and 12.9 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form D benzenesulfonate.

[0614] In some embodiments, the Form D besylate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0615]

[0616]

[0617] In some embodiments, Form D besylate is characterized by Fig.114 The x-ray powder diffraction (XRPD) pattern depicted in .

[0618] In some embodiments, Form D besylate is characterized by Fig.116 Thermogravimetric analysis (TGA) pattern depicted by trace 116A.

[0619] In some embodiments, Form D besylate is characterized by Fig.116The differential scanning calorimetry (DSC) pattern is depicted by trace 116B.

[0620] In some embodiments of the complex form of Compound 1, X is oxalic acid. In some such embodiments, the complex form of Compound 1 is an oxalate. In some embodiments, the oxalate of Compound 1 is a crystalline oxalate. In some embodiments, the oxalate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the oxalate of Compound 1 is a crystalline hydrate form of the oxalate. In some embodiments, the crystalline hydrate form of the oxalate of Compound 1 is characterized by one or more peaks selected from 4.7, 6.5, 9.4, 11.0, 11.9 and 12.5 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A oxalate.

[0621] In some embodiments, the Form A oxalate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0622]

[0623]

[0624] In some embodiments, Form A oxalate is characterized by Fig.117 The x-ray powder diffraction (XRPD) pattern depicted in .

[0625] In some embodiments, Form A oxalate is characterized by Fig.119 Thermogravimetric analysis (TGA) pattern depicted by trace 119A.

[0626] In some embodiments, Form A oxalate is characterized by Fig.119 The differential scanning calorimetry (DSC) pattern is depicted by trace 119B.

[0627] In some embodiments, the crystalline oxalate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.3, 8.7, and 12.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B oxalate.

[0628] In some embodiments, the Form B oxalate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0629]

[0630] In some embodiments, Form B oxalate is characterized by Fig.118 The x-ray powder diffraction (XRPD) pattern depicted in .

[0631] In some embodiments, Form B oxalate is characterized by Fig.120 Thermogravimetric analysis (TGA) pattern depicted by trace 120A.

[0632] In some embodiments, Form B oxalate is characterized by Fig.120 The differential scanning calorimetry (DSC) pattern is depicted by trace 120B.

[0633] In some embodiments of the complex form of Compound 1, X is maleic acid. In some such embodiments, the complex form of Compound 1 is a maleate. In some embodiments, the maleate of Compound 1 is a crystalline maleate. In some embodiments, the maleate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the maleate of Compound 1 is a crystalline hydrate form of the maleate. In some embodiments, the crystalline hydrate form of the maleate of Compound 1 is characterized by one or more peaks selected from 7.7, 11.5, 14.1, 15.4, 15.8 and 16.1 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A maleate.

[0634] In some embodiments, the Form A maleate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0635]

[0636]

[0637] In some embodiments, Form A maleate salt is characterized by Fig.121 The x-ray powder diffraction (XRPD) pattern depicted in .

[0638] In some embodiments, Form A maleate salt is characterized by Fig.122 Thermogravimetric analysis (TGA) pattern depicted by trace 122A.

[0639] In some embodiments, Form A maleate salt is characterized by Fig.122 The differential scanning calorimetry (DSC) pattern is depicted by trace 122B.

[0640] In some embodiments of the complex form of Compound 1, X is pamoic acid. In some such embodiments, the complex form of Compound 1 is a pamoate salt. In some embodiments, the pamoate salt of Compound 1 is a crystalline pamoate salt. In some embodiments, the crystalline pamoate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.1, 10.7, 13.9, 15.4, 20.8, and 21.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A pamoate salt.

[0641] In some embodiments, the Form A pamoate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0642]

[0643]

[0644] In some embodiments, Form A pamoate is characterized by Fig.123 The x-ray powder diffraction (XRPD) pattern depicted in .

[0645] In some embodiments, Form A pamoate is characterized by Fig.124 Thermogravimetric analysis (TGA) pattern depicted by trace 124A.

[0646] In some embodiments, Form A pamoate is characterized by Fig.124 The differential scanning calorimetry (DSC) pattern is depicted by trace 124B.

[0647] In some embodiments of the complex form of Compound 1, X is 1-hydroxy-2-naphthoic acid. In some such embodiments, the complex form of Compound 1 is a 1-hydroxy-2-naphthoate salt. In some embodiments, the 1-hydroxy-2-naphthoate salt of Compound 1 is a crystalline 1-hydroxy-2-naphthoate salt. In some embodiments, the crystalline 1-hydroxy-2-naphthoate salt of Compound 1 is characterized by one or more peaks selected from 6.7, 8.4, 9.7, 10.8, and 16.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A 1-hydroxy-2-naphthoate salt.

[0648] In some embodiments, Form A 1-hydroxy-2-naphthoate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0649]

[0650]

[0651] In some embodiments, Form A 1-hydroxy-2-naphthoate salt is characterized by Fig.125 The x-ray powder diffraction (XRPD) pattern depicted in .

[0652] In some embodiments, Form A 1-hydroxy-2-naphthoate salt is characterized by Fig.126 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0653] In some embodiments of the complex form of Compound 1, X is malonic acid. In some such embodiments, the complex form of Compound 1 is a malonate salt. In some embodiments, the malonate salt of Compound 1 is a crystalline malonate salt. In some embodiments, the crystalline malonate salt of Compound 1 is characterized by one or more peaks selected from 7.8, 11.7, 13.2, 13.7, and 15.6 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A malonate salt.

[0654] In some embodiments, the Form A malonate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0655]

[0656]

[0657] In some embodiments, the Form A malonate salt is characterized by Fig.127 The x-ray powder diffraction (XRPD) pattern depicted in .

[0658] In some embodiments, the Form A malonate salt is characterized by Fig.128 Thermogravimetric analysis (TGA) pattern depicted by trace 128A.

[0659] In some embodiments, the Form A malonate salt is characterized by Fig.128 The differential scanning calorimetry (DSC) pattern is depicted by trace 128B.

[0660] In some embodiments, the crystalline malonate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.6, 7.3, 11.2, 12.3, 14.5, and 16.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B malonate salt.

[0661] In some embodiments, the Form B malonate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0662]

[0663] In some embodiments, the Form B malonate salt is characterized by Fig.129 The x-ray powder diffraction (XRPD) pattern depicted in .

[0664] In some embodiments, the Form B malonate salt is characterized by Fig.130 Thermogravimetric analysis (TGA) pattern depicted by trace 130A.

[0665] In some embodiments, Form B malonate is characterized by Fig.130 The differential scanning calorimetry (DSC) pattern is depicted by trace 130B.

[0666] In some embodiments, the crystalline malonate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.8, 11.7, 15.7, and 17.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C malonate.

[0667] In some embodiments, the Form C malonate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0668]

[0669] In some embodiments, the Form C malonate salt is characterized by Fig.131 The x-ray powder diffraction (XRPD) pattern depicted in .

[0670] In some embodiments, the Form C malonate salt is characterized by Fig.132 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0671] In some embodiments of the complex form of Compound 1, X is L-tartaric acid. In some such embodiments, the complex form of Compound 1 is an L-tartrate salt. In some embodiments, the L-tartrate salt of Compound 1 is a crystalline L-tartrate salt. In some embodiments, the crystalline L-tartrate salt of Compound 1 is characterized by one or more peaks selected from 9.7, 11.1, 14.9, 16.6, 19.8, and 21.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A L-tartrate salt.

[0672] In some embodiments, the Form A L-tartrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0673]

[0674] In some embodiments, Form A L-tartrate is characterized by Fig.133 The x-ray powder diffraction (XRPD) pattern depicted in .

[0675] In some embodiments, Form A L-tartrate is characterized by Fig.134 Thermogravimetric analysis (TGA) pattern depicted by trace 134A.

[0676] In some embodiments, Form A L-tartrate is characterized by Fig.134 The differential scanning calorimetry (DSC) pattern is depicted by trace 134B.

[0677] In some embodiments, the crystalline L-tartrate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 9.7, 11.2, 11.7, and 14.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B L-tartrate.

[0678] In some embodiments, Form B L-tartrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0679]

[0680] In some embodiments, Form B L-tartrate is characterized by Fig.135 The x-ray powder diffraction (XRPD) pattern depicted in .

[0681] In some embodiments, Form B L-tartrate is characterized by Fig.136 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0682] In some embodiments, the crystalline L-tartrate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 9.7, 11.2, 12.5, and 14.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C L-tartrate.

[0683] In some embodiments, Form C L-tartrate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0684]

[0685]

[0686] In some embodiments, Form C L-tartrate is characterized by Fig.137The x-ray powder diffraction (XRPD) pattern depicted in .

[0687] In some embodiments, Form C L-tartrate is characterized by Fig.138 Thermogravimetric analysis (TGA) pattern depicted by trace 138A.

[0688] In some embodiments, Form C L-tartrate is characterized by Fig.138 The differential scanning calorimetry (DSC) pattern is depicted by trace 138B.

[0689] In some embodiments, the crystalline L-tartrate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.7, 7.4, 9.5, 11.1, 13.1, 13.5, and 18.3 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D L-tartrate.

[0690] In some embodiments, Form D L-tartrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0691]

[0692]

[0693] In some embodiments, Form D L-tartrate is characterized by Fig.139 The x-ray powder diffraction (XRPD) pattern depicted in .

[0694] In some embodiments, Form D L-tartrate is characterized by Fig.140 Thermogravimetric analysis (TGA) pattern depicted by trace 140A.

[0695] In some embodiments, Form D L-tartrate is characterized by Fig.140 The differential scanning calorimetry (DSC) pattern is depicted by trace 140B.

[0696] In some embodiments of the complex form of Compound 1, X is fumaric acid. In some such embodiments, the complex form of Compound 1 is a fumarate salt. In some embodiments, the fumarate salt of Compound 1 is a crystalline fumarate salt. In some embodiments, the crystalline fumarate salt of Compound 1 is characterized by one or more peaks selected from 6.7, 12.3, 13.4, 14.3, and 15.4 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A fumarate salt.

[0697] In some embodiments, the Form A fumarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0698]

[0699]

[0700] In some embodiments, the Form A fumarate salt is characterized by Fig.141 The x-ray powder diffraction (XRPD) pattern depicted in .

[0701] In some embodiments, the Form A fumarate salt is characterized by Fig.142 Thermogravimetric analysis (TGA) pattern depicted by trace 142A.

[0702] In some embodiments, the Form A fumarate salt is characterized by Fig.142 The differential scanning calorimetry (DSC) pattern is depicted by trace 142B.

[0703] In some embodiments, the crystalline fumarate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.0, 14.1, 14.6, 15.3, and 19.0 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B fumarate salt.

[0704] In some embodiments, the Form B fumarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0705]

[0706] In some embodiments, Form B fumarate salt is characterized by Fig.143 The x-ray powder diffraction (XRPD) pattern depicted in .

[0707] In some embodiments, Form B fumarate salt is characterized by Fig.144 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0708] In some embodiments, the crystalline fumarate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.6, 11.4, 15.2, and 19.0 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C fumarate.

[0709] In some embodiments, the Form C fumarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0710]

[0711] In some embodiments, Form C fumarate salt is characterized by Fig.145 The x-ray powder diffraction (XRPD) pattern depicted in .

[0712] In some embodiments, Form C fumarate salt is characterized by Fig.146 Thermogravimetric analysis (TGA) pattern depicted by trace 146A.

[0713] In some embodiments, Form C fumarate salt is characterized by Fig.146 The differential scanning calorimetry (DSC) pattern is depicted by trace 146B.

[0714] In some embodiments, the crystalline fumarate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 14.0, 17.6, 23.3, 23.9, and 25.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D fumarate.

[0715] In some embodiments, the Form D fumarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0716]

[0717] In some embodiments, Form D fumarate salt of Compound 1 is characterized by Fig.147 The x-ray powder diffraction (XRPD) pattern depicted in .

[0718] In some embodiments, Form D fumarate salt of Compound 1 is characterized by Fig.148 Thermogravimetric analysis (TGA) pattern depicted by trace 148A.

[0719] In some embodiments, Form D fumarate salt of Compound 1 is characterized by Fig.148 The differential scanning calorimetry (DSC) pattern is depicted by trace 148B.

[0720] In some embodiments of the complex form of Compound 1, X is citric acid. In some such embodiments, the complex form of Compound 1 is a citrate. In some embodiments, the citrate salt of Compound 1 is a crystalline citrate. In some embodiments, the crystalline citrate salt of Compound 1 is characterized by one or more peaks selected from 7.5, 11.3, 13.5, 15.1, 18.9, and 19.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A citrate.

[0721] In some embodiments, the Form A citrate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0722]

[0723] In some embodiments, Form A citrate salt is characterized by Fig.149 The x-ray powder diffraction (XRPD) pattern depicted in .

[0724] In some embodiments, Form A citrate salt is characterized by Fig.150 Thermogravimetric analysis (TGA) pattern depicted by trace 150A.

[0725] In some embodiments, Form A citrate salt is characterized by Fig.150 The differential scanning calorimetry (DSC) pattern is depicted by trace 150B.

[0726] In some embodiments of the complex form of Compound 1, X is L-lactic acid. In some such embodiments, the complex form of Compound 1 is an L-lactate salt. In some embodiments, the L-lactate salt of Compound 1 is a crystalline L-lactate salt. In some embodiments, the crystalline L-lactate salt of Compound 1 is characterized by one or more peaks selected from 7.5, 8.2, 11.2, 12.3, and 16.0 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form AL-lactate.

[0727] In some embodiments, the Form A L-lactate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0728]

[0729] In some embodiments, Form A L-lactate is characterized by Fig.151 The x-ray powder diffraction (XRPD) pattern depicted in .

[0730] In some embodiments, Form A L-lactate is characterized by Fig.152 Thermogravimetric analysis (TGA) pattern depicted by trace 152A.

[0731] In some embodiments, Form A L-lactate is characterized by Fig.152 The differential scanning calorimetry (DSC) pattern is depicted by trace 152B.

[0732] In some embodiments of the complex form of Compound 1, X is acetic acid. In some such embodiments, the complex form of Compound 1 is an acetate salt. In some embodiments, the acetate salt of Compound 1 is a crystalline acetate salt. In some embodiments, the crystalline acetate salt of Compound 1 is characterized by one or more peaks selected from 8.9, 11.6, 11.9, 13.5, 14.1, and 17.9 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A acetate salt.

[0733] In some embodiments, the Form A acetate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0734]

[0735] In some embodiments, Form A acetate is characterized by Fig.153 The x-ray powder diffraction (XRPD) pattern depicted in .

[0736] In some embodiments, Form A acetate is characterized by Fig.154 Thermogravimetric analysis (TGA) pattern depicted by trace 154A.

[0737] In some embodiments, Form A acetate is characterized by Fig.154 The differential scanning calorimetry (DSC) pattern is depicted by trace 154B.

[0738] In some embodiments, the crystalline acetate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 10.3, 11.6, 12.8, 15.6, 17.6, and 19.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B acetate salt.

[0739] In some embodiments, the Form B acetate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0740]

[0741] In some embodiments, Form B acetate is characterized by Fig.155 The x-ray powder diffraction (XRPD) pattern depicted in .

[0742] In some embodiments, Form B acetate is characterized by Fig.156 Thermogravimetric analysis (TGA) pattern depicted by trace 156A.

[0743] In some embodiments, Form B acetate is characterized by Fig.156The differential scanning calorimetry (DSC) pattern is depicted by trace 156B.

[0744] In some embodiments of the complex form of Compound 1, X is propionic acid. In some such embodiments, the complex form of Compound 1 is a propionate salt. In some embodiments, the propionate salt of Compound 1 is a crystalline propionate salt. In some embodiments, the crystalline propionate salt of Compound 1 is characterized by one or more peaks selected from 8.6, 9.7, 12.4, 14.0, 16.4, and 17.7 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A propionate salt.

[0745] In some embodiments, the Form A propionate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0746]

[0747] In some embodiments, Form A propionate salt is characterized by Fig.157 The x-ray powder diffraction (XRPD) pattern depicted in .

[0748] In some embodiments, Form A propionate salt is characterized by Fig.158 Thermogravimetric analysis (TGA) pattern depicted by trace 158A.

[0749] In some embodiments, Form A propionate salt is characterized by Fig.158 The differential scanning calorimetry (DSC) pattern is depicted by trace 158B.

[0750] In some embodiments of the complex form of Compound 1, X is DL-lactic acid. In some such embodiments, the complex form of Compound 1 is a DL-lactate. In some embodiments, the DL-lactate of Compound 1 is a crystalline DL-lactate. In some embodiments, the crystalline DL-lactate of Compound 1 is characterized by one or more peaks selected from 8.3, 12.4, 15.9, 17.6, and 18.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A DL-lactate.

[0751] In some embodiments, Form A DL-lactate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0752]

[0753] In some embodiments, Form A DL-lactate is characterized by Fig.159 The x-ray powder diffraction (XRPD) pattern depicted in .

[0754] In some embodiments, Form A DL-lactate is characterized by Fig.160 Thermogravimetric analysis (TGA) pattern depicted by trace 160A.

[0755] In some embodiments, Form A DL-lactate is characterized by Fig.160 The differential scanning calorimetry (DSC) pattern is depicted by trace 160B.

[0756] In some embodiments of the complex form of Compound 1, X is D-gluconic acid. In some such embodiments, the complex form of Compound 1 is a D-gluconate salt. In some embodiments, the D-gluconate salt of Compound 1 is a crystalline D-gluconate salt. In some embodiments, the crystalline D-gluconate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.1, 11.7, 14.7, 16.1, and 16.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A D-gluconate salt.

[0757] In some embodiments, the Form A D-gluconate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0758]

[0759] In some embodiments, Form A D-gluconate is characterized by Fig.161 The x-ray powder diffraction (XRPD) pattern depicted in .

[0760] In some embodiments, Form A D-gluconate is characterized by Fig.162 Differential Scanning Calorimetry (DSC) pattern depicted in .

[0761] In some embodiments of the complex form of Compound 1, X is DL-malic acid. In some such embodiments, the complex form of Compound 1 is a DL-malate salt. In some embodiments, the DL-malate salt of Compound 1 is a crystalline DL-malate salt. In some embodiments, the crystalline DL-malate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.5, 9.7, 11.3, 15.1, 16.3, and 21.0 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A DL-malate salt.

[0762] In some embodiments, Form A DL-malate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0763]

[0764] In some embodiments, Form A DL-malate salt is characterized by Fig.163 The x-ray powder diffraction (XRPD) pattern depicted in .

[0765] In some embodiments, Form A DL-malate is characterized by Fig.164 Thermogravimetric analysis (TGA) pattern depicted by trace 164A.

[0766] In some embodiments, Form A DL-malate salt is characterized by Fig.164 The differential scanning calorimetry (DSC) pattern is depicted by trace 164B.

[0767] In some embodiments, the crystalline DL-malate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.6, 8.3, 11.7, 13.9, and 18.6 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B DL-malate salt.

[0768] In some embodiments, Form B DL-malate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0769]

[0770] In some embodiments, Form B DL-malate salt is characterized by Fig.165 The x-ray powder diffraction (XRPD) pattern depicted in .

[0771] In some embodiments, Form B DL-malate salt is characterized by Fig.166 Thermogravimetric analysis (TGA) pattern depicted by trace 166A.

[0772] In some embodiments, Form B DL-malate salt is characterized by Fig.166 The differential scanning calorimetry (DSC) pattern is depicted by trace 166B.

[0773] In some embodiments of the complex form of Compound 1, X is glycolic acid. In some such embodiments, the complex form of Compound 1 is a glycolate salt. In some embodiments, the glycolate salt of Compound 1 is a crystalline glycolate salt. In some embodiments, the crystalline glycolate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.4, 8.6, 10.6, 12.7, and 16.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A glycolate.

[0774] In some embodiments, the Form A glycolic acid salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0775]

[0776] In some embodiments, Form A glycolic acid salt is characterized by Fig.167 The x-ray powder diffraction (XRPD) pattern depicted in .

[0777] In some embodiments, Form A glycolic acid salt is characterized by Fig.168 Thermogravimetric analysis (TGA) pattern depicted by trace 168A.

[0778] In some embodiments, Form A glycolic acid salt is characterized by Fig.168 The differential scanning calorimetry (DSC) pattern is depicted by trace 168B.

[0779] In some embodiments of the complex form of Compound 1, X is glutaric acid. In some such embodiments, the complex form of Compound 1 is a glutarate salt. In some embodiments, the glutarate salt of Compound 1 is a crystalline glutarate salt. In some embodiments, the crystalline glutarate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 11.1, 14.9, 16.1, 18.6, and 18.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A glutarate salt.

[0780] In some embodiments, the Form A glutarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0781]

[0782] In some embodiments, Form A glutarate salt is characterized by Fig.169 The x-ray powder diffraction (XRPD) pattern depicted in .

[0783] In some embodiments, Form A glutarate salt is characterized by Fig.170Thermogravimetric analysis (TGA) pattern depicted by trace 170A.

[0784] In some embodiments, Form A glutarate salt is characterized by Fig.170 The differential scanning calorimetry (DSC) pattern is depicted by trace 170B.

[0785] In some embodiments, the crystalline glutarate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.8, 5.8, 9.5, 11.3, and 14.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B glutarate salt.

[0786] In some embodiments, Form B glutarate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0787]

[0788] In some embodiments, Form B glutarate is characterized by Fig.171 The x-ray powder diffraction (XRPD) pattern depicted in .

[0789] In some embodiments, Form B glutarate salt is characterized by Fig.172 Thermogravimetric analysis (TGA) pattern depicted by trace 172A.

[0790] In some embodiments, Form B glutarate is characterized by Fig.172 The differential scanning calorimetry (DSC) pattern is depicted by trace 172B.

[0791] In some embodiments of the complex form of Compound 1, X is L-malic acid. In some such embodiments, the complex form of Compound 1 is an L-malate salt. In some embodiments, the L-malate salt of Compound 1 is a crystalline L-malate salt. In some embodiments, the crystalline L-malate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.5, 9.6, 11.3, 15.1, 16.2, and 16.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A L-malate salt.

[0792] In some embodiments, the Form A L-malate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0793]

[0794] In some embodiments, Form A L-malate salt is characterized by Fig.173The x-ray powder diffraction (XRPD) pattern depicted in .

[0795] In some embodiments, Form A L-malate salt is characterized by Fig.174 Thermogravimetric analysis (TGA) pattern depicted by trace 174A.

[0796] In some embodiments, Form A L-malate salt is characterized by Fig.174 The differential scanning calorimetry (DSC) pattern is depicted by trace 174B.

[0797] In some embodiments of the complex form of Compound 1, X is camphoric acid. In some such embodiments, the complex form of Compound 1 is a camphorate. In some embodiments, the camphorate of Compound 1 is a crystalline camphorate. In some embodiments, the crystalline camphorate of Compound 1 is characterized by one or more peaks selected from 6.7, 8.3, 9.9, 15.0, and 15.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A camphorate.

[0798] In some embodiments, the Form A camphorate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0799]

[0800] In some embodiments, the Form A camphorate salt is characterized by Fig.175 The x-ray powder diffraction (XRPD) pattern depicted in .

[0801] In some embodiments, the Form A camphorate salt is characterized by Fig.176 Thermogravimetric analysis (TGA) pattern depicted by trace 176A.

[0802] In some embodiments, the Form A camphorate salt is characterized by Fig.176 The differential scanning calorimetry (DSC) pattern is depicted by trace 176B.

[0803] In some embodiments, the crystalline camphorate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.9, 9.9, 11.5, 15.3, 16.1, and 16.8 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B camphorate salt.

[0804] In some embodiments, the Form B camphorate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0805]

[0806] In some embodiments, the Form B camphorate salt is characterized by Fig.177 The x-ray powder diffraction (XRPD) pattern depicted in .

[0807] In some embodiments, the Form B camphorate salt is characterized by Fig.178 Thermogravimetric analysis (TGA) pattern depicted by trace 178A.

[0808] In some embodiments, the Form B camphorate salt is characterized by Fig.178 The differential scanning calorimetry (DSC) pattern is depicted by trace 178B.

[0809] In some embodiments, the crystalline camphorate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.9, 10.3, 13.6, 15.5, and 16.2 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C camphorate salt.

[0810] In some embodiments, the Form C camphorate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0811]

[0812] In some embodiments, Form C camphorate is characterized by Fig.179 The x-ray powder diffraction (XRPD) pattern depicted in .

[0813] In some embodiments, Form C camphorate is characterized by Fig.180 Thermogravimetric analysis (TGA) pattern depicted by trace 180A.

[0814] In some embodiments, Form C camphorate is characterized by Fig.180 The differential scanning calorimetry (DSC) pattern is depicted by trace 180B.

[0815] In some embodiments, the crystalline camphorate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.7, 8.6, 9.6, 12.1, 13.5, and 15.3 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D camphorate salt.

[0816] In some embodiments, the Form D camphorate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0817]

[0818] In some embodiments, the Form D camphorate salt is characterized by Fig.181 The x-ray powder diffraction (XRPD) pattern depicted in .

[0819] In some embodiments, the Form D camphorate salt is characterized by Fig.182 Thermogravimetric analysis (TGA) pattern depicted by trace 182A.

[0820] In some embodiments, the Form D camphorate salt is characterized by Fig.182 The differential scanning calorimetry (DSC) pattern is depicted by trace 182B.

[0821] In some embodiments of the complex form of Compound 1, X is DL-mandelic acid. In some such embodiments, the complex form of Compound 1 is a DL-mandelate salt. In some embodiments, the DL-mandelate salt of Compound 1 is a crystalline DL-mandelate salt. In some embodiments, the crystalline DL-mandelate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 11.1, 13.8, 14.9, and 16.3 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form A DL-mandelate salt.

[0822] In some embodiments, Form A DL-mandelate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0823]

[0824] In some embodiments, Form A DL-mandelate salt is characterized by Fig.183 The x-ray powder diffraction (XRPD) pattern depicted in .

[0825] In some embodiments, Form A DL-mandelate salt is characterized by Fig.184 Thermogravimetric analysis (TGA) pattern depicted by trace 184A.

[0826] In some embodiments, Form A DL-mandelate salt is characterized by Fig.184 The differential scanning calorimetry (DSC) pattern is depicted by trace 184B.

[0827] In some embodiments, the crystalline DL-mandelate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.5, 9.2, 11.3, 15.1, and 15.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B DL-mandelate salt.

[0828] In some embodiments, Form B DL-mandelate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0829]

[0830] In some embodiments, Form B DL-mandelate salt is characterized by Fig.185 The x-ray powder diffraction (XRPD) pattern depicted in .

[0831] In some embodiments, Form B DL-mandelate salt is characterized by Fig.186 Thermogravimetric analysis (TGA) pattern depicted by trace 186A.

[0832] In some embodiments, Form B DL-mandelate salt is characterized by Fig.186 The differential scanning calorimetry (DSC) pattern is depicted by trace 186B.

[0833] In some embodiments, the crystalline DL-mandelate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.4, 9.9, 10.9, 14.0, and 14.6 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C DL-mandelate salt.

[0834] In some embodiments, Form C DL-mandelate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0835]

[0836]

[0837] In some embodiments, Form C DL-mandelate salt is characterized by Fig.187 The x-ray powder diffraction (XRPD) pattern depicted in .

[0838] In some embodiments, Form C DL-mandelate salt is characterized by Fig.188 Thermogravimetric analysis (TGA) pattern depicted by trace 188A.

[0839] In some embodiments, Form C DL-mandelate salt is characterized by Fig.188 The differential scanning calorimetry (DSC) pattern is depicted by trace 188B.

[0840] In some embodiments of the complex form of Compound 1, X is saccharin. In some such embodiments, the complex form of Compound 1 is a saccharin co-crystal. In some embodiments, the saccharin co-crystal of Compound 1 is a crystalline saccharin co-crystal. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of saccharin. In some embodiments, the crystalline saccharin co-crystal of Compound 1 is characterized by one or more peaks selected from 3.9, 7.9, 11.8, 15.0 and 15.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A saccharin co-crystal.

[0841] In some embodiments, Form A saccharin cocrystals are characterized by the following peaks in their X-ray powder diffraction pattern:

[0842]

[0843] In some embodiments, Form A saccharin cocrystal is characterized by Fig.189 FT-Raman spectra depicted in .

[0844] In some embodiments, Form A saccharin cocrystal is characterized by Fig.190 The x-ray powder diffraction (XRPD) pattern depicted in .

[0845] In some embodiments, Form A saccharin cocrystal is characterized by Fig.191 Thermogravimetric analysis (TGA) pattern depicted by trace 191A.

[0846] In some embodiments, Form A saccharin cocrystal is characterized by Fig.191 The differential scanning calorimetry (DSC) pattern is depicted by trace 191B.

[0847] In some embodiments, Form A saccharin cocrystal is characterized by Fig.192 Depicted in 1 H NMR spectroscopy.

[0848] In some embodiments of the complex form of Compound 1, X is nicotinic acid. In some such embodiments, the complex form of Compound 1 is a nicotinic acid salt. In some embodiments, the nicotinic acid salt of Compound 1 is a crystalline nicotinic acid salt. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of nicotinic acid. In some embodiments, the crystalline nicotinic acid salt of Compound 1 is characterized by one or more peaks selected from 7.8, 8.9, 14.0, 16.8, and 17.9 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A nicotinic acid salt.

[0849] In some embodiments, Form A nicotinate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0850]

[0851] In some embodiments, Form A nicotinate is characterized by Fig.193 FT-Raman spectra depicted in .

[0852] In some embodiments, Form A nicotinate is characterized by Fig.194 The x-ray powder diffraction (XRPD) pattern depicted in .

[0853] In some embodiments, Form A nicotinate is characterized by Fig.195 Thermogravimetric analysis (TGA) pattern depicted by trace 195A.

[0854] In some embodiments, Form A nicotinate is characterized by Fig.195 The differential scanning calorimetry (DSC) pattern is depicted by trace 195B.

[0855] In some embodiments, Form A nicotinate is characterized by Fig.196 Depicted in 1 H NMR spectroscopy.

[0856] In some embodiments, the nicotinic acid salt of Compound 1 is a hydrate. In some embodiments, the hydrated form of the nicotinic acid salt of Compound 1 is a crystalline hydrated form of the nicotinic acid salt. In some embodiments, the crystalline hydrated form of the nicotinic acid salt of Compound 1 is characterized by one or more peaks selected from 8.2, 12.4, 15.3, 17.9 and 18.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form B nicotinic acid salt.

[0857] In some embodiments, Form B nicotinate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0858]

[0859] In some embodiments, Form B nicotinate is characterized by Fig.197 The x-ray powder diffraction (XRPD) pattern depicted in .

[0860] In some embodiments, Form B nicotinate is characterized by Fig.198 Thermogravimetric analysis (TGA) pattern depicted by trace 198A.

[0861] In some embodiments, Form B nicotinate is characterized by Fig.198The differential scanning calorimetry (DSC) pattern is depicted by trace 198B.

[0862] In some embodiments, the crystalline nicotinate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 3.8, 7.5, 11.3, 15.0, and 18.7 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form C nicotinate.

[0863] In some embodiments, the Form C nicotinate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0864]

[0865] In some embodiments, Form C nicotinate is characterized by Fig.199 The x-ray powder diffraction (XRPD) pattern depicted in .

[0866] In some embodiments, Form C nicotinate is characterized by Fig.200 Thermogravimetric analysis (TGA) pattern depicted by trace 200A.

[0867] In some embodiments, Form C nicotinate is characterized by Fig.200 The differential scanning calorimetry (DSC) pattern is depicted by trace 200B.

[0868] In some embodiments of the complex form of Compound 1, X is ascorbic acid. In some such embodiments, the complex form of Compound 1 is an ascorbate. In some embodiments, the ascorbate of Compound 1 is a crystalline ascorbate. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of ascorbic acid. In some embodiments, the ascorbate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the ascorbate of Compound 1 is a crystalline hydrate form of the ascorbate. In some embodiments, the crystalline hydrate form of the ascorbate of Compound 1 is characterized by one or more peaks selected from 3.7, 7.5, 11.3, 15.0, and 18.8 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A ascorbate.

[0869] In some embodiments, Form A ascorbate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0870]

[0871] In some embodiments, Form A ascorbate is characterized by Fig.201 FT-Raman spectra depicted in .

[0872] In some embodiments, Form A ascorbate is characterized by Fig.202 The x-ray powder diffraction (XRPD) pattern depicted in .

[0873] In some embodiments, Form A ascorbate is characterized by Fig.203 Thermogravimetric analysis (TGA) pattern depicted by trace 203A.

[0874] In some embodiments, Form A ascorbate is characterized by Fig.203 The differential scanning calorimetry (DSC) pattern is depicted by trace 203B.

[0875] In some embodiments, Form A ascorbate is characterized by Fig.204 Depicted in 1 H NMR spectroscopy.

[0876] In some embodiments, the crystalline ascorbate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.4, 9.8, 11.2, 14.9, and 16.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B ascorbate.

[0877] In some embodiments, Form B ascorbate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0878]

[0879] In some embodiments, Form B ascorbate is characterized by Fig.234 The x-ray powder diffraction (XRPD) pattern depicted in .

[0880] In some embodiments, Form B ascorbate is characterized by Fig.235 Thermogravimetric analysis (TGA) pattern depicted by trace 235A.

[0881] In some embodiments, Form B ascorbate is characterized by Fig.235 The differential scanning calorimetry (DSC) pattern is depicted by trace 235B.

[0882] In some embodiments of the complex form of Compound 1, X is gallic acid. In some such embodiments, the complex form of Compound 1 is a gallate. In some embodiments, the gallate of Compound 1 is a crystalline gallate. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of gallic acid. In some embodiments, the gallate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the gallate of Compound 1 is a crystalline hydrate form of the gallate. In some embodiments, the crystalline hydrate form of the gallate of Compound 1 is characterized by one or more peaks selected from 3.8, 7.6, 11.5, 15.4 and 19.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A gallate.

[0883] In some embodiments, the Form A gallic acid salt is characterized by the following peaks in its X-ray powder diffraction pattern:

[0884]

[0885] In some embodiments, Form A gallic acid salt is characterized by Fig.205 FT-Raman spectra depicted in .

[0886] In some embodiments, Form A gallic acid salt is characterized by Fig.206 The x-ray powder diffraction (XRPD) pattern depicted in .

[0887] In some embodiments, Form A gallic acid salt is characterized by Fig.207 Thermogravimetric analysis (TGA) pattern depicted by trace 207A.

[0888] In some embodiments, Form A gallic acid salt is characterized by Fig.207 The differential scanning calorimetry (DSC) pattern is depicted by trace 207B.

[0889] In some embodiments, Form A gallic acid salt is characterized by Fig.208 Depicted in 1 H NMR spectroscopy.

[0890] In some embodiments of the complex form of Compound 1, X is salicylic acid. In some such embodiments, the complex form of Compound 1 is a salicylate. In some embodiments, the salicylate of Compound 1 is a crystalline salicylate. In some embodiments, the salicylate of Compound 1 is a hydrate. In some embodiments, the hydrate form of the salicylate of Compound 1 is a crystalline hydrate form of salicylate. In some embodiments, the crystalline hydrate form of the salicylate of Compound 1 is characterized by one or more peaks selected from 3.8, 7.6, 11.5, 15.4 and 19.2 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A salicylate.

[0891] In some embodiments, the Form A salicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0892]

[0893]

[0894] In some embodiments, Form A salicylate is characterized by Fig.209 FT-Raman spectra depicted in .

[0895] In some embodiments, Form A salicylate is characterized by Fig.210 The x-ray powder diffraction (XRPD) pattern depicted in .

[0896] In some embodiments, Form A salicylate is characterized by Fig.211 Thermogravimetric analysis (TGA) pattern depicted by trace 211A.

[0897] In some embodiments, Form A salicylate is characterized by Fig.211 The differential scanning calorimetry (DSC) pattern is depicted by trace 211B.

[0898] In some embodiments, Form A salicylate is characterized by Fig.212 Depicted in 1 H NMR spectroscopy.

[0899] In some embodiments, the crystalline salicylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.1, 7.0, 10.9, 13.9, 15.9, and 16.2 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B salicylate.

[0900] In some embodiments, Form B salicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0901]

[0902]

[0903] In some embodiments, Form B salicylate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in Figure 241.

[0904] In some embodiments, the Form B salicylate is characterized by the thermogravimetric analysis (TGA) pattern depicted by trace 242A in Figure 242.

[0905] In some embodiments, the Form B salicylate is characterized by the differential scanning calorimetry (DSC) pattern depicted in Figure 242, trace 242B.

[0906] In some embodiments of Compound 1, X is orotic acid. In some such embodiments, the complex form of Compound 1 is orotate. In some embodiments, the orotate of Compound 1 is crystalline orotate. In some embodiments, the complex form of Compound 1 comprises 1 equivalent of orotate. In some embodiments, the crystalline orotate of Compound 1 is characterized by one or more peaks selected from 4.7, 17.6, and 20.9 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A orotate.

[0907] In some embodiments, Form A orotate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0908]

[0909] In some embodiments, Form A orotate is characterized by Fig.213 The x-ray powder diffraction (XRPD) pattern depicted in .

[0910] In some embodiments, Form A orotate is characterized by Fig.214 Thermogravimetric analysis (TGA) pattern depicted by trace 214A.

[0911] In some embodiments, Form A orotate is characterized by Fig.214 The differential scanning calorimetry (DSC) pattern is depicted by trace 214B.

[0912] In some embodiments, the crystalline orotate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.8, 8.6, 9.5, 10.0, 15.5, and 21.1 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form D orotate.

[0913] In some embodiments, Form D orotate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0914]

[0915] In some embodiments, Form D orotate is characterized by Fig.217 The x-ray powder diffraction (XRPD) pattern depicted in .

[0916] In some embodiments, Form D orotate is characterized by Fig.218 Thermogravimetric analysis (TGA) pattern depicted by trace 218A.

[0917] In some embodiments, Form D orotate is characterized by Fig.218 The differential scanning calorimetry (DSC) pattern is depicted by trace 218B.

[0918] In some embodiments, the crystalline orotate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.4, 5.0, 6.2, 9.9, 12.4, and 14.9 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form F orotate.

[0919] In some embodiments, Form F orotate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0920]

[0921] In some embodiments, Form F orotate is characterized by Fig.222 FT-Raman spectra depicted in .

[0922] In some embodiments, Form F orotate is characterized by Fig.223 The x-ray powder diffraction (XRPD) pattern depicted in .

[0923] In some embodiments, Form F orotate is characterized by Fig.224 Thermogravimetric analysis (TGA) pattern depicted by trace 224A.

[0924] In some embodiments, Form F orotate is characterized by Fig.224The differential scanning calorimetry (DSC) pattern is depicted by trace 224B.

[0925] In some embodiments, Form F orotate is characterized by Fig.225 Depicted in 1 H NMR spectroscopy.

[0926] In some embodiments, the crystalline orotate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 5.3, 9.0, 11.9, 13.9, 16.8, and 20.3 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form H orotate.

[0927] In some embodiments, Form H orotate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0928]

[0929] In some embodiments, Form H orotate is characterized by Fig.226 FT-Raman spectra depicted in .

[0930] In some embodiments, Form H orotate is characterized by Fig.227 The x-ray powder diffraction (XRPD) pattern depicted in .

[0931] In some embodiments, Form H orotate is characterized by Fig.228 Thermogravimetric analysis (TGA) pattern depicted by trace 228A.

[0932] In some embodiments, Form H orotate is characterized by Fig.228 The differential scanning calorimetry (DSC) pattern is depicted by trace 228B.

[0933] In some embodiments, Form H orotate is characterized by Fig.229 Depicted in 1 H NMR spectroscopy.

[0934] In some embodiments of the complex form of Compound 1, X is acetylsalicylic acid. In some such embodiments, the complex form of Compound 1 is acetylsalicylate. In some embodiments, the acetylsalicylate of Compound 1 is crystalline acetylsalicylate. In some embodiments, the crystalline acetylsalicylate of Compound 1 is characterized by one or more peaks selected from 7.6, 10.3, 11.4, 13.5, and 15.3 ± 0.2 degrees 2θ in its X-ray powder diffraction pattern. In some such embodiments, the complex form of Compound 1 is Form A acetylsalicylate.

[0935] In some embodiments, Form A acetylsalicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0936]

[0937] In some embodiments, the crystalline acetylsalicylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 3.6, 5.0, 5.6, 7.0, 7.9, 9.0, 9.9, and 10.5 ± 0.2 degrees 2θ. In some such embodiments, the complex form of Compound 1 is Form B acetylsalicylate.

[0938] In some embodiments, Form B acetylsalicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

[0939]

[0940] In some embodiments, Form B acetylsalicylate is characterized by Fig.239 The x-ray powder diffraction (XRPD) pattern depicted in .

[0941] In some embodiments, Form B acetylsalicylate is characterized by Fig.240 Thermogravimetric analysis (TGA) pattern depicted by trace 240A.

[0942] In some embodiments, Form B acetylsalicylate is characterized by Fig.240 The differential scanning calorimetry (DSC) pattern is depicted by trace 240B.

[0943] Use, preparation and administration

[0944] Pharmaceutically acceptable compositions

[0945] According to another embodiment, the present disclosure provides a composition comprising compound 1 or a crystalline form or complex thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the amount of compound 1 or a crystalline form or complex thereof in the composition of the present disclosure is effective to measurably inhibit JAK2 or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0946] According to the methods of the present invention, compounds and compositions are administered using any amount and any route of administration that is effective for treating or alleviating the severity of the conditions provided herein (i.e., JAK2-mediated diseases or conditions). The exact amount required varies from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. Compound 1 or its crystalline form or complex is preferably formulated in a unit dosage form for ease of administration and uniform dosage.

[0947] The compositions of the present disclosure can be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternal, or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0948] The sterile injectable form of the composition of the present disclosure can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media.

[0949] For this purpose, any bland, fixed oil may be used, including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, may be used to prepare injectables, as may natural pharmaceutically acceptable oils, such as olive oil or castor oil (especially in polyoxyethylated form). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used to achieve formulation purposes.

[0950] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0951] In order to prolong the effect of compound 1 or its crystalline form or complex, it is often necessary to slow down the absorption of the compound injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of compound 1 or its crystalline form or complex depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, the delayed absorption of compound 1 or its crystalline form or complex administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating compound 1 or its crystalline form or complex in liposomes or microemulsions compatible with body tissues.

[0952] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0953] The pharmaceutically acceptable compositions of the present disclosure can be orally administered in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, available diluents include lactose and dry corn starch. When an aqueous suspension is needed for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavorings or coloring agents may also be added.

[0954] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, Compound 1 or its crystalline form or complex is mixed with at least one inert pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and / or the following substances: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarder such as paraffin; f) absorption promoters such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0955] Solid compositions of similar types may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules with coatings and shells such as enteric coatings and other coatings known in the field of pharmaceutical formulation may be prepared. They may optionally contain an emulsifier and may also have a composition that allows them to release one or more active ingredients only or preferentially in a delayed manner in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar types may also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (lactose / milk sugar) and high molecular weight polyethylene glycol.

[0956] Compound 1 or its crystalline form or complex may also be in the form of microcapsules with one or more of the above excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the field of pharmaceutical formulation may be prepared. In such solid dosage forms, compound 1 or its crystalline form or complex may be mixed with at least one inert diluent, such as sucrose, lactose or starch. It is common practice that such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain a buffer. They may optionally contain an opacifier and may also have a composition that allows it to release only or preferentially one or more active ingredients in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0957] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to Compound 1 or its crystalline form or complex, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0958] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing Compound 1 or its crystalline form or complex with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0959] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing Compound 1 or its crystalline form or complex with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0960] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0961] Topical application for the lower intestinal tract can be achieved using a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0962] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment containing compound 1 or its crystalline form or complex suspended or dissolved in one or more carriers. Carriers for topical application of compound 1 or its crystalline form or complex include, but are not limited to, mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated into a suitable lotion or cream containing compound 1 or its crystalline form or complex suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0963] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably, as solutions in isotonic, pH-adjusted sterile saline with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as ointments such as petrolatum.

[0964] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0965] The dosage form for topical or transdermal administration of compound 1 or its crystalline form or complex includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. If necessary, compound 1 or its crystalline form or complex is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer under sterile conditions. Ophthalmic formulations, ear drops and eye drops are also included in the scope of the present invention. In addition, the present disclosure encompasses the use of transdermal patches, which have the advantage of increasing, that is, providing controlled delivery of compound 1 or its crystalline form or complex to the body. Such dosage forms can be prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of compound 1 or its crystalline form or complex through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing compound 1 or its crystalline form or complex in a polymer matrix or gel.

[0966] In some embodiments, the compositions described herein contain an amount of Compound 1 or a crystalline form or complex thereof that is a molar equivalent of the free base N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide. For example, a 100 mg formulation of Compound 1 (i.e., the unsolvated free base parent N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide, MW=524.26) contains 117.30 mg of the dihydrochloride monohydrate form of Compound 1 (MW=614.22).

[0967] In some embodiments, the present disclosure provides a composition comprising Compound 1 or a crystalline form or complex thereof and one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients are selected from a binder and a lubricant.

[0968] In some embodiments, the binder is microcrystalline cellulose. In some such embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

[0969] In some embodiments, the binder is sodium stearyl fumarate.

[0970] In some embodiments, the composition comprises:

[0971]

[0972] In certain embodiments, the composition comprises:

[0973]

[0974]

[0975] Uses of compounds and pharmaceutically acceptable compositions

[0976] The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes.Examples of kinases inhibited by the compounds and compositions described herein and for which the methods described herein can be used include JAK2 or a mutant thereof.

[0977] The activity of Compound 1 or its crystalline form or complex as an inhibitor of JAK2 kinase or mutants thereof can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine phosphorylation activity and / or subsequent functional consequences or inhibition of ATPase activity of activated JAK2 kinase or mutants thereof.

[0978] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with Compound 1 or its crystalline form or complex or a combination thereof.

[0979] According to another embodiment, the present invention relates to a method for inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with Compound 1 or its crystalline form or complex or a composition thereof.

[0980] According to another embodiment, the present invention relates to a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering compound 1 or its crystalline form or complex or a composition thereof to the patient. In other embodiments, the present disclosure provides a method of treating a JAK2-mediated disease or condition in a patient in need thereof, the method comprising the step of administering compound 1 or its crystalline form or complex or a pharmaceutically acceptable composition thereof to the patient. Such conditions are described in detail herein.

[0981] Compound 1 or its crystalline form or complex can be used to treat a variety of conditions, including but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy and other angiogenesis-related conditions, including solid tumors and other types of cancer, eye diseases, inflammation, psoriasis and viral infections. The types of cancer that can be treated include but are not limited to digestive tract / gastrointestinal cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

[0982] Some examples of diseases and conditions that can be treated also include ocular neovascularization, infantile hemangioma; organ hypoxia, vascular proliferation, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and diabetic complications, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopy, dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, cytokine-related disorders; and other autoimmune diseases, including glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, disease), autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis or allergic rhinitis), chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft-versus-host disease; neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, impact, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia and ischemia / reperfusion injury in platelet aggregation.

[0983] Some other examples of diseases and conditions that can be treated also include cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLVI, varicella-zoster virus, human papillomavirus), food allergies, skin inflammation, and immunosuppression induced by solid tumors.

[0984] In some embodiments, Compound 1 or its crystalline form or complex can be used to treat a myeloproliferative disorder. In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis, polycythemia vera, and essential thrombocythemia. In some embodiments, the myeloproliferative disorder is selected from primary myelofibrosis and secondary myelofibrosis. In some embodiments, the myeloproliferative disorder is secondary myelofibrosis. In some such embodiments, the secondary myelofibrosis is selected from post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

[0985] In some embodiments, the methods provided include administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with a JAK2 inhibitor. In some such embodiments, the methods provided include administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with ruxolitinib. The patient is treated by administering Compound 1 or a crystalline form or complex thereof.

[0986] In some embodiments, the methods provided include administering Compound 1, or a crystalline form or complex thereof, to a patient suffering from or diagnosed with a myeloproliferative disorder that is unresponsive to ruxolitinib. In some embodiments, the patient suffers from or has been diagnosed with a myeloproliferative disorder that is refractory or resistant to ruxolitinib.

[0987] In some embodiments, the patient has relapsed during or after ruxolitinib therapy.

[0988] In some embodiments, the patient is intolerant to ruxolitinib. In some embodiments, the patient's intolerance to ruxolitinib is demonstrated by hematologic toxicity (e.g., anemia, thrombocytopenia, etc.) or non-hematologic toxicity.

[0989] In some embodiments, the patient has an inadequate response to or intolerance to hydroxyurea.

[0990] In some embodiments, the patient is exhibiting or experiencing or has exhibited or experienced one or more of the following during treatment with ruxolitinib: lack of response, disease progression, or loss of response at any time during ruxolitinib treatment. In some embodiments, disease progression is evidenced by an increase in spleen size during ruxolitinib treatment.

[0991] In some embodiments, the patient previously treated with ruxolitinib has a somatic mutation or clonal marker associated with or indicative of a myeloproliferative disorder. In some embodiments, the somatic mutation is selected from a JAK2 mutation, a CALR mutation, or an MPL mutation. In some embodiments, the JAK2 mutation is V617F. In some embodiments, the CALR mutation is a mutation in exon 9. In some embodiments, the MPL mutation is selected from W515K and W515L.

[0992] In some embodiments, the present disclosure provides a method of treating a relapsed or refractory myeloproliferative disorder, wherein the myeloproliferative disorder is relapsed or refractory to ruxolitinib.

[0993] In some embodiments, the myeloproliferative disorder is selected from intermediate-risk myelofibrosis and high-risk myelofibrosis.

[0994] In some embodiments, the intermediate-risk myelofibrosis is selected from primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis, and post-essential thrombocythemia (post-ET) myelofibrosis. In some embodiments, the myelofibrosis is intermediate-risk grade 1 (also referred to as intermediate grade 1 risk). In some embodiments, the myelofibrosis is intermediate-risk grade 2 (also referred to as intermediate grade 2 risk).

[0995] In some embodiments, the high-risk myelofibrosis is selected from primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis, and post-essential thrombocythemia (post-ET) myelofibrosis.

[0996] In some embodiments, the present disclosure provides an article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material. In some embodiments, the packaging material comprises a label indicating that the pharmaceutical composition can be used to treat one or more of the conditions identified above.

[0997] Additional embodiments

[0998] Embodiment 1. A crystalline form of Compound 1:

[0999]

[1000] Embodiment 2. The crystalline form of Embodiment 1, wherein said form is unsolvated.

[1001] Embodiment 3. The crystalline form of Embodiment 2, wherein said form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of 9.7, 14.6, 19.5, 24.3 and 25.6 ± 0.2 degrees 2θ.

[1002] Embodiment 4. The crystalline form of Embodiment 2, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

[1003]

[1004] Embodiment 5. The crystalline form of Embodiment 1, wherein said form is solvated.

[1005] Embodiment 6. The crystalline form of Embodiment 5, wherein said form is a 2-methyl-tetrahydrofuran solvate.

[1006] Embodiment 7. The crystalline form of Embodiment 6, wherein said form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of 12.5, 18.3, 18.9, 20.1 and 23.8 ± 0.2 degrees 2θ.

[1007] Embodiment 8. The crystalline form of Embodiment 6, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

[1008]

[1009] Embodiment 9. The crystalline form of Embodiment 1, wherein said form is a hydrate.

[1010] Embodiment 10. The crystalline form of Embodiment 9, wherein said form is a monohydrate.

[1011] Embodiment 11. The crystalline form of Embodiment 10, wherein said form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of 8.7, 15.2, 17.3, 18.0 and 19.4 ± 0.2 degrees 2θ.

[1012] Embodiment 12. The crystalline form of Embodiment 10, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

[1013]

[1014] Embodiment 13. The crystalline form of Embodiment 9, wherein said form is a tetrahydrate.

[1015] Embodiment 14. The crystalline form of Embodiment 13, wherein said form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of 12.4, 18.5, 19.3, 20.3 and 23.6 ± 0.2 degrees 2θ.

[1016] Embodiment 15. The crystalline form of Embodiment 13, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

[1017]

[1018]

[1019] Embodiment 16. A sample comprising the crystalline form of any one of embodiments 1-15, wherein the sample is substantially free of impurities.

[1020] Embodiment 17. The sample of Embodiment 16, wherein the sample comprises at least about 90% by weight of Compound 1.

[1021] Embodiment 18. The sample of Embodiment 16, wherein the sample comprises at least about 95% by weight of Compound 1.

[1022] Embodiment 19. The sample of Embodiment 16, wherein the sample comprises at least about 99% by weight of Compound 1.

[1023] Embodiment 20. The sample of Embodiment 16, wherein the sample comprises no more than about 5.0% total organic impurities.

[1024] Embodiment 21. The sample of Embodiment 16, wherein the sample comprises no more than about 3.0% total organic impurities.

[1025] Embodiment 22. The sample of Embodiment 16, wherein the sample comprises no more than about 1.5% total organic impurities.

[1026] Embodiment 23. The sample of Embodiment 16, wherein the sample comprises no more than about 1.0% total organic impurities.

[1027] Embodiment 24. The sample of Embodiment 16, wherein the sample comprises no more than about 0.5% total organic impurities.

[1028] Embodiment 25. A complex comprising compound 1:

[1029]

[1030] and coformer X;

[1031] wherein the complex is crystalline, and

[1032] X is selected from the group consisting of hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide and sodium hydroxide.

[1033] Embodiment 26. A complex comprising compound 1:

[1034]

[1035] and coformer X;

[1036] in:

[1037] X is selected from the group consisting of 2-naphthalenesulfonic acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1,5-disulfonic acid, (S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, fumaric acid, L-lactic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glutamic acid, glycolic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, niacin, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid and choline.

[1038] Embodiment 27. The complex of Embodiment 25, wherein X is hydrobromic acid.

[1039] Embodiment 28. The complex of Embodiment 25, wherein X is sulfuric acid.

[1040] Embodiment 29. The complex of Embodiment 25, wherein X is toluenesulfonic acid.

[1041] Embodiment 30. The complex of Embodiment 25, wherein X is methanesulfonic acid.

[1042] Embodiment 31. The complex of Embodiment 25 or Embodiment 26, wherein X is 2-naphthalenesulfonic acid.

[1043] Embodiment 32. The complex of Embodiment 25, wherein X is phosphoric acid.

[1044] Embodiment 33. The complex of Embodiment 25, wherein X is DL-tartaric acid.

[1045] Embodiment 34. The complex of Embodiment 25 or Embodiment 26, wherein X is succinic acid.

[1046] Embodiment 35. The complex of Embodiment 25 or Embodiment 26, wherein X is gentisic acid.

[1047] Embodiment 36. The complex of Embodiment 25 or Embodiment 26, wherein X is hippuric acid.

[1048] Embodiment 37. The complex of Embodiment 25 or Embodiment 26, wherein X is adipic acid.

[1049] Embodiment 38. The complex of embodiment 25 or embodiment 26, wherein X is galactaric acid.

[1050] Embodiment 39. The complex of Embodiment 25 or Embodiment 26, wherein X is 1,5-naphthalene disulfonic acid.

[1051] Embodiment 40. The complex of Embodiment 25 or Embodiment 26, wherein X is (S)-camphorsulfonic acid.

[1052] Embodiment 41. The complex of Embodiment 25 or Embodiment 26, wherein X is 1,2-ethanedisulfonic acid.

[1053] Embodiment 42. The complex of Embodiment 25 or Embodiment 26, wherein X is ethanesulfonic acid.

[1054] Embodiment 43. The complex of Embodiment 25 or Embodiment 26, wherein X is benzenesulfonic acid.

[1055] Embodiment 44. The complex of Embodiment 25, wherein X is oxalic acid.

[1056] Embodiment 45. The complex of Embodiment 25 or Embodiment 26, wherein X is maleic acid.

[1057] Embodiment 46. The complex of Embodiment 25 or Embodiment 26, wherein X is pamoic acid.

[1058] Embodiment 47. The complex of Embodiment 25 or Embodiment 26, wherein X is 1-hydroxy-2-naphthoic acid.

[1059] Embodiment 48. The complex of Embodiment 25 or Embodiment 26, wherein X is malonic acid.

[1060] Embodiment 49. The complex of Embodiment 25, wherein X is L-tartaric acid.

[1061] Embodiment 50. The complex of Embodiment 25 or Embodiment 26, wherein X is fumaric acid.

[1062] Embodiment 51. The complex of Embodiment 25, wherein X is citric acid.

[1063] Embodiment 52. The complex of Embodiment 25 or Embodiment 26, wherein X is L-lactic acid.

[1064] Embodiment 53. The complex of Embodiment 25, wherein X is acetic acid.

[1065] Embodiment 54. The complex of Embodiment 25 or Embodiment 26, wherein X is propionic acid.

[1066] Embodiment 55. The complex of Embodiment 25 or Embodiment 26, wherein X is DL-lactic acid.

[1067] Embodiment 56. The complex of Embodiment 25 or Embodiment 26, wherein X is D-gluconic acid.

[1068] Embodiment 57. The complex of Embodiment 25 or Embodiment 26, wherein X is DL-malic acid.

[1069] Embodiment 58. The complex of Embodiment 25 or Embodiment 26, wherein X is glycolic acid.

[1070] Embodiment 59. The complex of Embodiment 25 or Embodiment 26, wherein X is glutaric acid.

[1071] Embodiment 60. The complex of Embodiment 25 or Embodiment 26, wherein X is L-malic acid.

[1072] Embodiment 61. The complex of Embodiment 25 or Embodiment 26, wherein X is camphoric acid.

[1073] Embodiment 62. The complex of Embodiment 25, wherein X is DL-mandelic acid.

[1074] Embodiment 63. The complex of Embodiment 25 or Embodiment 26, wherein X is saccharin.

[1075] Embodiment 64. The complex of Embodiment 25 or Embodiment 26, wherein X is nicotinic acid.

[1076] Embodiment 65. The complex of Embodiment 25 or Embodiment 26, wherein X is ascorbic acid.

[1077] Embodiment 66. The complex of Embodiment 25 or Embodiment 26, wherein X is gallic acid.

[1078] Embodiment 67. The complex of Embodiment 25 or Embodiment 26, wherein X is salicylic acid.

[1079] Embodiment 68. The complex of Embodiment 25 or Embodiment 26, wherein X is orotic acid.

[1080] Embodiment 69. The complex of Embodiment 25 or Embodiment 26, wherein X is acetylsalicylic acid.

[1081] Embodiment 70. A sample comprising the complex of any one of embodiments 25-69, wherein the sample is substantially free of impurities.

[1082] Embodiment 71. A sample of Embodiment 70, wherein the sample comprises at least about 90% by weight of the complex.

[1083] Embodiment 72. A sample of Embodiment 70, wherein the sample comprises at least about 95% by weight of the complex.

[1084] Embodiment 73. A sample of Embodiment 70, wherein the sample comprises at least about 99% by weight of the complex.

[1085] Embodiment 74. The sample of Embodiment 70, wherein the sample comprises no more than about 5.0% total organic impurities.

[1086] Embodiment 75. The sample of Embodiment 70, wherein the sample comprises no more than about 3.0% total organic impurities.

[1087] Embodiment 76. The sample of Embodiment 70, wherein the sample comprises no more than about 1.5% total organic impurities.

[1088] Embodiment 77. The sample of Embodiment 70, wherein the sample comprises no more than about 1.0% total organic impurities.

[1089] Embodiment 78. The sample of Embodiment 70, wherein the sample comprises no more than about 0.5% total organic impurities.

[1090] Embodiment 79. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the crystalline form or composition thereof of any one of embodiments 1-15.

[1091] Embodiment 80. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient a crystalline form of any one of embodiments 1-15 or a composition thereof.

[1092] Embodiment 81. A method of treating a JAK2-mediated disease or condition in a patient in need thereof, the method comprising the step of administering to the patient a crystalline form of any one of Embodiments 1-15 or a pharmaceutically acceptable composition thereof.

[1093] Embodiment 82. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the complex or composition thereof according to any one of embodiments 25-69.

[1094] Embodiment 83. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient a complex or composition thereof according to any one of embodiments 25-69.

[1095] Embodiment 84. A method of treating a JAK2-mediated disease or condition in a patient in need thereof, comprising the step of administering to the patient a complex of any one of embodiments 25-69 or a pharmaceutically acceptable composition thereof.

[1096] Embodiment 85. The complex of Embodiment 27, wherein the complex comprises 1 equivalent of hydrobromic acid.

[1097] Embodiment 86. The complex of Embodiment 27, wherein the complex comprises 2 equivalents of hydrobromic acid.

[1098] Embodiment 87. The complex of Embodiment 28, wherein the complex comprises 0.5 equivalents of sulfuric acid.

[1099] Embodiment 88. The complex of Embodiment 29, wherein the complex comprises 1 equivalent of toluenesulfonic acid.

[1100] Embodiment 89. The complex of Embodiment 30, wherein the complex comprises 1.2 equivalents of methanesulfonic acid.

[1101] Embodiment 90. The complex of Embodiment 31, wherein the complex comprises 1.5 equivalents of 2-naphthalenesulfonic acid.

[1102] Embodiment 91. The complex of Embodiment 32, wherein the complex comprises 1 equivalent of phosphoric acid.

[1103] Embodiment 92. The complex of Embodiment 33, wherein the complex comprises 1 equivalent of DL-tartaric acid.

[1104] Embodiment 93. The complex of Embodiment 34, wherein the complex comprises 1 equivalent of succinic acid.

[1105] Embodiment 94. The complex of Embodiment 35, wherein the complex comprises 1 equivalent of gentisic acid.

[1106] Embodiment 95. The complex of Embodiment 36, wherein the complex comprises 1 equivalent of hippuric acid.

[1107] Embodiment 96. The complex of Embodiment 37, wherein the complex comprises 0.9 equivalents of adipic acid.

[1108] Embodiment 97. The complex of Embodiment 38, wherein the complex comprises 1 equivalent of galactaric acid.

[1109] Embodiment 98. The complex of Embodiment 63, wherein the complex comprises 1 equivalent of saccharin.

[1110] Embodiment 99. The complex of Embodiment 64, wherein the complex comprises 1 equivalent of niacin.

[1111] Embodiment 100. The complex of Embodiment 65, wherein the complex comprises 1 equivalent of ascorbic acid.

[1112] Embodiment 101. The complex of Embodiment 66, wherein the complex comprises 1 equivalent of gallic acid.

[1113] Embodiment 102. The complex of Embodiment 68, wherein the complex comprises 1 equivalent of orotic acid.

[1114] Embodiment 103. The complex of any one of Embodiments 27, 33, 41, 43, 44, 45, 64, 65, 66, 67, 86 and 92, wherein the complex is a hydrate.

[1115] Embodiment 104. The complex of Embodiment 28, wherein the complex is a heterosolvate.

[1116] Embodiment 105. The complex of Embodiment 104, wherein the heterosolvate is water:tetrahydrofuran.

[1117] Embodiment 106. The complex of any one of Embodiments 28, 32 and 91, wherein the complex is a solvate.

[1118] Embodiment 107. The complex of Embodiment 106, wherein the solvate is an acetone solvate.

[1119] Embodiment 108. The complex of Embodiment 106, wherein the solvate is a methanol solvate.

[1120] example

[1121] instrument

[1122] FT-Raman spectroscopy. Raman spectra were collected using a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with a 1064 nm Nd:YVO4 excitation laser, InGaAs and liquid N2-cooled Ge detectors, and MicroStage. -1 All spectra were acquired with 100 nm resolution, 64 scans, using the Happ-Genzel apodization function and 2-level zero filling.

[1123] Powder X-ray diffraction (PXRD or XRPD) was performed on a PANalytical X′Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV / 40 mA) radiation and a 0.02° 2θ step size and an X′celerator TM The PXRD (or XRPD) diffraction pattern was obtained with an RTMS (real-time multiple stripe) detector. Configuration on the incident beam side: fixed divergence slit (0.25°), 0.04 rad Soller slit, anti-scatter slit (0.25°) and 10 mm beam mask. Configuration on the diffracted beam side: fixed divergence slit (0.25°) and 0.04 rad Soller slit. The sample was placed flat on a zero-background Si wafer.

[1124] Differential Scanning Calorimetry (DSC).DSC was performed using a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and refrigerated cooling system under a 40 mL / min N2 purge.DSC thermograms were obtained at 15°C / min in a crimped A1 pan.

[1125] Thermogravimetric Analysis (TGA). TGA thermograms were obtained using a TA Instruments Q500 thermogravimetric analyzer at 15°C / min in a Pt or Al pan under a 40 mL / min N2 purge.

[1126] Thermogravimetric analysis with infrared exhaust gas detection (TGA-IR). TGA-IR was performed using a TA Instruments Q5000 thermogravimetric analyzer interfaced with a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module with a gas flow cell and a DTGS detector. TGA was performed in a Pt or Al pan at a 60 mL / min N2 flow rate and a 15°C / min heating rate. The 4 cm -1 The IR spectra were collected at 32 scans per time point.

[1127] High Performance Liquid Chromatography (HPLC). HPLC analysis was performed using an HP1100 system equipped with a G1131 quadrupole pump, a G1367A autosampler, and a G1315B diode array detector. Column: Luna C18 (2) (50 x 2.0 mm, 3 μm). Mobile phase: 100% water (0.05% TFA) to 95% ACN (0.05% TFA) in 8 minutes and 2 minutes re-equilibration. Flow rate: 1 mL / min. Detection: 254 nm.

[1128] Proton NMR ( 1 H NMR). Prepare the solid by dissolving it in DMSO-d6 1H NMR spectra were collected using an Agilent DD2 500 MHz spectrometer with a TMS reference.

[1129] Ion chromatography (IC). Ion chromatography was performed on a Dionex ICS-3000. Column: Dionex IonPacAS12A 4x200 mm; Detection: suppressed conductivity, ASRS 300 with 22 mA suppressive current; Eluent (2.7 mM Na2CO3 / 0.3 mM NaHCO3), 1.5 mL / min.

[1130] Example 1. Compound 1 Free Base (Form C)

[1131] Compound 1 dihydrochloride (44.5 g) was dissolved in water (498 mL). Aqueous sodium hydroxide solution (2.0 equivalents; 5N; 28.9 mL) was slowly added, followed by acetonitrile (80 mL) and seeds of Compound 1 Form C (400 mg). The suspension was stirred at room temperature for 2 hours. The crystalline solid was separated by vacuum filtration, washed with water (2x100 mL) and MTBE (2x50 mL), and air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven while passing nitrogen for 24 hours. The yield of the crystalline free base was 97.5% (37 g).

[1132] Compound 1 Form C is a white crystalline powder and is identified by XRPD ( Figure 5 )、TGA( Fig. 6A )、DSC( Figure 6B ) and DVS( Figure 7 ) characterization. Thermal data showed that the free base was in the form of a monohydrate with a weight loss of 3.2% water. HPLC analysis indicated a purity of 99.5%. IC data did not detect the presence of chloride, confirming conversion to the free base.

[1133] The solubility of compound 1 free alkali (form C) is estimated by visual assessment of dissolution in various solvents at room temperature and 40 ℃. An aliquot of solvent is added to 10mg free alkali at room temperature until completely dissolved or until the maximum volume of 1.8mL is added. The undissolved suspension at room temperature is heated to 40 ℃ and the dissolution is checked. After visual assessment of solubility, additional form C is added to the dissolved sample to produce a dilute suspension. The suspension is stirred at room temperature for 18 hours, and the solid is separated by vacuum filtration. Solid is analyzed by PXRD, and compared with the parent group identified during the simultaneous salt screening.

[1134] Example 2. Primary Salt Screening of Fedratinib

[1135] Filtratinib has two basic sites (pK a=9.3, 6.4) for salt formation. Fifty-three counterions and stoichiometric combinations were selected. Table 1 provides the additives, pK a A summary of the values, method of administration, and dose equivalents for each additive.

[1136] Table 1 - Additives used in screening studies

[1137]

[1138]

[1139] Various crystallization modes were used for salt screening studies and are as follows:

[1140] 1. Mature the solution / suspension by temperature cycling between 40°C and 5°C for two days.

[1141] 2. The solvent was evaporated quickly under reduced pressure.

[1142] 3. Chill the solution at 5 °C for up to two days.

[1143] 4. Slowly evaporate the solvent at room temperature for up to seven days.

[1144] At the end of each crystallization mode, all samples were checked for crystallinity by polarized light microscopy (PLM). If the experiment yielded a birefringent candidate, the solid was isolated by vacuum filtration and air-dried for up to two hours at room temperature while applying a vacuum. The solid was analyzed by FT-Raman spectroscopy and / or PXRD.

[1145] FT-Raman spectra / PXRD patterns of samples prepared using the same additives were compared to determine if they were the same crystalline form. Representative samples from each unique group were further characterized using PXRD, DSC, TGA and TGA-IR analysis (as appropriate).

[1146] The results of the salt screening studies are summarized in Table 2. The salt screening experiments yielded crystalline salt hits from 36 of the 42 unique additives. All remaining experiments yielded non-crystalline products (gels / amorphous glassy materials) and were not isolated.

[1147] Table 2 - Salt screening results of Fidrotinib

[1148]

[1149]

[1150] Symbol table:

[1151] Letters represent the Raman / PXRD grouping of each counterion.

[1152]

[1153] Example 3. Secondary Salt Screening of Feldotinib

[1154] Of the 36 salt selections, the following 13 salts were scaled up to 200 mg scale: HBr (Forms A and B), sulfate (Form A), tosylate (Form A), methanesulfonate (Form A), 2-naphthalenesulfonate (Form A / B mixture), phosphate (Form D), DL-tartrate (Form A), succinate (Form A), gentisate (Form A), hippurate (Form A), adipate (Form A), and galactarate (Form A).

[1155] Example 3.1. Hydrobromide

[1156] Two crystalline forms of the hydrobromide salt were identified from salt screening experiments and designated Form A and Form B. Form A was identified using 1 equivalent of HBr, while Form B was identified using 2 equivalents of HBr. Both Forms A and B had promising thermal properties and were selected for scale-up.

[1157] Preparation of Form A. THF (6.3 mL) was combined with crystalline free base Form C (315 mg) and aqueous hydrobromic acid (1.0 equiv.; 3 M aqueous solution; 200 μL). Seed crystals of Form A hydrobromide (approximately 1 mg) were added. The suspension was stirred at room temperature (approximately 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 1 hour. The yield of crystalline Form A was 89.9% (327 mg).

[1158] By FT-Raman ( Fig.10 ) and PXRD( Fig.11 ) determined that Form A was crystalline, and PLM determined that this material was birefringent with small irregular particles. DSC analysis showed two large endotherms at 215°C and 231°C ( Fig.12 , trace 12B), while TGA analysis showed a weight loss of 0.4% until 100°C ( Fig.12 , trace 12A). Form A was determined by ion chromatography to be a 1.1:1.0 (counterion:parent) salt. The slight excess of HBr may be due to trace amounts of Form B (dihydrobromide).

[1159] Preparation of Form B. 2-Propanol (6.0 mL) was combined with crystalline free base Form C (300 mg) and aqueous hydrobromic acid (2.0 equiv.; 3M aqueous solution; 381 μL). Seed crystals of the hydrobromide salt (approximately 1 mg) were added. The suspension was stirred at room temperature (approximately 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 1 hour. The yield of crystalline Form B was 83.8% (329 mg).

[1160] By FT-Raman ( Fig.13 ) and PXRD( Fig.14 ) confirmed that Form B was crystalline, and PLM determined that this material was birefringent with tiny needles. DSC analysis showed a small broad endotherm at 72°C and a large sharp endotherm at 233°C ( Fig.15 , trace 15B), while TGA-IR analysis showed a weight loss of 2.4% water until 100°C, with traces of IPA ( Fig.15 , trace 15A). DVS analysis showed a moisture uptake of 0.9% ( Fig.16 The PXRD patterns of the samples after DVS did not show any changes in the crystal form ( Fig.17 Form B was determined by ion chromatography to be a 2.0:1.0 (counterion:parent) salt.

[1161] Example 3.2. Sulfate

[1162] At least three crystalline forms of the sulfate salt were identified from salt screening experiments and designated Forms A, B and C. Fig.18 )、PXRD( Fig.19 )、TGA-IR( Fig. 20 , trace 20A) and DSC ( Fig. 20 , trace 20B) characterizes form A. By FT-Raman ( Fig.21 )、PXRD( Fig. 22 )、TGA-IR( Fig.23 , trace 23A) and DSC ( Fig.23 , trace 23B) characterizes form B. By FT-Raman ( Fig.24 )、PXRD( Fig.25 ) and DSC( Fig.26 )Representation form C.

[1163] Form A had the most promising thermal properties and was selected for scale-up. A new form, Form D, was identified from the scale-up experiments.

[1164] Preparation of Form D. Acetone (7.4 mL) was combined with crystalline free base Form C (372 mg) and aqueous sulfuric acid (0.5 eq; 2.5 M; 142 μL). Seed crystals of the sulfate salt (approximately 1 mg) were added. The suspension was stirred at room temperature (approximately 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline sulfate salt was 77.4% (315 mg).

[1165] By FT-Raman ( Fig. 27 ) and PXRD( Fig.28 ) determined that Form D was crystalline but did not match Form A. DSC analysis showed multiple complex endothermic lines ( Fig.29 , trace 29B), while TGA-IR analysis showed a weight loss of 1.0% water followed by 6.7% acetone until 160°C ( Fig.29 , trace 29A). Thermal data indicated that Form D was an acetone solvate. Form D was determined by ion chromatography to be a 0.5:1.0 (counterion:parent) sulfate salt.

[1166] Example 3.3. Tosylate

[1167] Two crystalline forms were identified from the salt screening experiments and designated as Form A and Form B. Form A was identified using 1 equivalent of p-toluenesulfonic acid, while Form B was identified using 2 equivalents of p-toluenesulfonic acid. Fig.30 )、TGA-IR( Fig.31 , trace 31A) and DSC ( Fig.31 , trace 31B) characterizes Form A. By PXRD ( Fig.32 )、TGA-IR( Fig.33 , trace 33A) and DSC ( Fig.33 , trace 33B) represents form B.

[1168] Form A had the most promising thermal properties and was selected for scale-up. A new form, Form C, was identified from the scale-up experiments.

[1169] Preparation of Form C. Acetone (5.3 mL) was combined with crystalline free base Form C (265 mg) and aqueous toluenesulfonic acid solution (1.0 equiv; 3 M; 168 μL). Seed crystals of the tosylate salt (Form A, about 1 mg) were added. The suspension was stirred at room temperature (about 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline tosylate salt was 86.7% (305 mg).

[1170] By FT-Raman ( Fig.34 ) and PXRD( Fig.35 ) determined that the tosylate salt was crystalline but did not match Form A. DSC analysis ( Fig.36 , trace 36B) shows a sharp higher temperature endotherm at 241°C, while TGA analysis ( Fig.36 , trace 36A) shows a weight loss of 0.1% until 100°C. The thermal data indicate that Form C is non-solvated and is a more stable form than Form A. DVS analysis ( Fig.37 ) showed a moisture uptake of 1.2% between 5-95% RH. The PXRD pattern of the sample after DVS did not show any change in the crystal form ( Fig.38 ).pass 1 H NMR ( Fig.39 ) determined that Form C is a 1.0:1.0 (counterion:parent) tosylate salt.

[1171] Example 3.4. Methanesulfonate

[1172] Three crystalline forms were identified from the salt screening experiments and designated as Forms A, B, and C. Forms A and B were identified using 1 equivalent of methanesulfonic acid, while Form C was identified using 2 equivalents of methanesulfonic acid. Fig.44 ) and DSC( Fig.46 , trace 46B) characterizes Form B. By PXRD ( Fig.45 ) and DSC( Fig.46 , trace 46C) characterizes Form C. Form A had the most promising thermal properties and was selected for scale-up.

[1173] Preparation of Form A. Acetone (6.0 mL) was combined with crystalline free base Form C (298 mg) and aqueous methanesulfonic acid (1.0 equiv; 3M; 189 μL). Seed crystals of the mesylate salt (Form A, about 1 mg) were added to the solution, and the solution was concentrated to dryness in vacuo. Acetone (3.0 mL) was added, and the suspension was reseeded with Form A. The suspension was stirred at room temperature (about 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline mesylate salt was 91.3% (322 mg).

[1174] By FT-Raman ( Fig.40 ) and PXRD( Fig.41 ) determined that the mesylate salt was crystalline and generally consistent with Form A. DSC analysis ( Fig.42 , trace 42B) shows a sharp endotherm at 207°C, while TGA analysis ( Fig.42 , trace 42A) shows a weight loss of 0.3% until 100°C. 1 H NMR ( Fig.43) determined that Form A is a 1.2:1.0 (counterion:parent) mesylate salt. 1 H NMR data indicated that trace amounts of additional peaks in the PXRD of Form A may be due to the dimesylate impurity and that the stoichiometry may be difficult to control.

[1175] Example 3.5.2-Naphthalenesulfonate

[1176] A crystalline form of the 2-naphthalenesulfonate salt (Form A) was identified from salt screening experiments using 1 or 2 equivalents of 2-naphthalenesulfonic acid. Form A had promising thermal properties and was selected for scale-up.

[1177] Preparation of Form A. Acetone (5.0 mL) was combined with crystalline free base Form C (252 mg) and 2-naphthalenesulfonic acid (1.0 equiv; 3M THF solution; 160 μL). Seed crystals of 2-naphthalenesulfonate (Form A, about 1 mg) were added. The suspension was stirred at room temperature (about 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 4 hours. The yield of crystalline 2-naphthalenesulfonate was 86.8% (349 mg).

[1178] By FT-Raman ( Fig.47 ) and PXRD( Fig.48 ) confirmed that the 2-naphthalenesulfonate salt was crystalline. Form A was found to be a mixture with Group B (acetone solvate) ( Fig.49 The thermal data are quite complex and show a gradual loss of 0.9% water until 75°C, followed by a loss of 2.6% acetone between 75-175°C ( Fig.50 ).pass 1 H NMR ( Fig.51 ) determined that Form A is a 1.5:1.0 (counterion:parent) 2-naphthalenesulfonate salt with 0.5 equivalents of acetone. Thermal data and 1 H NMR data indicated the presence of an acetone solvate impurity (Form B) and that the stoichiometry may be difficult to control.

[1179] Example 3.6. Phosphate

[1180] Four crystalline forms of the phosphate salt were identified from the salt screening experiments and designated as Forms A, B, C and D. The crystalline forms of the phosphate salt were identified by PXRD ( Fig.52 ) and DSC( Fig.56 , trace 56A) characterizes Form A. By PXRD ( Fig.53 ) and DSC( Fig.56 , trace 56B) characterizes Form B. By PXRD ( Fig.54 ) and DSC( Fig.56 , trace 56C) characterizes Form C. By PXRD ( Fig.55 ) and DSC( Fig.56 , trace 56D) represents form D.

[1181] Form D had the most promising thermal properties and was selected for scale-up. A new form, Form E, was identified from the scale-up experiments.

[1182] Preparation of Form E. Methanol (7.0 mL) was combined with crystalline free base Form C (350 mg) and aqueous phosphoric acid (1.0 equiv.; 3 M; 222 μL). Seed crystals of the phosphate salt (Form D, approximately 1 mg) were added to the solution, and the solution was concentrated to dryness in vacuo. Methanol (3.0 mL) was added, and the suspension was reseeded. The suspension was stirred at room temperature (approximately 25° C.) for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 1 hour and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline phosphate salt was 81.4% (338 mg).

[1183] By FT-Raman ( Fig.57 ) and PXRD( Fig.58 ) determined that the phosphate was crystalline but did not match the target form, Form D. DSC analysis showed multiple complex endothermic lines ( Fig.59 , trace 59B), while TGA-IR analysis showed a weight loss of 3.8% water and methanol ( Fig.59 , trace 59A). Thermal data indicated that Form E was a methanol solvate. Form E was determined by ion chromatography to be a 1.0:1.0 (counterion:parent) phosphate salt.

[1184] Example 3.7. DL-Tartrate

[1185] Crystalline DL-tartrate salt candidates were isolated from all eight salt formation experiments. The eight candidates were divided into two groups (designated as Form A and Form B) based on FT-Raman spectral matching. Form A was isolated from seven of the eight experiments and scaled up on a 200 mg scale. The results were obtained by PXRD ( Fig.65 )、TGA( Fig.66 , trace 66A) and DSC ( Fig.66 , trace 66B) represents form B.

[1186] Preparation of Form A. THF (4.0 mL) was combined with crystalline free base Form C (198.88 mg) and DL-tartaric acid (1.0 equivalent, dosed as a solid). Seed crystals of the DL-tartrate salt (approximately 1 mg) were added. The suspension was heated to 50° C., stirred at 50° C. for 15 minutes, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline DL-tartrate salt was 66.8% (171 mg).

[1187] By FT-Raman ( Fig.60 ) and PXRD( Fig.61 ) confirmed that Form A was crystalline. DSC data showed a small, broad endotherm starting at 25.4°C, followed by a second sharp endotherm at 194.4°C ( Fig.62 , trace 62B). TGA data showed a loss of approximately 3 wt% between 30-85°C ( Fig.62 , trace 62A). TGA-IR analysis of the evolved gas showed water loss, indicating that Form A of the DL-tartrate salt is a hydrate. DVS analysis ( Fig.63 ) showed a moisture absorption of about 2.2% between 5-95% RH. The PXRD pattern of the sample after DVS did not show any change in the crystal form. 1 H NMR analysis ( Fig.64 ), the stoichiometry of DL-tartrate salt showed 1.0:1.0 (counter ion: parent).

[1188] Example 3.8. Succinate

[1189] Crystalline succinate salt candidates were isolated from four of the eight salt formation experiments. The FT-Raman spectra of all four candidates were consistent with each other, indicating a single crystalline form (designated Form A). Fig.67 )、TGA( Fig.68 , trace 68A) and DSC ( Fig.68 , trace 68B) characterizes Form A. Attempts to prepare the succinate salt Form A on a 200 mg scale were unsuccessful and resulted in a new crystalline form (designated Form B).

[1190] Preparation of Form B. IPA (7.5 mL) was combined with crystalline free base Form C (213.26 mg) and succinic acid (1.0 equivalent, administered as a solid). Seed crystals of succinate were added (approximately 1 mg). The suspension was heated to 40° C., stirred at 40° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. MeOH (0.75 mL) was added to the suspension. The suspension was heated to 50° C., stirred at 50° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of crystalline succinate was 76.2% (199.3 mg).

[1191] By FT-Raman ( Fig.69 ) and PXRD( Fig.70 ) confirmed that Form B is crystalline. DSC data ( Fig.71 , trace 71B) shows a single endothermic line at 153.2°C. TGA data ( Fig.71 , trace 71A) shows a loss of about 0.8 wt% between 30-165°C, indicating that Form B may be a non-solvated form. 1 H NMR analysis ( Fig.72 ), the stoichiometry of succinate showed 1.0:1.0 (counterion:parent).

[1192] Example 3.9. Gentisate

[1193] Crystalline gentisate hits were isolated from six of the eight salt formation experiments. The remaining experiments yielded gums / oils. The FT-Raman spectra of all six hits were consistent with each other, indicating a single crystalline form (designated Form A). Form A was scaled up on a 200 mg scale.

[1194] Preparation of Form A. IPA (7.5 mL) was combined with crystalline free base Form C (230.82 mg) and gentisic acid (1.0 equivalent, dosed as a solid). Seed crystals of gentisate (approximately 1 mg) were added. The suspension was heated to 40° C., stirred at 40° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of crystalline gentisate was 79.3% (237.2 mg).

[1195] By FT-Raman ( Fig.73 ) and PXRD( Fig.74 ) confirmed that Form A was crystalline. DSC data showed a single endotherm at 200.2°C ( Fig.75 , trace 75B). TGA data showed a loss of about 0.8 wt% between 30-196°C, indicating that Form A gentisate may be in a non-solvated form ( Fig.75 , trace 75A). 1 H NMR analysis ( Fig.76 ), the stoichiometry of gentisate showed 1.0:1.0 (counter ion: parent).

[1196] Example 3.10. Hippurate

[1197] Crystalline hippurate hits were isolated from six of the eight salt formation experiments. The remaining experiments yielded gums / oils. The FT-Raman spectra of all six hits were consistent with each other, indicating a single crystalline form (designated Form A). Hippurate Form A was scaled up on a 200 mg scale.

[1198] Preparation of Form A. Acetone (7.5 mL) was combined with crystalline free base Form C (218.98 mg) and hippuric acid (1.0 equivalent, dosed as a solid). Seed crystals of hippurate (approximately 1 mg) were added. The suspension was heated to 40° C., stirred at 40° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of crystalline hippurate was 73.7% (217 mg).

[1199] By FT-Raman ( Fig.77 ) and PXRD( Fig.78 ) confirmed that Form A was crystalline. DSC data showed a single endotherm at 170.1°C ( Fig.79 , trace 79B). TGA data showed a loss of approximately 0.1 wt% between 30-157°C, indicating that hippurate Form A is a non-solvated form ( Fig.79 , trace 79A). 1 H NMR analysis ( Fig.80 ), the stoichiometry of hippurate showed 1.0:1.0 (counter ion: parent).

[1200] Example 3.11. Adipate

[1201] Crystalline adipate salt hits were isolated from six of the eight salt formation experiments. The FT-Raman spectra of five of the six crystalline hits were consistent with each other, indicating a single crystalline form (designated Form A), while the FT-Raman spectrum of the sample isolated from acetone indicated a mixture of forms. Fig.81 )、TGA( Fig.82 , trace 82A) and DSC ( Fig.82 , trace 82B) characterizes Form A. Attempts to prepare Form A on a 200 mg scale were unsuccessful and resulted in a new crystalline form (designated Form C).

[1202] Preparation of Group C. EtOAc (7.5 mL) was combined with crystalline free base Form C (210.27 mg) and adipic acid (1.0 equiv., dosed as a solid). Seed crystals of the adipate salt (approximately 1 mg) were added. The suspension was heated to 40° C., stirred at 40° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The suspension was heated to 50° C., stirred at 50° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of the crystalline adipate salt was 76.2% (205.2 mg).

[1203] By FT-Raman ( Fig.83 ) and PXRD( Fig.84 ) confirmed that Form C was crystalline. DSC data showed a small endotherm starting at 93.2°C, followed by two sharp endotherms at 132.6°C and 171.2°C ( Fig.85 , trace 85B). TGA data showed a loss of approximately 0.9 wt% between 30 and 180°C ( Fig.85 , trace 85A). 1 H NMR analysis ( Fig.86 ), the stoichiometry of the adipate salt showed 0.9:1.0 (counter ion: parent).

[1204] Example 3.12. Galactarate

[1205] Crystalline galactarate salt candidates were isolated from five of the eight salt formation experiments. The remaining experiments yielded either gum / oil, free base, or counterion. The FT-Raman spectra of all five salt candidates were consistent with each other, indicating a single crystalline form (designated Form A). Galactarate Form A was scaled up on a 200 mg scale.

[1206] Preparation of Form A. Acetone (7.5 mL) was combined with crystalline free base Form C (194.89 mg) and galactaric acid (1.0 equivalent, dosed as a solid). Seed crystals of galactaric acid salt (approximately 1 mg) were added. The suspension was heated to 40° C., stirred at 40° C. for 5 hours, slowly cooled (0.1° C. / min) to 25° C., and stirred at 25° C. for 16 hours. The crystalline solid was isolated by vacuum filtration, air-dried under vacuum for 2 hours and dried in a 40° C. vacuum oven for 4 hours. The yield of crystalline galactaric acid salt was 86.9 (237.5 mg).

[1207] By FT-Raman ( Fig.87 ) and PXRD( Fig.88 ) confirmed that Form A was crystalline. DSC data showed a single endotherm at 184.4°C ( Fig.89 , trace 89B). TGA data showed a loss of approximately 0.7 wt% between 30-157°C, indicating that galactarate salt Form A is a non-solvated form ( Fig.89 , trace 89A). 1 H NMR analysis ( Fig.90 ), the stoichiometry of galactarate salt showed 1.0:1.0 (counter ion: parent).

[1208] Example 3.13. Crystalline Salt Selection

[1209] In addition to the crystalline salts discussed in Examples 3.1-3.12, salt screening studies also resulted in salts from a variety of additives. Characterization data for these salt candidates are provided in Table 3.

[1210] Table 3 - Crystallization hits from screening

[1211]

[1212]

[1213]

[1214]

[1215] Example 4. Primary cocrystal screening of Filtratinib

[1216] A total of 24 co-crystal formers (CCFs) were selected based on hydrogen bonding propensity, molecular diversity and pharmaceutical acceptability. One equivalent of CCF was given in all screening experiments. Table 4 presents the collection of CCFs utilized.

[1217] Table 4 - Cocrystal formers used in screening

[1218]

[1219]

[1220] A total of five pure solvents and two binary mixtures were utilized in the cocrystal screening experiments presented: THF, EtOAc, DCM, MIBK, MeOH, THF / cyclohexane (2:8 v / v) and IPA:water (9:1 v / v). The selection was based on the diversity of the molecular structure and the properties of the solvent (e.g., polarity, chemical diversity) as well as the solubility of the free base Form C ("API") from visual assessment of solubility.

[1221] A total of about 240 cocrystal screening trials were performed using 24 CCFs and the following combinations: i) solvent drop grinding (SDG) - using four solvents, ii) slurry ripening (SR) in six solvents, and iii) evaporation of the solution obtained in step ii.

[1222] Solvent drop grinding (SDG). Several preliminary experiments were performed to determine the appropriate grinding parameters for SDG experiments. Table 5 summarizes the results of these experiments (milling at 15 Hz for 15 minutes with one grinding ball). The data indicate that for 100 mg API with 2-15 μL of solvent, milling at 15 Hz for 15 minutes with one grinding ball is appropriate. The specific (initial) solvent volumes selected for the four solvents were: THF - 5 μL; EtOAc, DCM and MIBK - 15 μL.

[1223] Table 5 - Determination of Appropriate Solvent Drop Grinding (SDG) Parameters

[1224]

[1225]

[1226] For SDG experiments, API (about 100 mg), stoichiometric CCF (1 equivalent) and solvents THF, EtOAc, DCM or MIBK were combined in a stainless steel grinding jar (10 mL). Grinding was performed at room temperature (about 23° C.) on a Retsch mill (model MM301) with one grinding ball (7 mm) at 15 Hz for 15 minutes. In cases where these parameters (based on the properties of CCF) were observed or expected to result in low yield or agglomeration, the grinding time was reduced to 10 minutes or manual grinding was performed using a mortar and pestle.

[1227] Slurry Ripening (SR). SR studies were performed using the product from the SDG experiments and combined with the same four pure solvents used in the SDG experiments, except that THF:cyclohexane (2:8 v / v) was used instead of THF. For CCFs that gave potential co-crystals (or salts) from SDG, saturated solutions of CCF were prepared in the specific solvents that gave the potential co-crystals or salts and used in SR experiments.

[1228] For the other two solvents (MeOH and IPA:water (9:1 v / v)), a 1:1 (API:CCF) equivalent mixture was prepared and combined with both solvent systems.

[1229] A saturated solution of CCF was prepared by combining CCF (estimated amount to obtain a suspension) with 2 mL of solvent, followed by mixing for 16 hours at 23° C. The suspension was filtered through a 0.20 μm PTFE filter to obtain a saturated solution.

[1230] SR experiments were performed in 2 mL vials containing flip-flop stir discs and up to 1.9 mL of solvent [THF: cyclohexane (2: 8 v / v), EtOAc, DCM, MIBK, MeOH or IPA: water (9: 1 v / v)]. The samples were mixed and temperature cycled between 40°C and 5°C for 7 days, followed by mixing at 25°C for 5 days. During this treatment time, additional solvent was added to obtain a miscible suspension with sufficient solids for separation and analysis. The suspended solids were separated by filtration and air dried for 18 hours.

[1231] Evaporation (EV). The solution obtained in the slurry maturation experiment was slowly evaporated (by loosening the vial cap) in a fume hood until dryness. The birefringence of the product was first checked by PLM and, if birefringent, further analyzed by PXRD.

[1232] All solid outputs screened were analyzed by PXRD to assess co-crystal formation. Where appropriate and if sample quantity permitted, possible co-crystals were analyzed by additional techniques (FT-Raman, DSC, TGA-IR, PLM, etc.).

[1233] The experiments performed obtained potential cocrystals (pure or mixed with the parent and / or CCF) of Form C free base and isonicotinamide, pyrogallol, saccharin and xylitol, as well as potential salts with L-ascorbic acid, nicotinic acid, gallic acid, orotic acid, salicylic acid and acetylsalicylic acid. Most potential cocrystals (or salts) were obtained from SR / EV experiments. It was observed that the PXRD patterns of salicylic acid Form A and acetylsalicylic acid Form A were identical. Proton NMR analysis confirmed that acetylsalicylate Form A was consistent with salicylate Form A because no acetyl group was observed. This may be due to the hydrolysis of acetylsalicylic acid to salicylic acid during slurry maturation.

[1234] Cocrystal formers that did not give potential cocrystals included urea, caffeine, nicotinamide, L-prolinamide, vanillin, methylparaben, propylparaben, butylated hydroxyanisole, chrysin, resveratrol, quercetin, aspartame, sucralose, and D-mannitol. These cocrystal formers gave amorphous material, parent form, CCF, or a combination thereof. The products obtained in the SDG and SR / EV experiments are shown in Tables 6 and 7, respectively.

[1235] Table 6 - Cocrystal or salt screening products obtained from the SDG method

[1236]

[1237]

[1238] Symbol table:

[1239]

[1240] Note : A, B - identified crystal forms

[1241]

[1242]

[1243]

[1244] Table 8 - Properties of scaled-up cocrystals or salts

[1245]

[1246] Example 5. Scale-up of the eutectic.

[1247] Of the potential cocrystal (or salt) candidates, the following seven exhibited desirable physicochemical properties and were scaled up on a 250 mg scale: saccharin Form A, niacin Form A, ascorbic acid Form A, gallic acid Form A, salicylic acid Form A, and orotic acid Forms F and H. The results are described in detail below.

[1248] Example 5.1. Saccharin cocrystal

[1249] Saccharin co-crystal selects were obtained from six SR experiments. PXRD analysis of the samples indicated one form, designated Form A. Form A (non-solvated) was scaled up (250 mg scale) and characterized in detail.

[1250] Preparation of Form A (non-solvated). Form C free base (244.5 mg) was combined with saccharin (83.1 mg; 1 eq.) and solvent (DCM, 3.5 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (approximately 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a slurry of medium consistency. The solid was isolated by vacuum filtration for 2 hours and dried in a 40° C. vacuum oven for 18 hours. The product weight was 287 mg Form A (87% yield relative to the cocrystal).

[1251] By FT-Raman ( Fig.189 ) and PXRD( Fig.190 ) confirmed that Form A was a crystalline powder. DSC analysis showed a melting endotherm starting at 183.8°C (ΔH = 104.2 J / g) Fig.191 , trace 191B). TGA analysis showed a weight loss of 0.1% between 26-174°C, indicating a non-solvated form ( Fig.191 , trace 191A). Proton NMR analysis of Form A indicated that Form A contained 1 equivalent of saccharin ( Fig.192 ).

[1252] Example 5.2. Nicotinate

[1253] Nicotinate selects were obtained from three SR and one EV experiments. PXRD analysis of the samples indicated three forms, designated Form A, Form B, and Form C. Form A (non-solvated) was scaled up (250 mg scale) and characterized in detail. Fig.197 )、TGA( Fig.198 , trace 198A) and DSC ( Fig.198 , trace 198B) characterizes Form B. By PXRD ( Fig.199 )、TGA( Fig.200 , trace 200A) and DSC ( Fig.200 , trace 200B) represents form C.

[1254] Preparation of Form A (non-solvated). Form C free base (252.8 mg) was combined with nicotinic acid (57.9 mg; 1 eq.) and solvent (THF / cyclohexane (2:8), 3.0 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (approximately 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a slurry of medium consistency. The solid was isolated by vacuum filtration for 2 hours and dried in a 40° C. vacuum oven for 18 hours. The product weight was 247 mg of nicotinic acid salt Form A (79% yield relative to the salt).

[1255] By FT-Raman ( Fig.193 ) and PXRD( Fig.194 ) confirmed that Form A was a crystalline powder. DSC analysis showed a melting endotherm starting at 179.9°C (ΔH = 120.4 J / g) Fig.195 , trace 195B). TGA analysis showed a weight loss of 0.2% between 29-168°C, indicating a non-solvated form ( Fig.195 , trace 195A). Proton NMR analysis of Form A indicated that Form A contained 1 equivalent of niacin ( Fig.196 ).

[1256] Example 5.3. L-ascorbate

[1257] Ascorbate hits were obtained from six SR experiments. PXRD analysis of the samples indicated two forms, designated Form A and Form B. Form A (hydrate) was scaled up (250 mg scale) and characterized in detail.

[1258] Preparation of Form A (hydrate). Form C free base (249.7 mg) was combined with L-ascorbic acid (81.6 mg; 1 eq.) and solvent (IPA / water (9:1) v / v, 6.0 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (approximately 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a slurry of medium consistency. The solids were isolated by vacuum filtration for 4 hours and kept open in a fume hood for 18 hours. The product weight was 294 mg ascorbate salt Form A (83% yield relative to the salt).

[1259] By FT-Raman ( Fig.201 ) and PXRD( Fig.202 ) confirmed that Form A was a crystalline powder. DSC analysis showed a dehydration endotherm starting at 46.0°C (ΔH = 168.5 J / g), followed by a small endotherm at 116.8°C (ΔH = 7.5 J / g) and a melting endotherm starting at 157.0°C (ΔH = 71.4 J / g) (possibly two merged) ( Fig.203 , trace 203B). TGA analysis showed a 5.4 wt% (2.2 eq.) water loss between 29-140°C, indicating a hydrated form ( Fig.203 , trace 203A). Proton NMR analysis of Form A indicated that Form A contained 1 equivalent of L-ascorbic acid ( Fig.204 ).

[1260] Example 5.4. Gallic acid salt

[1261] Gallate selects were obtained from four SR experiments. PXRD analysis of the samples indicated two forms, designated Form A and Form B. Form A was obtained in pure form, while Form B was obtained only in a mixture with Form A. Gallate Form A (hydrate) was scaled up (250 mg scale) and characterized in detail.

[1262] Preparation of Form A (hydrate). Form C free base (245.0 mg) was combined with gallic acid (77.0 mg; 1 equivalent) and solvent (MeOH, 4.0 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (approximately 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 4 hours and kept open in a fume hood for 18 hours. The product weight was 256 mg gallate Form A (77% yield relative to the salt).

[1263] By FT-Raman ( Fig.205 ) and PXRD( Fig.206 ) confirmed that Form A was a crystalline powder. DSC analysis showed a dehydration endotherm starting at 48.5°C (ΔH = 79.8 J / g), followed by a melting endotherm starting at 193.5°C (ΔH = 176.1 J / g). Fig.207 , trace 207B). TGA analysis showed a 2.4 wt% (1.0 eq.) water loss between 22-89°C, indicating a hydrated form ( Fig.207 , trace 207A). Proton NMR analysis of Form A indicated that Form B contained 1 equivalent of gallic acid ( Fig.208 ).

[1264] Example 5.5. Salicylate

[1265] Salicylate hits were obtained from one SDG experiment and six SR experiments; however, the hits from SDG were a mixture of potential salts, precursors, and CCF. PXRD analysis of the six SR hits indicated two forms, designated Form A and Form B. Most hits (5 / 6) were consistent with Form A. Salicylate Form A (hydrate) was scaled up (250 mg scale) and characterized in detail.

[1266] Preparation of Form A (hydrate). Form C free base (253.8 mg) was combined with salicylic acid (64.7 mg; 1 equivalent) and solvent (IPA / water 9:1, 4.5 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (about 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 18 hours. The product weight was 272 mg salicylate Form A (83% yield relative to the salt).

[1267] By FT-Raman ( Fig.209 ) and PXRD( Fig.210 ) confirmed that Form A was a crystalline powder. DSC analysis showed a dehydration endotherm starting at 34.9°C (ΔH = 71.0 J / g), followed by a melting endotherm starting at 159.8°C (ΔH = 83.8 J / g). Fig.211 , trace 211B). TGA analysis showed a 2.5 wt% (1.0 eq.) water loss between 26-96 °C, indicating a hydrated form ( Fig.211 , trace 211A). Proton NMR analysis of Form A indicated that Form A contained 1 equivalent of salicylic acid ( Fig.212 ).

[1268] Example 5.6. Orotate

[1269] Orotate selections were obtained from six SR experiments. PXRD analysis of the selection indicated six forms, designated as Form A, Form B, Form C, Form D, Form E and Form F. Scale-up experiments (250 mg) were performed for Form E and F (hydrates), and other groups were deprioritized due to solvation or because they were mixtures of two groups, as shown in Table 7. Scale-up experiments for Form E were unsuccessful and produced two new groups: Form G and Form H. Form G is a MeOH / water solvate desolvated to Form H hydrate under ambient conditions. The PXRD analysis of the selection indicated six forms, designated as Form A, Form B, Form C, Form D, Form E and Form F. Scale-up experiments (250 mg) were performed for Form E and F (hydrates), and other groups were deprioritized due to solvation or because they were mixtures of two groups, as shown in Table 7. Scale-up experiments for Form E were unsuccessful and produced two new groups: Form G and Form H. Form G is a MeOH / water solvate desolvated to Form H hydrate under ambient conditions. Fig.213 )、TGA( Fig.214 , trace 214A) and DSC ( Fig.214 , trace 214B) characterizes Form A. By PXRD ( Fig.215 ) characterizes the mixture of Form B and Form E. By PXRD ( Fig.216 ) characterizes the mixture of Form C and Form E. By PXRD ( Fig.217 )、TGA( Fig.218 , trace 218A) and DSC ( Fig.218 , trace 218B) characterizes Form D. By PXRD ( Fig.219 )、TGA( Fig.220, trace 220A) and DSC ( Fig.220 , trace 220B) characterizes Form E. By PXRD ( Fig.221 ) Characterization of Form G. Form F and Form H (hydrate) of the orotate salt were scaled up (250 mg) and characterized in detail.

[1270] Preparation of Form F (hydrate). Form C free base (250.0 mg) was combined with orotic acid (77.0 mg; 1 equivalent) and solvent (IPA / water 9:1, 10.0 mL) and mixed at 40° C. for 30 minutes to give a suspension. Seed crystals (approximately 5 mg) were added and the suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 60 hours to give a slurry of medium consistency. The solid was isolated by vacuum filtration for 22 hours. The product weight was 297 mg orotic acid salt Form F (82% yield relative to the cocrystal).

[1271] By FT-Raman ( Fig.222 ) and PXRD( Fig.223 ) confirmed that Form F was a crystalline powder. DSC analysis showed two dehydration endotherms starting at 56.5°C (ΔH = 86.1 J / g) and 104.7°C (ΔH = 15.4 J / g), respectively, followed by a melting endotherm starting at 135.2°C (ΔH = 12.3 J / g). Fig.224 , trace 224B). TGA analysis showed a 10.8 wt% (4.5 eq.) water loss between 24°-129°C, indicating a hydrated form ( Fig.224 , trace 224A). Proton NMR analysis of Form F indicated that Form F contained 1 equivalent of orotic acid ( Fig.225 ).

[1272] PXRD analysis of the sample after heating indicated a significant loss of crystallinity but no change in form.

[1273] Preparation of Form H (hydrate). Form C free base (251.7 mg) was combined with orotic acid (72.7 mg; 1 eq.) and solvent (MeOH, 1.0 mL) and mixed at 40° C. for 10 minutes to give a nearly clear solution. Seed crystals (Group E, approximately 5 mg) were added and the suspension became very thick, so additional solvent (MeOH, 1.5 mL) was added. The suspension was mixed at 40° C. for 2 hours, slowly cooled to 20° C., and mixed at 20° C. for 18 hours to give a slurry of medium consistency. PXRD indicated a new form, and DSC / TGA-IR indicated a MeOH / water solvate, designated Form G. The batch solids were isolated by vacuum filtration for 18 hours. The product weight was 178 mg. PXRD again indicated a new form, and DSC / TGA-IR indicated a hydrate, designated Form H (53% yield relative to the salt).

[1274] By FT-Raman ( Fig.226 ) and PXRD( Fig.227 ) confirmed that Form H was a crystalline powder. DSC analysis showed a broad dehydration endotherm starting at 34.3°C (ΔH = 23.4 J / g), followed by two small endotherms at 134.5°C and 144.4°C, respectively, a large endotherm starting at 165.8°C (ΔH = 44.6 J / g), and a broad endotherm starting at 203.4°C (ΔH = 11.1 J / g). Fig.228 , trace 228B). TGA analysis showed a 3.2 wt% (1.2 eq.) water loss between 23-95°C, indicating a hydrated form ( Fig.228 , trace 228A). Proton NMR analysis of Form H indicated that Form H contained 1 equivalent of orotic acid ( Fig.229 ).

[1275] PXRD analysis of the heated sample indicated some loss of crystallinity and loss of several major peaks.

[1276] Example 5.7. Other co-crystals or salts

[1277] Acetylsalicylate Form A was scaled up, however, and a PXRD pattern was observed to be identical to that of salicylate Form A. Proton NMR analysis confirmed that acetylsalicylate Form A was identical to salicylate Form A because no acetyl groups were observed. This may be due to the hydrolysis of acetylsalicylic acid to salicylic acid during slurry maturation.

[1278] In addition to the scaled-up co-crystals (or salts), several other potential co-crystals were obtained from the screening. These candidates were not fully characterized and / or scaled-up due to:

[1279] - Limited sample size,

[1280] - Unsatisfactory physical and chemical properties (poor crystallinity / poor thermal properties),

[1281] - Identified as a mixture with the parent and / or CCF.

[1282] Table 9 summarizes representative samples of these co-crystal (or salt) selections.

[1283] Table 9 - Properties of other cocrystal or salt hits identified in the screen

[1284]

[1285]

[1286] Example 6. Water solubility of certain complexes

[1287] The solid / salt form (about 20-30 mg) was transferred to a transparent glass vial (4 ml). Water (about 0.2-2 ml) was added to each vial containing the solid form. The volume of water added and the weight of the solid / salt form were appropriately adjusted to obtain an excess of undissolved solid / salt form. The vial containing the solid / salt form / water mixture was transferred to a rotating rack and the sample was balanced for 24 hours while stirring at ambient temperature. At the end of the equilibration process, the suspension was visually observed, and the sample was removed and centrifuged (14,000 rpm for 3 minutes) in a Costar SPIN-X polypropylene centrifuge tube (2.0 ml) filter (0.22 mm nylon filter) to separate any undissolved drug. The drug content of the clarified filtrate was determined, and the solubility of the active substance in the solution was determined after appropriate dilution in acetonitrile / water (50:50) when necessary. A standard curve was prepared using the free base in the concentration range of 0.126 mg / ml to 0.001 mg / ml. The drug content of the samples and standards was determined using HPLC. The results are listed in Table 10:

[1288] Table 10 - Solubility of Certain Forms of Compound 1

[1289] Solid form Solubility (mg / mL) Free base form A 0.003 HBr Form A 2.3 HBr Form B 14.6 Sulfate Form D 2.9 Tosylate Form C 0.1 Mesylate Form A 11.0 2-Naphthalenesulfonate A 0.1 Phosphate Form E 5.0 Gentisate Form A 0.1 Hippurate form A 1.4 Adipate Form A 9.7 Succinate Form B 10.6 DL-Tartrate Form A 0.6 Galactarate Form A 15.3 Niacin Form A 4.0 Saccharin Form A 0.1 Ascorbic acid form A 5.4 Gallic acid form A 0.2 Orotate Form F 0.9 Orotate Form H 0.6 Salicylic Acid Form A 0.05

Claims

1. A crystalline form of Compound 1: wherein the form is a monohydrate; The form described herein is characterized by an X-ray powder diffraction pattern having the following peaks:

2. A sample comprising the crystalline form of claim 1, wherein the sample comprises at least 90% by weight of the crystalline form of Compound 1 and / or comprises no more than 5.0% by weight of total organic impurities.

3. Use of the crystalline form or a composition thereof according to claim 1 in the preparation of a medicament for inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample.

4. Use of the crystalline form of claim 1 or a composition thereof for the preparation of a medicament for inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, wherein the patient suffers from a myeloproliferative disorder.

5. The use of claim 4, wherein the myeloproliferative disorder is selected from primary myelofibrosis, polycythemia vera and essential thrombocythemia.

6. Use of the crystalline form of claim 1 or a pharmaceutically acceptable composition thereof in the preparation of a medicament for treating a JAK2-mediated disease or disorder in a patient in need thereof, wherein the JAK2-mediated disease or disorder is a myeloproliferative disorder.

7. The use of claim 6, wherein the myeloproliferative disorder is selected from primary myelofibrosis, polycythemia vera and essential thrombocythemia.

Images