CRYSTALLINE FORMS OF A JAK2 INHIBITOR

Abstract

The present disclosure provides crystalline forms of a JAK2 inhibitor, compositions thereof and methods of treating a JAK2-mediated disorder.

Description

FIELD OF THE INVENTION

The present invention provides compounds, and compositions thereof, useful as inhibitors of protein kinases.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One important class of enzymes that has been the subject of extensive study is protein kinases.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).

In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, 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)). An extracellular stimulus may affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events as described above. 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. Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

SUMMARY OF THE INVENTION

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

In some embodiments, the present disclosure provides one or more complex forms comprising Compound 1 and a co-former X, 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

In some embodiments, Compound 1, or a crystalline form or complex thereof, is useful in treating a myeloproliferative disorder. In some embodiments, a 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 and post-essential thrombocythemia.

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

According to another embodiment, the present disclosure relates to a method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient Compound 1, or a crystalline form or complex thereof, or a composition thereof. In other embodiments, the present disclosure provides a method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to said patient Compound 1, or a crystalline form or complex thereof, or a composition thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the X-ray powder diffraction (XRPD) pattern of Form A of Compound 1.

FIG. 2A depicts the thermogravimetric analysis (TGA) pattern of Form A of Compound 1. FIG. 2B depicts the differential scanning calorimetry (DSC) pattern of Form A of Compound 1.

FIG. 2C depicts the dynamic vapor sorption (DVS) isotherm of Form A of Compound 1.

FIG. 3 depicts the XRPD pattern of Form B of Compound 1.

FIG. 4A depicts the TGA pattern of Form B of Compound 1. FIG. 4B depicts the DSC pattern of Form B of Compound 1.

FIG. 5 depicts the XRPD pattern of Form C of Compound 1.

FIG. 6A depicts the TGA pattern of Form C of Compound 1. FIG. 6B depicts the DSC pattern of Form C of Compound 1.

FIG. 7 depicts the DVS isotherm of Form C of Compound 1.

FIG. 8 depicts the XRPD pattern of Form D of Compound 1.

FIG. 9A depicts the TGA pattern of Form D of Compound 1. FIG. 9B depicts the DSC pattern of Form D of Compound 1.

FIG. 10 depicts the FT-Raman spectrum of Form A hydrobromide salt of Compound 1.

FIG. 11 depicts the XRPD pattern of Form A hydrobromide salt of Compound 1.

FIG. 12 depicts the TGA pattern of Form A hydrobromide salt of Compound 1 (12A), and the DSC pattern of Form A hydrobromide salt of Compound 1 (12B).

FIG. 13 depicts the FT-Raman spectrum of Form B hydrobromide salt of Compound 1.

FIG. 14 depicts the XRPD pattern of Form B hydrobromide salt of Compound 1.

FIG. 15 depicts the TGA pattern of Form B hydrobromide salt of Compound 1 (15A), and the DSC pattern of Form B hydrobromide salt of Compound 1 (15B).

FIG. 16 depicts the dynamic vapor sorption (DVS) isotherm of Form B hydrobromide salt of Compound 1.

FIG. 17 depicts the XRPD pattern of Form B hydrobromide salt of Compound 1 post-DVS.

FIG. 18 depicts the FT-Raman spectrum of Form A sulfate salt of Compound 1.

FIG. 19 depicts the XRPD pattern of Form A sulfate salt of Compound 1.

FIG. 20 depicts the TGA pattern of Form A sulfate salt of Compound 1 (20A), and the DSC pattern of Form A sulfate salt of Compound 1 (20B).

FIG. 21 depicts the FT-Raman spectrum of Form B sulfate salt of Compound 1.

FIG. 22 depicts the XRPD pattern of Form B sulfate salt of Compound 1.

FIG. 23 depicts the TGA pattern of Form B sulfate salt of Compound 1 (23A), and the DSC pattern of Form B sulfate salt of Compound 1 (23B).

FIG. 24 depicts the FT-Raman spectrum of Form C sulfate salt of Compound 1.

FIG. 25 depicts the XRPD pattern of Form C sulfate salt of Compound 1.

FIG. 26 depicts the DSC pattern of Form C sulfate salt of Compound 1.

FIG. 27 depicts the FT-Raman spectrum of Form D sulfate salt of Compound 1.

FIG. 28 depicts the XRPD pattern of Form D sulfate salt of Compound 1.

FIG. 29 depicts the TGA pattern of Form D sulfate salt of Compound 1 (29A), and the DSC pattern of Form D sulfate salt of Compound 1 (29B).

FIG. 30 depicts the XRPD pattern of Form A tosylate salt of Compound 1.

FIG. 31 depicts the TGA pattern of Form A tosylate salt of Compound 1 (31A), and the DSC pattern of Form A tosylate salt of Compound 1 (31B).

FIG. 32 depicts the XRPD pattern of Form B tosylate salt of Compound 1.

FIG. 33 depicts the TGA pattern of Form B tosylate salt of Compound 1 (33A), and the DSC pattern of Form B tosylate salt of Compound 1 (33B).

FIG. 34 depicts the FT-Raman spectrum of Form C tosylate salt of Compound 1.

FIG. 35 depicts the XRPD pattern of Form C tosylate salt of Compound 1.

FIG. 36 depicts the TGA pattern of Form C tosylate salt of Compound 1 (36A), and the DSC pattern of Form C tosylate salt of Compound 1 (36B).

FIG. 37 depicts the DVS isotherm of Form C tosylate salt of Compound 1.

FIG. 38 depicts the XRPD pattern of Form C tosylate salt of Compound 1 post-DVS.

FIG. 39 depicts the ¹H-NMR spectrum of Form C tosylate salt of Compound 1.

FIG. 40 depicts the FT-Raman spectrum of Form A mesylate salt of Compound 1.

FIG. 41 depicts the XRPD pattern of Form A mesylate salt of Compound 1.

FIG. 42 depicts the TGA pattern of a dried sample of Form A mesylate salt of Compound 1 (42A), and the DSC pattern of a dried sample of Form A mesylate salt of Compound 1 (42B).

FIG. 43 depicts the ¹H-NMR spectrum of Form A mesylate salt of Compound 1.

FIG. 44 depicts the XRPD pattern of Form B mesylate salt of Compound 1.

FIG. 45 depicts the XRPD pattern of Form C mesylate salt of Compound 1.

FIG. 46 depicts the DSC pattern of Form A mesylate salt of Compound 1 (46A), the DSC pattern of Form B mesylate salt of Compound 1 (46B), and the DSC pattern of Form C mesylate salt of Compound 1 (46C).

FIG. 47 depicts the FT-Raman spectrum of Form A 2-naphthalenesulfonate salt of Compound 1.

FIG. 48 depicts the XRPD pattern of Form A 2-naphthalenesulfonate salt of Compound 1.

FIG. 49 depicts the XRPD pattern of a mixture of Form A and Form B 2-naphthalene sulfonate salt of Compound 1.

FIG. 50 depicts the TGA pattern of Form A 2-naphthalenesulfonate salt of Compound 1 (50A), and the DSC pattern of Form A 2-naphthalenesulfonate salt of Compound 1 (50B).

FIG. 51 depicts the ¹H NMR of a mixture of Form A and Form B 2-naphthalenesulfonate salt of Compound 1.

FIG. 52 depicts the XRPD pattern of Form A phosphate salt of Compound 1.

FIG. 53 depicts the XRPD pattern of Form B phosphate salt of Compound 1.

FIG. 54 depicts the XRPD pattern of Form C phosphate salt of Compound 1.

FIG. 55 depicts the XRPD pattern of Form D phosphate salt of Compound 1.

FIG. 56 depicts the DSC pattern of Form A phosphate salt of Compound 1 (56A), the DSC pattern of Form B phosphate salt of Compound 1 (56B), the DSC pattern of Form C phosphate salt of Compound 1 (56C), and the DSC pattern of Form D phosphate salt of Compound 1 (56D).

FIG. 57 depicts the FT-Raman spectrum of Form E phosphate salt of Compound 1.

FIG. 58 depicts the XRPD pattern of Form E phosphate salt of Compound 1.

FIG. 59 depicts the TGA pattern of Form E phosphate salt of Compound 1 (59A), and the DSC pattern of Form E phosphate salt of Compound 1 (59B).

FIG. 60 depicts the FT-Raman spectrum of Form A DL-tartrate salt of Compound 1.

FIG. 61 depicts the XRPD pattern of Form A DL-tartrate salt of Compound 1.

FIG. 62 depicts the TGA pattern of Form A DL-tartrate salt of Compound 1 (62A), and the DSC pattern of Form A DL-tartrate salt of Compound 1 (62B).

FIG. 63 depicts the DVS isotherm of Form A DL-tartrate salt of Compound 1.

FIG. 64 depicts the ¹H-NMR spectrum of Form A DL-tartrate salt of Compound 1.

FIG. 65 depicts the XRPD pattern of Form B DL-tartrate salt of Compound 1.

FIG. 66 depicts the TGA pattern of Form B DL-tartrate salt of Compound 1 (66A), and the DSC pattern of Form B DL-tartrate salt of Compound 1 (66B).

FIG. 67 depicts the XRPD pattern of Form A succinate salt of Compound 1.

FIG. 68 depicts the TGA pattern of Form A succinate salt of Compound 1 (68A), and the DSC pattern of Form A succinate salt of Compound 1 (68B).

FIG. 69 depicts the FT-Raman spectrum of Form B succinate salt of Compound 1.

FIG. 70 depicts the XRPD pattern of Form B succinate salt of Compound 1.

FIG. 71 depicts the TGA pattern of Form B succinate salt of Compound 1 (71A), and the DSC pattern of Form B succinate salt of Compound 1 (71B).

FIG. 72 depicts the ¹H-NMR spectrum of Form B succinate salt of Compound 1.

FIG. 73 depicts the FT-Raman spectrum of Form A gentisate salt of Compound 1.

FIG. 74 depicts the XRPD pattern of Form A gentisate salt of Compound 1.

FIG. 75 depicts the TGA pattern of Form A gentisate salt of Compound 1 (75A), and the DSC pattern of Form A gentisate salt of Compound 1 (75B).

FIG. 76 depicts the ¹H-NMR spectrum of Form A gentisate salt of Compound 1.

FIG. 77 depicts the FT-Raman spectrum of Form A hippurate salt of Compound 1.

FIG. 78 depicts the XRPD pattern of Form A hippurate salt of Compound 1.

FIG. 79 depicts the TGA pattern of Form A hippurate salt of Compound 1 (79A), and the DSC pattern of Form A hippurate salt of Compound 1 (79B).

FIG. 80 depicts the ¹H-NMR spectrum of Form A hippurate salt of Compound 1.

FIG. 81 depicts the XRPD pattern of Form A adipate salt of Compound 1.

FIG. 82 depicts the TGA pattern of Form A adipate salt of Compound 1 (82A), and the DSC pattern of Form A adipate salt of Compound 1 (82B).

FIG. 83 depicts the FT-Raman spectrum of Form C adipate salt of Compound 1.

FIG. 84 depicts the XRPD pattern of Form C adipate salt of Compound 1.

FIG. 85 depicts the TGA pattern of Form C adipate salt of Compound 1 (85A), and the DSC pattern of Form C adipate salt of Compound 1 (85B).

FIG. 86 depicts the ¹H-NMR spectrum of Form C adipate salt of Compound 1.

FIG. 87 depicts the FT-Raman spectrum of Form A galactarate salt of Compound 1.

FIG. 88 depicts the XRPD pattern of Form A galactarate salt of Compound 1.

FIG. 89 depicts the TGA pattern of Form A galactarate salt of Compound 1 (89A), and the DSC pattern of Form A galactarate salt of Compound 1 (89B).

FIG. 90 depicts the ¹H-NMR spectrum of Form A galactarate salt of Compound 1.

FIG. 91 depicts the XRPD pattern of Form A napadisylate salt of Compound 1.

FIG. 92 depicts the XRPD pattern of Form B napadisylate salt of Compound 1.

FIG. 93 depicts the XRPD pattern of Form C napadisylate salt of Compound 1.

FIG. 94 depicts the DSC pattern of Form A napadisylate salt of Compound 1 (94A), the DSC pattern of Form B napadisylate salt of Compound 1 (94B), and the DSC pattern of Form C napadisylate salt of Compound 1 (94C).

FIG. 95 depicts the FT-Raman spectrum of Form A (S)-camphorsulfonate salt of Compound 1.

FIG. 96 depicts the XRPD pattern of Form A (S)-camphorsulfonate salt of Compound 1.

FIG. 97 depicts the TGA pattern of Form A (S)-camphorsulfonate salt of Compound 1 (97A), and the DSC pattern of Form A (S)-camphorsulfonate salt of Compound 1 (97B).

FIG. 98 depicts the FT-Raman spectrum of Form B (S)-camphorsulfonate salt of Compound 1.

FIG. 99 depicts the XRPD pattern of Form B (S)-camphorsulfonate salt of Compound 1.

FIG. 100 depicts the TGA pattern of Form B (S)-camphorsulfonate salt of Compound 1 (100A), and the DSC pattern of Form B (S)-camphorsulfonate salt of Compound 1 (100B).

FIG. 101 depicts the XRPD pattern of Form A edisylate salt of Compound 1.

FIG. 102 depicts the XRPD pattern of Form B edisylate salt of Compound 1.

FIG. 103 depicts the XRPD pattern of Form C edisylate salt of Compound 1.

FIG. 104 depicts the XRPD pattern of Form D edisylate salt of Compound 1.

FIG. 105 depicts the TGA pattern of Form A edisylate salt salt of Compound 1 (105A), and the DSC pattern of Form A edisylate salt salt of Compound 1 (105B).

FIG. 106 depicts the DSC pattern of Form C edisylate salt of Compound 1 (106A), the DSC pattern of Form B edisylate salt of Compound 1 (106B), the DSC pattern of Form D edisylate salt of Compound 1 (106C), and the DSC pattern of Form A edisylate salt of Compound 1 (106D).

FIG. 107 depicts the XRPD pattern of Form A esylate salt of Compound 1.

FIG. 108 depicts the XRPD pattern of Form B esylate salt of Compound 1.

FIG. 109 depicts the TGA pattern of Form A esylate salt of Compound 1 (109A), and the DSC pattern of Form A esylate salt of Compound 1 (109B).

FIG. 110 depicts the TGA pattern of Form B esylate salt of Compound 1 (110A), and the DSC pattern of Form B esylate salt of Compound 1 (110B).

FIG. 111 depicts the XRPD pattern of Form A besylate salt of Compound 1.

FIG. 112 depicts the XRPD pattern of Form B besylate salt of Compound 1.

FIG. 113 depicts the XRPD pattern of Form C besylate salt of Compound 1.

FIG. 114 depicts the XRPD pattern of Form D besylate salt of Compound 1.

FIG. 115 depicts the DSC pattern of Form A besylate salt of Compound 1 (115A), the DSC pattern of Form B besylate salt of Compound 1 (115B), the DSC pattern of Form C besylate salt of Compound 1 (115C), and the DSC pattern of Form D besylate salt of Compound 1 (115D).

FIG. 116 depicts the TGA pattern of Form D besylate salt of Compound 1 (116A), and the DSC pattern of Form D besylate salt of Compound 1 (116B).

FIG. 117 depicts the XRPD pattern of Form A oxalate salt of Compound 1.

FIG. 118 depicts the XRPD pattern of Form B oxalate salt of Compound 1.

FIG. 119 depicts the TGA pattern of Form A oxalate salt of Compound 1 (119A), and the DSC pattern of Form A oxalate salt of Compound 1 (119B).

FIG. 120 depicts the TGA pattern of Form B oxalate salt of Compound 1 (120A), and the DSC pattern of Form B oxalate salt of Compound 1 (120B).

FIG. 121 depicts the XRPD pattern of Form A maleate salt of Compound 1.

FIG. 122 depicts the TGA pattern of Form A maleate salt of Compound 1 (122A), and the DSC pattern of Form A maleate salt of Compound 1 (122B).

FIG. 123 depicts the XRPD pattern of Form A pamoate salt of Compound 1.

FIG. 124 depicts the TGA pattern of Form A pamoate salt of Compound 1 (124A), and the DSC pattern of Form A pamoate salt of Compound 1 (124B).

FIG. 125 depicts the XRPD pattern of Form A 1-hydroxy-2-naphthoate salt of Compound 1.

FIG. 126 depicts the DSC pattern of Form A 1-hydroxy-2-naphthoate salt of Compound 1.

FIG. 127 depicts the XRPD pattern of Form A malonate salt of Compound 1.

FIG. 128 depicts the TGA pattern of Form A malonate salt of Compound 1 (128A), and the DSC pattern of Form A malonate salt of Compound 1 (128B).

FIG. 129 depicts the XRPD pattern of Form B malonate salt of Compound 1.

FIG. 130 depicts the TGA pattern of Form B malonate salt of Compound 1 (130A), and the DSC pattern of Form B malonate salt of Compound 1 (130B).

FIG. 131 depicts the XRPD pattern of Form C malonate salt of Compound 1.

FIG. 132 depicts the DSC pattern of Form C malonate salt of Compound 1.

FIG. 133 depicts the XRPD pattern of Form A L-tartrate salt of Compound 1.

FIG. 134 depicts the TGA pattern of Form A L-tartrate salt of Compound 1 (134A), and the DSC pattern of Form A L-tartrate salt of Compound 1 (134B).

FIG. 135 depicts the XRPD pattern of Form B L-tartrate salt of Compound 1.

FIG. 136 depicts the DSC pattern of Form B L-tartrate salt of Compound 1.

FIG. 137 depicts the XRPD pattern of Form C L-tartrate salt of Compound 1.

FIG. 138 depicts the TGA pattern of Form C L-tartrate salt of Compound 1 (138A), and the DSC pattern of Form C L-tartrate salt of Compound 1 (138B).

FIG. 139 depicts the XRPD pattern of Form D L-tartrate salt of Compound 1.

FIG. 140 depicts the TGA pattern of Form D L-tartrate salt of Compound 1 (140A), and the DSC pattern of Form D L-tartrate salt of Compound 1 (140B).

FIG. 141 depicts the XRPD pattern of Form A fumarate salt of Compound 1.

FIG. 142 depicts the TGA pattern of Form A fumarate salt of Compound 1 (142A), and the DSC pattern of Form A fumarate salt of Compound 1 (142B).

FIG. 143 depicts the XRPD pattern of Form B fumarate salt of Compound 1.

FIG. 144 depicts the DSC pattern of Form B fumarate salt of Compound 1.

FIG. 145 depicts the XRPD pattern of Form C fumarate salt of Compound 1.

FIG. 146 depicts the TGA pattern of Form C fumarate salt of Compound 1 (146A), and the DSC pattern of Form C fumarate salt of Compound 1 (146B).

FIG. 147 depicts the XRPD pattern of Form D fumarate salt of Compound 1.

FIG. 148 depicts the TGA pattern of Form D fumarate salt of Compound 1 (148A), and the DSC pattern of Form D fumarate salt of Compound 1 (148B).

FIG. 149 depicts the XRPD pattern of Form A citrate salt of Compound 1.

FIG. 150 depicts the TGA pattern of Form A citrate salt of Compound 1 (150A), and the DSC pattern of Form A citrate salt of Compound 1 (150B).

FIG. 151 depicts the XRPD pattern of Form A L-lactate salt of Compound 1.

FIG. 152 depicts the TGA pattern of Form A L-lactate salt of Compound 1 (152A), and the DSC pattern of Form A L-lactate salt of Compound 1 (152B).

FIG. 153 depicts the XRPD pattern of Form A acetate salt of Compound 1.

FIG. 154 depicts the TGA pattern of Form A acetate salt of Compound 1 (154A), and the DSC pattern of Form A acetate salt of Compound 1 (154B).

FIG. 155 depicts the XRPD pattern of Form B acetate salt of Compound 1.

FIG. 156 depicts the TGA pattern of Form B acetate salt of Compound 1 (156A), and the DSC pattern of Form B acetate salt of Compound 1 (156B).

FIG. 157 depicts the XRPD pattern of Form A propionate salt of Compound 1.

FIG. 158 depicts the TGA pattern of Form A propionate salt of Compound 1 (158A), and the DSC pattern of Form A propionate salt of Compound 1 (158B).

FIG. 159 depicts the XRPD pattern of Form A DL-lactate salt of Compound 1.

FIG. 160 depicts the TGA pattern of Form A DL-lactate salt of Compound 1 (160A), and the DSC pattern of Form A DL-lactate salt of Compound 1 (160B).

FIG. 161 depicts the XRPD pattern of Form A D-gluconate salt of Compound 1.

FIG. 162 depicts the DSC pattern of Form A D-gluconate salt of Compound 1.

FIG. 163 depicts the XRPD pattern of Form A DL-malate salt of Compound 1.

FIG. 164 depicts the TGA pattern of Form A DL-malate salt of Compound 1 (164A), and the DSC pattern of Form A DL-malate salt of Compound 1 (164B).

FIG. 165 depicts the XRPD pattern of Form B DL-malate salt of Compound 1.

FIG. 166 depicts the TGA pattern of Form B DL-malate salt of Compound 1 (166A), and the DSC pattern of Form B DL-malate salt of Compound 1 (166B).

FIG. 167 depicts the XRPD pattern of Form A glycolate salt of Compound 1.

FIG. 168 depicts the TGA pattern of Form A glycolate salt of Compound 1 (168A), and the DSC pattern of Form A glycolate salt of Compound 1 (168B).

FIG. 169 depicts the XRPD pattern of Form A glutarate salt of Compound 1.

FIG. 170 depicts the TGA pattern of Form A glutarate salt of Compound 1 (170A), and the DSC pattern of Form A glutarate salt of Compound 1 (170B).

FIG. 171 depicts the XRPD pattern of Form B glutarate salt of Compound 1.

FIG. 172 depicts the TGA pattern of Form B glutarate salt of Compound 1 (172A), and the DSC pattern of Form B glutarate salt of Compound 1 (172B).

FIG. 173 depicts the XRPD pattern of Form A L-malate salt of Compound 1.

FIG. 174 depicts the TGA pattern of Form A L-malate salt of Compound 1 (174A), and the DSC pattern of Form A L-malate salt of Compound 1 (174B).

FIG. 175 depicts the XRPD pattern of Form A camphorate salt of Compound 1.

FIG. 176 depicts the TGA pattern of Form A camphorate salt of Compound 1 (176A), and the DSC pattern of Form A camphorate salt of Compound 1 (176B).

FIG. 177 depicts the XRPD pattern of Form B camphorate salt of Compound 1.

FIG. 178 depicts the TGA pattern of Form B camphorate salt of Compound 1 (178A), and the DSC pattern of Form B camphorate salt of Compound 1 (178B).

FIG. 179 depicts the XRPD pattern of Form C camphorate salt of Compound 1.

FIG. 180 depicts the TGA pattern of Form C camphorate salt of Compound 1 (180A), and the DSC pattern of Form C camphorate salt of Compound 1 (180B).

FIG. 181 depicts the XRPD pattern of Form D camphorate salt of Compound 1.

FIG. 182 depicts the TGA pattern of Form D camphorate salt of Compound 1 (182A), and the DSC pattern of Form D camphorate salt of Compound 1 (182B).

FIG. 183 depicts the XRPD pattern of Form A DL-mandelate salt of Compound 1.

FIG. 184 depicts the TGA pattern of Form A DL-mandelate salt of Compound 1 (184A), and the DSC pattern of Form A DL-mandelate salt of Compound 1 (184B).

FIG. 185 depicts the XRPD pattern of Form B DL-mandelate salt of Compound 1.

FIG. 186 depicts the TGA pattern of Form B DL-mandelate salt of Compound 1 (186A), and the DSC pattern of Form B DL-mandelate salt of Compound 1 (186B).

FIG. 187 depicts the XRPD pattern of Form C DL-mandelate salt of Compound 1.

FIG. 188 depicts the TGA pattern of Form C DL-mandelate salt of Compound 1 (188A), and the DSC pattern of Form C DL-mandelate salt of Compound 1 (188B).

FIG. 189 depicts the FT-Raman spectrum of Form A saccharin co-crystal of Compound 1.

FIG. 190 depicts the XRPD pattern of Form A saccharin co-crystal of Compound 1.

FIG. 191 depicts the TGA pattern of Form A saccharin co-crystal of Compound 1 (191A), and the DSC pattern of Form A saccharin co-crystal of Compound 1 (191B).

FIG. 192 depicts the ¹H-NMR spectrum of Form A saccharin co-crystal of Compound 1.

FIG. 193 depicts the FT-Raman spectrum of Form A nicotinic acid salt of Compound 1.

FIG. 194 depicts the XRPD pattern of Form A nicotinic acid salt of Compound 1.

FIG. 195 depicts the TGA pattern of Form A nicotinic acid salt of Compound 1 (195A), and the DSC pattern of Form A nicotinic acid salt of Compound 1 (195B).

FIG. 196 depicts the ¹H-NMR spectrum of Form A nicotinic acid salt of Compound 1.

FIG. 197 depicts the XRPD pattern of Form B nicotinic acid salt of Compound 1.

FIG. 198 depicts the TGA pattern of Form B nicotinic acid salt of Compound 1. FIG. 198B depicts the DSC pattern of Form B nicotinic acid salt of Compound 1.

FIG. 199 depicts the XRPD pattern of Form C nicotinic acid salt of Compound 1.

FIG. 200 depicts the TGA pattern of Form C nicotinic acid salt of Compound 1 (200A), and the DSC pattern of Form C nicotinic acid salt of Compound 1 (200B).

FIG. 201 depicts the FT-Raman spectrum of Form A ascorbic acid salt of Compound 1.

FIG. 202 depicts the XRPD pattern of Form A ascorbic acid salt of Compound 1.

FIG. 203 depicts the TGA pattern of Form A ascorbic acid salt of Compound 1 (203A), and the DSC pattern of Form A ascorbic acid salt of Compound 1 (203B).

FIG. 204 depicts the ¹H-NMR spectrum of Form A ascorbic acid salt of Compound 1.

FIG. 205 depicts the FT-Raman spectrum of Form A gallic acid salt of Compound 1.

FIG. 206 depicts the XRPD pattern of Form A gallic acid salt of Compound 1.

FIG. 207 depicts the TGA pattern of Form A gallic acid salt of Compound 1 (207A), and the DSC pattern of Form A gallic acid salt of Compound 1 (207B).

FIG. 208 depicts the ¹H-NMR spectrum of Form A gallic acid salt of Compound 1.

FIG. 209 depicts the FT-Raman spectrum of Form A salicylic acid salt of Compound 1.

FIG. 210 depicts the XRPD pattern of Form A salicylic acid salt of Compound 1.

FIG. 211 depicts the TGA pattern of Form A salicylic acid salt of Compound 1 (211A), and the DSC pattern of Form A salicylic acid salt of Compound 1 (211B).

FIG. 212 depicts the ¹H-NMR spectrum of Form A salicylic acid salt of Compound 1.

FIG. 213 depicts the XRPD pattern of Form A orotic acid salt of Compound 1.

FIG. 214 depicts the TGA pattern of Form A orotic acid salt of Compound 1 (214A), and the DSC pattern of Form A orotic acid salt of Compound 1 (214B).

FIG. 215 depicts the XRPD pattern of a mixture of Form B and Form E orotic acid salts of Compound 1.

FIG. 216 depicts the XRPD pattern of a mixture of Form C and Form E orotic acid salts of Compound 1.

FIG. 217 depicts the XRPD pattern of Form D orotic acid salt of Compound 1.

FIG. 218 depicts the TGA pattern of Form D orotic acid salt of Compound 1 (218A), and the DSC pattern of Form D orotic acid salt of Compound 1 (218B).

FIG. 219 depicts the XRPD pattern of Form E orotic acid salt of Compound 1.

FIG. 220 depicts the TGA pattern of Form E orotic acid salt of Compound 1 (220A), and the DSC pattern of Form E orotic acid salt of Compound 1 (220B).

FIG. 221 depicts the XRPD pattern of Form G orotic acid salt of Compound 1.

FIG. 222 depicts the FT-Raman spectrum of Form F orotic acid salt of Compound 1.

FIG. 223 depicts the XRPD pattern of Form F orotic acid salt of Compound 1.

FIG. 224 depicts the TGA pattern of Form F orotic acid salt of Compound 1 (224A), and the DSC pattern of Form F orotic acid salt of Compound 1 (224B).

FIG. 225 depicts the ¹H-NMR spectrum of Form F orotic acid salt of Compound 1.

FIG. 226 depicts the FT-Raman spectrum of Form H orotic acid salt of Compound 1.

FIG. 227 depicts the XRPD pattern of Form H orotic acid salt of Compound 1.

FIG. 228 depicts the TGA pattern of Form H orotic acid salt of Compound 1 (228A), and the DSC pattern of Form H orotic acid salt of Compound 1 (228B).

FIG. 229 depicts the ¹H-NMR spectrum of Form H orotic acid salt of Compound 1.

FIG. 230 depicts the XRPD pattern of a mixture of Form A of Compound 1, Form A isonicotinamide co-crystal of Compound 1 and isonicotinamide co-former.

FIG. 231 depicts the XRPD pattern of Form A pyrogallol co-crystal of Compound 1 likely mixed with one or more forms of Compound 1 free base.

FIG. 232 depicts the TGA pattern of Form A pyrogallol co-crystal of Compound 1 likely mixed with one or more forms of Compound 1 free base (232A), and the DSC pattern of a mixture of Form A pyrogallol co-crystal of Compound 1 likely mixed with one or more forms of Compound 1 free base (232B).

FIG. 233 depicts the XRPD pattern of Form A xylitol co-crystal of Compound 1 likely mixed with one or more forms of Compound 1 free base, and xylitol co-former.

FIG. 234 depicts the XRPD pattern of Form B ascorbic acid salt of Compound 1.

FIG. 235 depicts the TGA pattern of Form B ascorbic acid salt of Compound 1 (235A), and the DSC pattern of Form B ascorbic acid salt of Compound 1 (235B).

FIG. 236 depicts the XRPD pattern of mixture of Form A gallic acid salt of Compound 1 and Form B gallic acid salt of Compound 1.

FIG. 237 depicts the XRPD pattern of Form B salicylic acid salt of Compound 1.

FIG. 238 depicts the TGA pattern of Form B salicylic acid salt of Compound 1, (238A), and the DSC pattern of Form B salicylic acid salt of Compound 1 (238B).

FIG. 239 depicts the XRPD pattern of Form B acetylsalicylic acid salt of Compound 1.

FIG. 240 depicts the TGA pattern of Form B acetylsalicylic acid salt of Compound 1 (240A), and the DSC pattern of Form B acetylsalicylic acid salt of Compound 1 (240B).

DETAILED DESCRIPTION OF THE INVENTION

General Description of Certain Aspects of the Invention

U.S. Pat. 7,528,143, issued May 5, 2009 (“the ‘143 patent”), the entirety of which is hereby incorporated herein by reference, describes certain 2,4-disubstituted pyrimidine compounds that are useful in treating myeloproliferative disorders, 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:

Compound 1, N-tert-butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide, is designated as compound number LVII and the synthesis of Compound 1 is described in detail at Example 90 of the ‘143 patent.

Compound 1 is active in a variety of assays and therapeutic models demonstrating inhibition of Janus kinase 2 (JAK2). Accordingly, Compound 1, or a crystalline form or complex thereof, is useful for treating one or more disorders associated with activity of JAK2.

Crystalline Forms of Compound 1

In some embodiments, the present disclosure provides a crystalline form of Compound 1. It will be appreciated that a crystalline form of Compound 1 can exist in a neat or unsolvated form, a hydrated form, and/or a solvated form. In some embodiments, a crystalline form of Compound 1 is a neat or unsolvated crystal form and thus does not have any water or solvent incorporated into the crystal structure. In some embodiments, a crystalline form of Compound 1 is a hydrated or solvated form. In some embodiments, a crystalline form of Compound 1 is a hydrate/solvate form (also referred to herein as a “heterosolvate”).

Accordingly, in some embodiments, the present disclosure provides one or more crystalline anhydrous forms of Compound 1:

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

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

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 contains no significant amount of extraneous matter. In some embodiments, a 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 a crystalline form of Compound 1. In certain embodiments, the sample comprises at least about 95% by weight of a crystalline form of Compound 1. In still other embodiments, the sample comprises at least about 99% by weight of a crystalline form of Compound 1.

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 a crystalline form of Compound 1, where the percentages are based on the total weight of the sample. According to some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 0.6 percent of total organic impurities. In some embodiments, a sample comprising a crystalline form of Compound 1 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

It has been found that Compound 1 can exist in at least four distinct crystal forms, or polymorphs.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.8	10.102	1414		20.4	4.360	4156
9.7	9.120	88376		21.0	4.229	4358
10.5	8.463	2192		22.7	3.914	1551
13.6	6.516	1881		23.0	3.874	2648
14.6	6.082	50409		23.5	3.781	1611
16.0	5.543	3640		23.9	3.730	9006
16.4	5.413	2620		24.3	3.660	13329
17.7	5.014	3311		24.6	3.614	1849
18.5	4.797	5807		25.6	3.479	7883
19.1	4.637	1316		28.0	3.192	1510
19.5	4.563	6885		28.6	3.119	1592
19.8	4.492	1686		29.4	3.043	2105
20.1	4.415	1686

In some embodiments, Form A of Compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 1.

In some embodiments, Form A of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 2A.

In some embodiments, Form A of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 2B.

In some embodiments, Form A of Compound 1 is characterized by the dynamic vapor sorption (DVS) isotherm depicted in FIG. 2C.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.6	11.633	715		23.8	3.734	25579
10.2	8.690	521		25.5	3.498	1600
11.9	7.430	2468		26.0	3.433	1425
12.5	7.096	3531		27.6	3.231	1295
12.7	6.963	2843		28.3	3.149	1147
14.1	6.265	2984		28.9	3.090	556
14.5	6.096	1620		30.4	2.937	356
16.1	5.494	2249		31.7	2.824	477
18.3	4.836	6390		34.2	2.620	224
18.9	4.699	5752		35.5	2.530	569
20.1	4.411	6304		36.0	2.497	405
21.4	4.147	1605		36.9	2.434	141
23.1	3.853	1981

In some embodiments, Form B of Compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 3.

In some embodiments, Form B of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 4A.

In some embodiments, Form B of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 4B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.7	10.184	23473		22.1	4.017	7400
10.6	8.332	6912		22.4	3.974	6455
14.4	6.172	8862		22.8	3.894	6416
15.2	5.825	11716		23.2	3.841	3537
15.5	5.719	3493		23.5	3.783	7215
16.3	5.439	5672		24.4	3.647	4592
16.6	5.329	5294		25.0	3.559	4787
16.9	5.244	7167		25.2	3.540	4028
17.3	5.120	51890		26.1	3.414	4525
18.0	4.917	15095		26.6	3.356	4349
19.4	4.578	10908		27.4	3.255	5512
20.2	4.388	8419		27.6	3.231	4683
21.8	4.078	5043

In some embodiments, Form C of Compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 5.

In some embodiments, Form C of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 6A.

In some embodiments, Form C of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 6B.

In some embodiments, Form C of Compound 1 is characterized by the dynamic vapor sorption (DVS) isotherm depicted in FIG. 7.

In some embodiments, a crystalline hydrate form of Compound 1 is a tetrahydrate. In some embodiments, a 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, a crystalline tetrahydrate form of Compound 1 is Form D.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.7	11.475	1223		20.0	4.435	3039
11.8	7.529	1943		20.3	4.380	4906
12.0	7.372	2255		20.8	4.267	1987
12.4	7.142	4460		21.3	4.163	1495
12.9	6.874	1805		21.9	4.066	999
13.4	6.619	1735		22.7	3.925	836
14.1	6.282	2143		23.6	3.770	22852
14.5	6.122	1529		24.8	3.585	1474
15.4	5.772	1552		25.8	3.453	907
16.4	5.397	3326		26.2	3.405	1278
18.5	4.800	7100		27.0	3.306	1347
19.3	4.591	4008		28.5	3.133	823
19.7	4.497	2119

In some embodiments, Form D of Compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 8.

In some embodiments, Form D of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 9A.

In some embodiments, Form D of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 9B.

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

Complex Forms of Compound 1

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

and a co-former X; 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

It will be appreciated that a complex comprising Compound 1 and a co-former X can exist in a neat or unsolvated form, a hydrated form, a solvated form, and/or a heterosolvated form. In some embodiments, a complex comprising Compound 1 and a co-former X is a neat or unsolvated crystal form and thus does not have any water or solvent incorporated into the crystal structure. In some embodiments, a complex comprising Compound 1 and a co-former X is a hydrated or solvated form. In some embodiments, a complex comprising Compound 1 and a co-former X is 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:

and a co-former X; 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

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

and a co-former X; 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

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

and a co-former X; 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

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

and a co-former X; 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, DL-mandelic acid, glutamic acid, glycolic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

In some embodiments, the term “complex” is used herein to refer to a form comprising Compound 1 non-covalently associated with a co-former. Such non-covalent associations include, by way of example, ionic interactions, dipole-dipole interactions, π-stacking interactions, hydrogen bond interactions, etc.

It will be appreciated that the term “complex” encompasses salt forms resulting from an ionic interaction between Compound 1 and an acid or base, as well as non-ionic associations between Compound 1 and a neutral species.

In some embodiments, the term “complex” is used herein to refer to a form comprising Compound 1 ionically associated with a co-former. Accordingly, in some such embodiments, the term “complex” is used herein to refer to a salt comprising Compound 1 and an acid or a base.

In some embodiments, a “complex” is an inclusion complex, a salt form, a co-crystal, a clathrate, or hydrates and/or solvates thereof, etc. In some embodiments, the term “complex” is used to refer to a 1:1 (i.e., stoichiometric) ratio of Compound 1 and co-former. In some embodiments, the term “complex” does not necessarily indicate any particular ratio of Compound 1 to co-former. In some embodiments, a complex is a salt form, or a hydrate or solvate thereof. In some embodiments, a complex is a co-crystal form, or a hydrate or solvate thereof. In some embodiments, a complex is an inclusion complex, or a hydrate or solvate thereof. In some embodiments, a complex is a clathrate, or a hydrate or solvate thereof.

In some embodiments, co-former X and Compound 1 are ionically associated. In some embodiments, Compound 1 is non-covalently associated with co-former X.

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

It will be appreciated that a complex comprising Compound 1 and a co-former X can comprise one equivalent of X. Accordingly, in some embodiments, complexes described herein comprise Compound 1 and one equivalent of X. In some embodiments, complexes described herein comprise Compound 1 and two equivalents of X. In some embodiments, complexes described herein comprise Compound 1 and three equivalents of X. In some embodiments, 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).

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, a sample comprising a complex form of Compound 1 is substantially free of any of excess co-former X, excess Compound 1, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, a complex form of Compound 1. In certain embodiments, the sample comprises at least about 90% by weight of a complex form of Compound 1. In certain embodiments, the sample comprises at least about 95% by weight of a complex form of Compound 1. In still other embodiments, the sample comprises at least about 99% by weight of a complex form of Compound 1.

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 a complex form of Compound 1, where the percentages are based on the total weight of the sample. According to some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 5.0 percent of total organic impurities. In some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 3.0 percent of total organic impurities. In some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 1.5 percent of total organic impurities. In some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 1.0 percent of total organic impurities. In some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 0.6 percent of total organic impurities. In some embodiments, a sample comprising a complex form of Compound 1 comprises no more than about 0.5 percent of total organic impurities. In some embodiments, the percent of total organic impurities is measured by HPLC.

The structure depicted for a complex form of Compound 1 includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

In some embodiments, a 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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, and acetylsalicylic acid.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
9.3	9.553	1045		21.5	4.130	707
12.6	7.052	604		21.9	4.065	1369
13.9	6.371	11592		23.5	3.779	1077
16.2	5.460	1922		24.2	3.683	1832
16.6	5.354	1052		24.6	3.623	636
16.9	5.248	1422		25.4	3.500	4118
17.4	5.088	848		26.0	3.432	2147
17.8	4.990	1208		26.3	3.393	732
18.6	4.780	1929		26.8	3.331	748
19.0	4.664	3197		27.2	3.273	7515
19.6	4.521	1183		27.9	3.198	2238
20.0	4.431	1797		29.0	3.083	1330
20.3	4.381	1077		29.9	2.986	601
20.9	4.253	2885		31.4	2.845	809

In some embodiments, Form A hydrobromide salt is characterized by the FT-Raman spectrum depicted in FIG. 10.

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

In some embodiments, Form A hydrobromide salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 12, trace 12A.

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

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.4	10.485	501		25.0	3.556	502
9.8	8.990	429		25.4	3.506	1351
12.2	7.229	419		25.8	3.456	1049
13.4	6.608	1155		27.2	3.282	1188
15.8	5.616	2263		27.7	3.226	522
16.9	5.256	3329		28.1	3.179	469
17.4	5.083	4997		28.8	3.103	482
17.8	4.985	6598		29.4	3.040	648
18.4	4.823	823		30.2	2.963	653
19.7	4.505	727		31.2	2.871	800
21.5	4.125	3852		31.4	2.849	597
22.3	3.983	459		34.1	2.632	1253
23.6	3.775	1559		34.9	2.569	653
23.9	3.725	1215		35.8	2.509	944
24.6	3.620	809		38.7	2.329	763

In some embodiments, Form B hydrobromide salt is characterized by the FT-Raman spectrum depicted in FIG. 13.

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

In some embodiments, Form B hydrobromide salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 15, trace 15A.

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

In some embodiments, Form B hydrobromide salt is characterized by the dynamic vapor sorption (DVS) isotherm depicted in FIG. 16.

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

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.9	14.964	521		18.4	4.833	548
7.4	11.907	303		18.9	4.699	374
8.0	10.991	390		19.6	4.540	438
10.0	8.860	559		20.3	4.380	289
10.8	8.215	471		21.2	4.188	1783
11.8	7.503	2427		22.7	3.919	1034
13.9	6.366	312		23.2	3.839	809
14.3	6.174	490		23.8	3.746	416
15.2	5.837	550		24.2	3.680	443
15.7	5.642	1321		24.9	3.579	646
16.1	5.522	994		25.5	3.488	707
16.4	5.408	655		26.5	3.366	263
17.1	5.176	1280		29.8	3.000	279
17.7	5.010	1379		31.8	2.817	296

In some embodiments, Form A sulfate salt is characterized by the FT-Raman spectrum depicted in FIG. 18.

In some embodiments, Form A sulfate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 19.

In some embodiments, Form A sulfate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 20, trace 20A.

In some embodiments, Form A sulfate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 20, trace 20B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.3	16.694	1898		19.1	4.649	580
6.9	12.877	210		20.4	4.344	707
7.5	11.754	400		21.1	4.210	569
10.0	8.834	665		22.0	4.043	528
10.5	8.408	2928		22.4	3.967	739
13.9	6.359	364		23.7	3.762	762
15.2	5.835	474		25.5	3.496	725
15.9	5.560	901		26.3	3.391	622
17.3	5.132	371		29.0	3.077	483
18.1	4.900	750		31.2	2.865	54
18.8	4.732	898		32.9	2.722	93

In some embodiments, Form B sulfate salt is characterized by the FT-Raman spectrum depicted in FIG. 21.

In some embodiments, Form B sulfate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 22.

In some embodiments, Form B sulfate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 23, trace 23A.

In some embodiments, Form B sulfate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 23, trace 23B.

In some embodiments, a 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, a complex form of Compound 1 is Form C sulfate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.1	14.499	278		16.8	5.272	538
6.5	13.627	281		18.3	4.840	326
7.1	12.487	773		19.0	4.665	826
8.3	10.592	294		19.6	4.524	1387
9.3	9.523	332		20.2	4.398	470
10.0	8.873	347		20.8	4.268	626
10.8	8.221	751		21.0	4.225	645
11.2	7.867	356		21.8	4.078	641
11.6	7.616	324		22.2	3.997	614
12.2	7.262	527		23.4	3.803	1045
12.6	7.032	318		24.0	3.707	402
13.0	6.829	546		24.7	3.599	594
13.6	6.503	365		25.2	3.530	580
14.5	6.121	410		25.6	3.475	486
15.0	5.902	328		26.3	3.391	591
15.4	5.746	444		27.0	3.304	621
16.4	5.405	559

In some embodiments, Form C sulfate salt is characterized by the FT-Raman spectrum depicted in FIG. 24.

In some embodiments, Form C sulfate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 25.

In some embodiments, Form C sulfate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 26.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.9	12.826	478		19.8	4.477	1406
8.1	10.898	3000		20.6	4.306	608
10.0	8.835	1906		21.5	4.125	707
11.6	7.641	2009		21.9	4.063	1120
12.1	7.324	2866		22.8	3.908	863
12.7	6.979	791		23.3	3.817	439
15.1	5.871	566		23.9	3.728	2467
16.0	5.542	848		24.2	3.672	1929
16.4	5.391	2833		24.8	3.596	4801
16.9	5.231	1708		26.9	3.314	1273
18.0	4.930	1291		28.6	3.119	262
18.8	4.719	8621		31.4	2.852	132
19.4	4.570	1096		32.7	2.738	295

In some embodiments, Form D sulfate salt is characterized by the FT-Raman spectrum depicted in FIG. 27.

In some embodiments, Form D sulfate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 28.

In some embodiments, Form D sulfate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 29, trace 29A.

In some embodiments, Form D sulfate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 29, trace 29B.

In some embodiments of a complex form of Compound 1, X is p-toluenesulfonic acid. In some such embodiments, a complex form of Compound 1 is a p-toluenesulfonate salt (also referred to as a “tosylate” salt). In some embodiments, a tosylate salt of Compound 1 is a crystalline tosylate salt.

In some embodiments, a 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, a complex form of Compound 1 is Form A tosylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.3	20.495	1088		19.9	4.463	2733
7.1	12.517	1173		20.3	4.384	1692
8.6	10.301	1772		21.3	4.173	299
9.3	9.460	727		21.9	4.051	467
11.3	7.858	435		22.4	3.973	588
11.8	7.517	587		22.6	3.934	582
12.8	6.896	536		23.0	3.866	404
13.7	6.482	284		23.9	3.730	616
14.1	6.262	505		25.1	3.553	832
14.7	6.044	434		26.6	3.357	319
15.5	5.708	412		27.2	3.274	189
16.9	5.251	631		28.6	3.126	101
17.2	5.155	2517		30.4	2.942	168
17.8	4.988	2650		32.3	2.773	99

In some embodiments, Form A tosylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 30.

In some embodiments, Form A tosylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 31, trace 31A.

In some embodiments, Form A tosylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 31, trace 31B.

In some embodiments, a 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, a complex form of Compound 1 is Form B tosylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.5	16.054	285		21.0	4.236	498
9.3	9.510	762		21.3	4.163	692
11.0	8.022	2884		22.5	3.948	342
13.7	6.471	369		23.7	3.754	1029
15.2	5.834	705		24.9	3.582	812
15.7	5.649	242		26.5	3.370	527
16.5	5.366	419		27.8	3.212	151
18.0	4.942	981		30.1	2.972	73
18.9	4.701	904		32.1	2.790	106
19.9	4.465	881		33.2	2.695	116
20.4	4.348	600		38.6	2.335	58

In some embodiments, Form B tosylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 32.

In some embodiments, Form B tosylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 33, trace 33A.

In some embodiments, Form B tosylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 33, trace 33B.

In some embodiments, a complex form of Compound 1 comprises one equivalent of p-toluenesulfonic acid. In some embodiments, a 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, a complex form of Compound 1 is Form C tosylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.3	12.067	1751		18.4	4.827	1508
7.6	11.672	5992		19.1	4.644	381
8.8	10.008	1435		19.5	4.543	1366
9.3	9.464	631		19.8	4.479	6683
10.0	8.807	361		20.3	4.376	2996
10.9	8.132	794		21.3	4.173	560
11.4	7.773	279		21.7	4.104	748
12.0	7.405	1679		22.4	3.969	3743
12.8	6.891	1481		23.3	3.822	21634
13.3	6.678	1232		23.8	3.742	1530
13.6	6.499	1006		24.1	3.685	6012
14.4	6.130	912		24.9	3.574	1845
15.9	5.590	16694		25.5	3.498	1225
16.1	5.500	1980		26.3	3.392	1838
17.2	5.143	444		26.7	3.340	1939
17.9	4.955	8213		27.4	3.260	1217

In some embodiments, Form C tosylate salt is characterized by the FT-Raman spectrum depicted in FIG. 34.

In some embodiments, Form C tosylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 35.

In some embodiments, Form C tosylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 36, trace 36A.

In some embodiments, Form C tosylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 36, trace 36B.

In some embodiments, Form C tosylate salt is characterized by the dynamic vapor sorption (DVS) isotherm depicted in FIG. 37.

In some embodiments, Form C tosylate salt is characterized by the post-DVS x-ray powder diffraction (XRPD) pattern depicted in FIG. 38.

In some embodiments, Form C tosylate salt is characterized by the ¹H NMR depicted in FIG. 39.

In some embodiments of a complex form of Compound 1, X is methanesulfonic acid. In some such embodiments, a complex form of Compound 1 is a methansulfonate salt (also referred to as a “mesylate” salt). In some embodiments, a complex form of Compound 1 comprises 1.2 equivalents of methanesulfonic acid. In some embodiments, a mesylate salt of Compound 1 is a crystalline mesylate salt.

In some embodiments, a 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, a complex form of Compound 1 is Form A mesylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
12.2	7.260	908		22.3	3.981	1353
12.6	7.051	1161		22.7	3.923	883
13.2	6.718	1024		22.9	3.884	1556
14.5	6.105	1594		23.3	3.825	502
15.0	5.917	2297		23.6	3.773	3272
15.9	5.581	1351		23.9	3.728	1633
16.7	5.301	2787		24.5	3.633	1366
17.3	5.139	3596		24.8	3.596	1304
17.5	5.080	1088		25.1	3.546	1222
18.9	4.694	8601		25.7	3.469	496
19.8	4.492	3231		26.0	3.426	946
20.0	4.432	798		26.9	3.317	1155
20.5	4.327	2042		27.6	3.235	501
20.8	4.273	1237		28.4	3.138	784
21.6	4.114	1469		33.0	2.713	435
22.0	4.034	1283

In some embodiments, Form A mesylate salt is characterized by the FT-Raman spectrum depicted in FIG. 40.

In some embodiments, Form A mesylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 41.

In some embodiments, Form A mesylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 42, trace 42A.

In some embodiments, Form A mesylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 42, trace 42B.

In some embodiments, Form A mesylate salt is characterized by the ¹H NMR depicted in FIG. 43.

In some embodiments, a 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, a complex form of Compound 1 is Form B mesylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
13.4	6.591	2087		21.0	4.227	783
13.6	6.491	3189		22.2	4.008	650
14.0	6.304	1065		22.7	3.916	670
15.2	5.842	2145		23.1	3.845	3754
16.0	5.546	1954		23.4	3.800	1660
16.4	5.395	873		23.7	3.761	1458
16.8	5.263	1348		24.1	3.688	4055
18.0	4.941	2513		24.7	3.601	478
18.2	4.884	2691		25.0	3.558	982
18.4	4.818	1636		25.2	3.534	839
18.9	4.702	8276		26.8	3.325	758
19.2	4.631	3862		29.3	3.050	1908
19.6	4.535	973		32.0	2.801	679
20.5	4.333	476		35.3	2.544	416

In some embodiments, Form B mesylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 44.

In some embodiments, Form B mesylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 46, trace 46B.

In some embodiments, a 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, a complex form of Compound 1 is Form C mesylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.6	19.377	1665		18.8	4.723	508
8.9	9.972	2136		19.4	4.579	1864
9.1	9.724	2497		20.1	4.418	1205
10.9	8.133	1151		21.2	4.200	1765
11.3	7.842	713		21.6	4.107	1230
13.0	6.830	1093		22.6	3.940	696
13.3	6.651	1156		23.3	3.825	1128
13.6	6.492	1681		23.9	3.731	883
14.6	6.058	433		24.9	3.572	527
15.6	5.664	460		25.2	3.535	514
17.1	5.175	1953		26.0	3.432	941
17.4	5.108	1706		26.6	3.353	628
17.8	4.988	9832		27.5	3.247	434
18.2	4.869	16084		31.6	2.830	457
18.5	4.783	1180

In some embodiments, Form C mesylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 45.

In some embodiments, Form C mesylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 46, trace 46C.

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

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

In some embodiments, a crystalline hemi acetone solvate form of a 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, a complex form of Compound 1 is Form A 2-naphthalenesulfonate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.6	13.461	659		19.4	4.566	1256
9.8	9.035	619		19.6	4.519	873
10.5	8.429	1275		20.1	4.417	1669
10.9	8.108	891		20.6	4.304	2050
11.1	7.937	923		20.9	4.252	1152
11.6	7.629	689		21.6	4.105	2381
12.0	7.357	503		22.3	3.980	609
12.6	7.036	1199		22.7	3.914	1810
13.1	6.751	647		23.1	3.847	933
13.6	6.528	646		23.4	3.808	983
14.3	6.198	1190		24.0	3.711	1079
15.2	5.846	1568		24.8	3.589	1591
15.7	5.648	1731		25.3	3.518	1173
16.5	5.380	1604		25.7	3.473	1566
16.8	5.276	3793		26.0	3.433	1078
17.5	5.056	3039		26.5	3.368	493
17.8	4.987	3847		27.0	3.299	836
18.2	4.876	1556		28.0	3.186	415
18.5	4.788	1841		28.3	3.150	520

In some embodiments, Form A 2-naphthalenesulfonate salt is characterized by the FT-Raman spectrum depicted in FIG. 47.

In some embodiments, Form A 2-naphthalenesulfonate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 48.

In some embodiments, Form A 2-naphthalenesulfonate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 50, trace 50A.

In some embodiments, Form A 2-naphthalenesulfonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 50, trace 50B.

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

In some embodiments, a 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, a complex form of Compound 1 is Form A phosphate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
9.2	9.644	145		21.8	4.077	336
10.9	8.109	293		22.9	3.881	458
12.6	7.042	311		24.0	3.711	407
13.5	6.551	362		25.5	3.499	665
15.0	5.915	464		26.1	3.417	379
15.6	5.675	556		26.7	3.343	259
16.1	5.511	578		27.8	3.214	346
16.4	5.420	361		29.7	3.005	183
16.7	5.309	1000		32.0	2.796	57
19.8	4.492	385

In some embodiments, Form A phosphate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 52.

In some embodiments, Form A phosphate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 56, trace 56A.

In some embodiments, a 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, a complex form of Compound 1 is Form B phosphate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.9	18.046	300		20.7	4.285	1867
8.3	10.634	368		21.3	4.170	1312
9.8	9.017	1856		22.0	4.044	1990
11.0	8.078	370		22.5	3.957	543
11.7	7.532	349		23.5	3.783	1164
14.0	6.308	281		25.0	3.558	258
16.2	5.484	544		25.4	3.511	472
16.5	5.357	473		26.2	3.397	571
17.2	5.166	919		26.7	3.340	308
17.7	4.999	471		27.2	3.275	249
18.6	4.763	281		29.0	3.075	222
19.7	4.512	3231		29.4	3.034	288
20.0	4.429	773		33.2	2.696	203

In some embodiments, Form B phosphate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 53.

In some embodiments, Form B phosphate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 56, trace 56B.

In some embodiments, a 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, a complex form of Compound 1 is Form C phosphate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	12.007	251		20.8	4.281	1134
9.1	9.694	323		21.1	4.210	2018
9.9	8.907	264		21.7	4.091	542
10.4	8.541	369		22.1	4.020	1889
11.8	7.499	534		23.1	3.851	1152
12.3	7.194	2459		23.4	3.795	1163
14.5	6.126	1531		23.7	3.755	1378
14.7	6.022	550		24.2	3.683	1529
15.5	5.704	1395		24.8	3.585	1388
16.1	5.504	2200		25.2	3.538	718
16.8	5.292	1139		25.9	3.443	494
18.4	4.813	1152		26.7	3.338	276
19.2	4.614	920		28.3	3.151	1099
19.6	4.527	836		29.6	3.017	426
20.1	4.419	607

In some embodiments, Form C phosphate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 54.

In some embodiments, Form C phosphate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 56, trace 56C.

In some embodiments, a 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, a complex form of Compound 1 is Form D phosphate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.1	12.521	1469		20.2	4.399	1507
7.9	11.130	605		20.8	4.263	587
9.7	9.154	824		21.9	4.060	1538
11.1	7.958	5253		22.3	3.982	15460
14.2	6.241	1090		23.4	3.799	3528
15.3	5.796	697		23.8	3.736	2832
15.9	5.562	878		25.0	3.555	837
16.9	5.262	1827		25.7	3.470	906
17.6	5.031	674		27.3	3.263	330
18.0	4.917	871		27.9	3.200	709
18.5	4.805	1777		29.1	3.071	1291
19.7	4.497	1006

In some embodiments, Form D phosphate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 55.

In some embodiments, Form D phosphate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 56, trace 56D.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.2	10.758	1688		22.5	3.946	698
10.1	8.790	1615		22.8	3.897	1439
10.9	8.086	3754		23.2	3.840	2339
13.0	6.826	717		23.8	3.732	627
14.5	6.128	1664		24.1	3.695	692
14.8	5.990	2416		24.8	3.593	399
15.8	5.611	3163		25.9	3.445	1952
16.5	5.386	3674		26.2	3.397	2062
16.8	5.289	2981		26.5	3.366	1368
18.0	4.940	4748		27.1	3.289	1303
19.0	4.667	778		27.3	3.268	1105
19.5	4.562	6039		28.5	3.130	312
20.2	4.401	1144		29.8	2.997	818
21.7	4.089	554		32.1	2.787	318
22.1	4.016	3380		32.9	2.719	571

In some embodiments, Form E phosphate salt is characterized by the FT-Raman spectrum depicted in FIG. 57.

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

In some embodiments, Form E phosphate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 59, trace 59A.

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

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

In some embodiments, a DL-tartrate salt of Compound 1 is a hydrate. In some embodiments, a hydrate form of a DL-tartrate salt of Compound 1 is a crystalline hydrate form of a DL-tartrate salt. In some embodiments, a crystalline hydrate form of a DL-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, 9.3, 11.0, and 13.0 ± 0.2 degrees 2θ. In some such embodiments, a complex form of Compound 1 is Form A DL-tartrate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.7	18.988	6462		19.1	4.640	230
6.2	14.286	80		20.7	4.300	288
7.4	11.921	780		21.2	4.187	243
9.3	9.502	1716		21.8	4.081	358
11.0	8.071	3146		22.5	3.953	68
11.8	7.510	69		24.2	3.674	276
13.0	6.819	519		25.4	3.513	312
13.5	6.557	208		26.1	3.419	283
14.0	6.341	524		26.9	3.319	114
14.8	5.966	391		27.4	3.258	92
16.7	5.322	304		28.4	3.147	123
17.3	5.126	264		30.0	2.977	145
18.2	4.883	809		33.0	2.717	76
18.6	4.759	486		35.0	2.563	149

In some embodiments, Form A DL-tartrate salt is characterized by the FT-Raman spectrum depicted in FIG. 60.

In some embodiments, Form A DL-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 61.

In some embodiments, Form A DL-tartrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 62, trace 62A.

In some embodiments, Form A DL-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 62, trace 62B.

In some embodiments, Form A DL-tartrate salt is characterized by the dynamic vapor sorption (DVS) isotherm pattern depicted in FIG. 63.

In some embodiments, Form A DL-tartrate salt is characterized by the ¹H NMR depicted in FIG. 64.

In some embodiments, a 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, a complex form of Compound 1 is Form B DL-tartrate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.9	14.882	1498		18.4	4.812	1275
9.7	9.106	790		18.8	4.732	5043
12.4	7.137	620		21.0	4.238	502
12.6	7.015	824		21.3	4.179	1777
13.1	6.736	5330		23.5	3.782	1835
13.4	6.615	1566		23.9	3.719	1302
14.0	6.330	1105		24.5	3.636	3815
14.6	6.076	632		25.4	3.507	1010
14.8	5.992	618		26.3	3.392	683
15.5	5.708	1622		27.6	3.228	1013
16.1	5.499	1159		28.2	3.170	1812
16.4	5.403	1491		29.4	3.041	1037
16.6	5.325	1196		29.6	3.014	1780
16.9	5.235	6795		30.1	2.972	496
17.4	5.083	1109		34.8	2.575	544
17.9	4.959	5788		18.4	4.812	1275

In some embodiments, Form B DL-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 65.

In some embodiments, Form B DL-tartrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 66, trace 66A.

In some embodiments, Form B DL-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 66, trace 66B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.0	17.537	1910		17.0	5.204	791
5.4	16.421	2826		17.3	5.115	683
6.0	14.743	490		18.5	4.786	672
6.4	13.832	573		19.2	4.612	626
6.8	13.004	447		20.1	4.427	541
8.0	11.026	270		20.8	4.274	393
10.1	8.794	903		22.9	3.885	365
10.8	8.222	383		23.5	3.782	271
12.0	7.378	384		24.5	3.629	562
12.8	6.903	463		25.0	3.566	525
13.6	6.506	801		25.4	3.509	512
13.9	6.364	499		25.8	3.455	448
15.1	5.853	494		27.3	3.267	219
16.0	5.549	845		28.0	3.188	215
16.7	5.301	1287		30.6	2.923	85

In some embodiments, Form A succinate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 67.

In some embodiments, Form A succinate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 68, trace 68A.

In some embodiments, Form A succinate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 68, trace 68B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.7	18.855	2977		15.4	5.753	1280
5.2	17.044	156		15.7	5.652	972
5.8	15.223	451		16.0	5.551	466
6.2	14.359	339		18.1	4.895	432
6.7	13.177	298		18.7	4.757	623
8.3	10.634	177		19.0	4.667	1040
9.4	9.437	1595		19.3	4.609	391
10.0	8.856	632		19.6	4.521	174
11.3	7.814	125		20.6	4.309	733
11.6	7.611	139		22.6	3.941	413
12.2	7.262	468		24.3	3.670	194
13.2	6.722	225		24.7	3.602	184
13.4	6.614	289		25.0	3.564	128
14.4	6.165	168		26.0	3.429	575

In some embodiments, Form B succinate salt is characterized by the FT-Raman spectrum depicted in FIG. 69.

In some embodiments, Form B succinate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 70.

In some embodiments, Form B succinate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 71, trace 71A.

In some embodiments, Form B succinate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 71, trace 71B.

In some embodiments, Form B succinate salt is characterized by the ¹H NMR depicted in FIG. 72.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.9	22.426	223		19.8	4.478	641
7.9	11.187	1891		20.7	4.300	256
9.0	9.790	169		21.6	4.106	565
11.9	7.460	5083		21.9	4.050	559
13.6	6.520	199		23.3	3.816	252
14.4	6.169	161		24.1	3.693	1008
14.8	6.006	350		25.1	3.543	1611
15.8	5.593	1922		25.7	3.462	617
16.3	5.424	326		26.3	3.384	123
17.0	5.215	451		27.3	3.266	102
17.5	5.066	479		27.9	3.202	131
18.1	4.902	256		28.7	3.113	104
18.8	4.714	1155		33.1	2.705	110

In some embodiments, Form A gentisate salt is characterized by the FT-Raman spectrum depicted in FIG. 73.

In some embodiments, Form A gentisate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 74.

In some embodiments, Form A gentisate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 75, trace 75A.

In some embodiments, Form A gentisate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 75, trace 75B.

In some embodiments, Form A gentisate salt is characterized by the ¹H NMR depicted in FIG. 76.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.8	23.433	214		19.8	4.487	756
7.6	11.687	2070		20.7	4.291	293
9.7	9.105	674		21.2	4.182	609
11.4	7.790	7720		22.2	4.001	577
13.5	6.558	428		22.8	3.908	2086
14.4	6.153	524		23.9	3.725	845
14.8	5.977	261		24.3	3.665	199
15.2	5.840	5003		24.5	3.636	219
16.1	5.496	202		24.8	3.589	742
16.9	5.239	578		25.2	3.539	388
17.3	5.115	467		26.2	3.404	287
18.0	4.933	528		27.2	3.279	1452
18.6	4.775	1963		27.7	3.224	288
19.0	4.670	721		28.1	3.174	256
19.5	4.546	456

In some embodiments, Form A hippurate salt is characterized by the FT-Raman spectrum depicted in FIG. 77.

In some embodiments, Form A hippurate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 78.

In some embodiments, Form A hippurate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 79, trace 79A.

In some embodiments, Form A hippurate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 79, trace 79B.

In some embodiments, Form A hippurate salt is characterized by the ¹H NMR depicted in FIG. 80.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.0	11.061	1244		19.0	4.661	1221
8.6	10.282	267		19.3	4.592	800
9.5	9.324	2272		20.1	4.424	1586
11.6	7.639	929		20.5	4.341	1593
12.0	7.373	3181		21.0	4.222	653
12.6	7.025	1189		21.4	4.152	322
13.0	6.820	1297		21.8	4.080	1138
13.6	6.514	245		22.4	3.973	246
15.1	5.860	1190		22.8	3.903	1511
15.4	5.738	2138		23.3	3.821	2125
16.1	5.489	3619		23.7	3.747	1462
16.8	5.288	294		24.2	3.670	323
17.3	5.138	881		24.8	3.595	821
17.7	5.016	1387		25.3	3.514	2458
17.9	4.942	965		25.9	3.439	332
18.4	4.825	1179		27.3	3.272	1419

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

In some embodiments, Form A adipate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 82, trace 82A.

In some embodiments, Form A adipate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 82, trace 82B.

In some embodiments, a 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, a complex form of Compound 1 is Form C adipate salt.

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

Position °2θ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.0	21.935	262		18.3	4.842	652
8.1	10.959	3207		19.1	4.647	353
9.5	9.270	649		20.2	4.406	1759
11.6	7.607	245		20.5	4.325	1123
12.1	7.328	5088		21.0	4.228	375
12.6	7.016	278		21.8	4.073	480
13.0	6.799	510		23.0	3.869	737
13.4	6.592	333		23.3	3.821	1130
13.8	6.440	192		23.8	3.737	894
15.2	5.844	252		24.3	3.670	453
15.5	5.720	624		24.8	3.595	350
15.7	5.653	1097		25.4	3.504	1850
16.1	5.502	2663		26.5	3.363	282
16.9	5.239	337		26.8	3.323	295
17.5	5.080	321		27.1	3.293	584
17.7	5.003	619		27.3	3.263	893

In some embodiments, Form C adipate salt is characterized by the FT-Raman spectrum depicted in FIG. 83.

In some embodiments, Form C adipate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 84.

In some embodiments, Form C adipate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 85, trace 85A.

In some embodiments, Form C adipate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 85, trace 85B.

In some embodiments, Form C adipate salt is characterized by the ¹H NMR depicted in FIG. 86.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.7	13.178	435		19.7	4.517	1146
9.3	9.519	2500		20.2	4.403	634
11.3	7.857	285		21.4	4.162	2178
12.1	7.326	301		22.4	3.965	321
12.5	7.076	386		23.0	3.875	407
13.0	6.805	127		24.3	3.659	637
13.8	6.406	959		27.0	3.299	991
15.2	5.831	1012		27.8	3.215	327
16.6	5.339	1447		28.3	3.155	159
17.0	5.226	1075		30.8	2.907	378
17.4	5.108	599		32.7	2.740	201
18.6	4.772	255		37.2	2.419	132
19.0	4.674	1133		37.7	2.387	131

In some embodiments, Form A galactarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 87.

In some embodiments, Form A galactarate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 89, trace 89A.

In some embodiments, Form A galactarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 89, trace 89B.

In some embodiments, Form A galactarate salt is characterized by the ¹H NMR depicted in FIG. 90.

In some embodiments of a complex form of Compound 1, X is 1,5-naphthalenedisulfonic acid. In some such embodiments, a complex form of Compound 1 is a 1,5-naphthalenedisulfonate salt (also referred to as a “napadisylate” salt). In some embodiments, a napadisylate salt of Compound 1 is a crystalline napadisylate salt. In some embodiments, a crystalline napadisylate salt of Compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 3.8, 6.5, and 7.5 ± 0.2 degrees 2θ. In some such embodiments, a complex form of Compound 1 is Form A napadisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.8	23.284	418		17.2	5.153	676
6.5	13.520	378		18.0	4.915	545
7.5	11.749	657		19.0	4.678	629
9.8	9.022	403		19.9	4.463	479
10.5	8.466	510		20.5	4.338	739
10.7	8.273	519		23.1	3.856	273
12.5	7.064	772		25.2	3.530	1908
13.4	6.587	738		27.0	3.300	386
15.4	5.737	462		29.6	3.019	107

In some embodiments, Form A napadisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 91.

In some embodiments, Form A napadisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 94, trace 94A.

In some embodiments, a crystalline napadisylate 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, a complex form of Compound 1 is Form B napadisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.0	22.302	443		17.7	5.004	617
7.9	11.219	2950		18.1	4.902	669
8.1	10.870	874		18.6	4.776	818
9.9	8.937	204		19.0	4.683	611
11.1	7.949	349		19.7	4.496	554
11.8	7.489	909		20.4	4.346	938
12.2	7.253	332		20.9	4.255	394
12.6	7.015	374		21.4	4.156	319
13.9	6.383	311		21.7	4.098	468
14.4	6.169	523		22.7	3.912	350
14.7	6.032	899		23.8	3.744	670
15.8	5.620	1254		24.6	3.624	393
16.3	5.441	533		25.3	3.518	872
16.5	5.370	559		25.9	3.440	752
17.1	5.193	713		27.3	3.272	197
17.4	5.092	713

In some embodiments, Form B napadisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 92.

In some embodiments, Form B napadisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 94, trace 94B.

In some embodiments, a crystalline napadisylate 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, a complex form of Compound 1 is Form C napadisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.6	24.308	45
5.6	15.871	131
13.4	6.614	225
14.4	6.169	341
17.8	4.988	221
18.6	4.766	245
19.7	4.515	417
22.0	4.049	192
22.9	3.876	327
23.6	3.768	433
26.4	3.381	169

In some embodiments, Form C napadisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 93.

In some embodiments, Form C napadisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 94, trace 94C.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.0	17.694	6353		18.0	4.922	985
6.3	14.118	427		18.4	4.822	396
6.7	13.123	443		18.8	4.716	929
9.9	8.896	8788		20.0	4.450	1448
10.4	8.470	995		20.3	4.378	550
11.1	7.986	702		20.7	4.293	539
12.5	7.059	423		21.0	4.226	950
13.1	6.771	823		21.6	4.107	711
13.5	6.562	406		22.8	3.896	890
14.3	6.204	1168		23.3	3.815	564
14.8	5.997	584		23.5	3.778	943
15.2	5.825	2014		24.1	3.690	989
15.8	5.603	1922		25.0	3.560	786
16.3	5.428	1031		25.7	3.467	555
16.6	5.334	1010		26.1	3.412	690
16.9	5.257	1302		27.3	3.273	407
17.7	5.024	701		28.0	3.188	835

In some embodiments, Form A (S)-camphorsulfonate salt is characterized by the FT-Raman spectrum depicted in FIG. 95.

In some embodiments, Form A (S)-camphorsulfonate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 96.

In some embodiments, Form A (S)-camphorsulfonate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 97, trace 97A.

In some embodiments, Form A (S)-camphorsulfonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 97, trace 97B.

In some embodiments, a crystalline (S)-camphorsulfonate 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, a complex form of Compound 1 is Form B (S)-camphorsulfonate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.9	12.733	754		18.7	4.747	644
7.9	11.123	270		19.4	4.565	615
10.2	8.655	1087		19.8	4.476	1389
11.4	7.742	1799		20.4	4.353	609
12.4	7.160	501		21.0	4.236	857
14.2	6.218	2102		21.3	4.178	1351
14.6	6.050	356		22.4	3.976	1462
15.0	5.908	3544		22.8	3.908	1083
15.3	5.805	1828		23.2	3.830	577
15.5	5.709	907		24.0	3.714	2791
15.9	5.562	1801		24.4	3.641	1067
16.3	5.444	417		24.9	3.582	351
16.6	5.346	2461		25.2	3.533	401
16.9	5.244	1270		25.7	3.466	870
17.7	5.022	456		26.9	3.315	534
18.3	4.858	2270		27.2	3.276	668

In some embodiments, Form B (S)-camphorsulfonate salt is characterized by the FT-Raman spectrum depicted in FIG. 98.

In some embodiments, Form B (S)-camphorsulfonate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 99.

In some embodiments, Form B (S)-camphorsulfonate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 100, trace 100A.

In some embodiments, Form B (S)-camphorsulfonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 100, trace 100B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.2	12.282	310		20.7	4.283	629
9.1	9.731	1774		21.4	4.162	1634
10.7	8.307	2111		22.0	4.037	1655
11.1	7.944	1834		22.3	3.978	1387
12.0	7.359	483		22.8	3.898	3682
14.0	6.338	920		23.9	3.718	524
14.4	6.163	403		24.3	3.660	570
14.7	6.022	1417		24.8	3.590	604
15.5	5.724	506		25.4	3.509	1312
16.0	5.526	627		26.0	3.424	1296
17.5	5.065	342		26.7	3.345	630
18.2	4.883	4716		27.8	3.206	578
19.0	4.664	3252		29.3	3.047	325
20.0	4.441	1004		31.1	2.877	327
20.4	4.352	1013		32.1	2.790	498

In some embodiments, Form A edisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 101.

In some embodiments, Form A edisylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 105, trace 105A.

In some embodiments, Form A edisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 105, trace 105B.

In some embodiments, a 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, a complex form of Compound 1 is Form B edisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
9.8	9.071	1169		20.9	4.254	1050
10.9	8.127	1534		21.3	4.181	1666
11.9	7.420	246		21.4	4.150	1957
12.9	6.881	864		21.9	4.058	232
13.1	6.768	938		22.4	3.968	1173
13.6	6.526	1272		22.8	3.905	1380
15.0	5.919	392		23.1	3.855	944
15.3	5.779	228		23.6	3.776	679
16.4	5.410	202		24.0	3.709	1478
17.3	5.141	576		24.5	3.641	876
18.6	4.772	984		25.0	3.564	334
19.1	4.636	1455		25.8	3.451	225
19.5	4.545	3916		26.3	3.384	948
19.9	4.472	1106		26.9	3.315	633
20.3	4.380	625

In some embodiments, Form B edisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 102.

In some embodiments, Form B edisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 106, trace 106B.

In some embodiments, a 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, a complex form of Compound 1 is Form C edisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.0	12.609	458		20.5	4.334	2657
8.8	10.105	224		22.2	4.008	1010
12.8	6.917	671		22.9	3.888	1420
13.3	6.648	623		24.0	3.713	1058
13.7	6.458	588		24.5	3.640	1785
14.7	6.025	1281		25.4	3.512	683
15.8	5.626	502		26.3	3.391	1044
16.7	5.313	1133		26.8	3.330	660
17.1	5.188	888		27.2	3.283	648
17.8	4.984	542		28.9	3.085	258
18.1	4.909	672		30.1	2.971	169
18.7	4.743	1374		32.0	2.797	185
19.2	4.619	894

In some embodiments, Form C edisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 103.

In some embodiments, Form C edisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 106, trace 106A.

In some embodiments, a 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, a complex form of Compound 1 is Form D edisylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.1	14.602	531		19.2	4.620	695
10.2	8.694	952		19.5	4.542	1849
10.4	8.514	882		20.0	4.442	4222
11.6	7.634	728		20.8	4.274	3499
11.9	7.465	295		21.4	4.155	569
12.5	7.105	2377		22.0	4.049	655
13.0	6.805	622		22.6	3.931	1039
13.3	6.633	799		23.3	3.822	1346
14.1	6.301	236		23.9	3.728	946
14.9	5.938	434		24.3	3.670	771
15.3	5.805	609		24.5	3.637	736
15.8	5.611	1574		24.9	3.578	671
16.0	5.534	1894		25.5	3.493	506
17.0	5.211	1611		25.8	3.450	220
17.8	4.974	419		26.2	3.406	426
18.2	4.878	674		26.5	3.363	1556
18.7	4.746	1516

In some embodiments, Form D edisylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 104.

In some embodiments, Form D edisylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 106, trace 106C.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.4	10.570	4144		23.2	3.839	1037
10.1	8.720	833		23.7	3.747	641
10.4	8.518	1651		24.5	3.631	782
13.8	6.407	1296		25.2	3.533	18991
17.0	5.228	6247		26.1	3.419	759
17.4	5.097	3323		26.4	3.382	1950
18.2	4.875	2694		27.3	3.269	1084
18.7	4.753	3679		27.9	3.201	804
19.2	4.619	1741		28.6	3.122	641
20.8	4.262	860		28.8	3.102	758
21.7	4.094	2850		33.4	2.680	1038
22.2	3.999	3947		33.8	2.650	713
22.8	3.909	591

In some embodiments, Form A esylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 107.

In some embodiments, Form A esylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 109, trace 109A.

In some embodiments, Form A esylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 109, trace 109B.

In some embodiments, a 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, a complex form of Compound 1 is Form B esylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.5	13.673	1941		19.9	4.458	904
9.8	8.987	1563		20.2	4.389	2319
10.7	8.261	194		20.6	4.320	2287
12.5	7.103	1980		20.9	4.247	1623
12.9	6.842	3137		21.5	4.129	467
13.5	6.541	495		22.3	3.995	570
14.1	6.293	422		22.7	3.924	387
14.4	6.141	268		22.9	3.876	1505
14.8	5.988	1487		23.3	3.818	1429
15.4	5.741	297		23.5	3.785	2645
16.0	5.534	616		23.9	3.717	3178
16.8	5.269	1151		24.2	3.677	1052
17.1	5.184	1269		24.7	3.607	477
17.6	5.035	1064		25.4	3.512	340
18.1	4.890	2035		25.8	3.451	1895
18.5	4.793	538		26.2	3.397	417
19.2	4.617	1762		27.5	3.247	1484
19.6	4.538	3087

In some embodiments, Form B esylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 108.

In some embodiments, Form B esylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 110, trace 110A.

In some embodiments, Form B esylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 110, trace 110B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.5	16.019	299		19.8	4.494	462
7.5	11.749	602		20.1	4.427	525
10.4	8.488	819		20.7	4.284	735
11.0	8.025	1001		21.3	4.168	550
12.8	6.931	715		22.5	3.956	1206
13.2	6.716	280		22.9	3.878	395
14.3	6.175	1709		23.2	3.830	647
14.9	5.932	1058		23.6	3.769	387
15.5	5.710	395		23.9	3.718	443
16.7	5.306	1108		24.6	3.620	281
17.0	5.202	1278		25.4	3.502	593
18.0	4.924	1316		25.7	3.466	443
18.6	4.776	567

In some embodiments, Form A besylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 111.

In some embodiments, Form A besylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 115, trace 115A.

In some embodiments, a 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, a complex form of Compound 1 is Form B besylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.860	154		18.9	4.696	452
9.2	9.588	144		19.9	4.455	207
11.1	7.962	607		20.8	4.276	474
12.1	7.308	508		21.7	4.093	211
14.1	6.284	642		22.3	3.983	235
15.1	5.871	610		22.8	3.892	848
17.5	5.075	1232		23.4	3.808	257
18.1	4.905	690		26.0	3.424	560
18.5	4.784	653		27.2	3.274	115

In some embodiments, Form B besylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 112.

In some embodiments, Form B besylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 115, trace 115B.

In some embodiments, a 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, a complex form of Compound 1 is Form C besylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.1	21.421	461		21.0	4.224	980
8.2	10.788	1502		21.8	4.076	1072
12.3	7.200	12721		22.4	3.962	408
15.2	5.826	929		23.6	3.770	1164
15.4	5.736	1445		24.1	3.697	348
16.1	5.516	402		24.4	3.642	4747
16.4	5.403	3281		25.4	3.501	532
16.9	5.253	788		26.2	3.400	3118
18.0	4.917	1061		26.8	3.324	383
18.4	4.820	473		27.3	3.263	861
19.4	4.577	294		27.8	3.211	552
19.7	4.498	458		28.9	3.088	1206
20.2	4.402	1047		33.2	2.700	356
20.5	4.323	5107

In some embodiments, Form C besylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 113.

In some embodiments, Form C besylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 115, trace 115C.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.1	14.417	145		18.7	4.744	528
7.2	12.281	167		19.8	4.479	405
11.5	7.682	953		21.0	4.233	560
12.1	7.305	541		21.7	4.094	402
12.6	7.025	478		22.4	3.963	291
12.9	6.887	468		23.3	3.821	355
14.0	6.322	252		23.8	3.740	402
14.6	6.053	987		24.1	3.696	1363
16.4	5.405	457		25.3	3.515	804
17.2	5.170	323		26.1	3.408	197
17.8	4.996	285		26.9	3.314	209
18.4	4.826	1021

In some embodiments, Form D besylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 114.

In some embodiments, Form D besylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 116, trace 116A.

In some embodiments, Form D besylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 116, trace 116B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.7	18.750	557		19.6	4.525	355
6.5	13.578	631		20.4	4.347	432
9.4	9.405	795		22.3	3.984	449
11.0	8.014	355		23.2	3.830	247
11.9	7.451	1031		24.2	3.679	1722
12.5	7.087	1642		25.6	3.481	305
14.2	6.257	364		26.0	3.424	302
14.8	5.969	317		27.2	3.282	180
15.4	5.760	259		31.8	2.816	82
17.2	5.162	358		33.0	2.712	66
17.7	5.016	847		38.4	2.343	66
18.9	4.688	401

In some embodiments, Form A oxalate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 117.

In some embodiments, Form A oxalate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 119, trace 119A.

In some embodiments, Form A oxalate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 119, trace 119B.

In some embodiments, a 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, a complex form of Compound 1 is Form B oxalate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.3	16.727	1710		18.2	4.865	446
8.1	10.931	188		18.7	4.758	915
8.7	10.151	280		19.3	4.594	585
11.1	7.961	224		19.7	4.505	735
12.5	7.109	453		20.5	4.339	818
12.9	6.884	807		21.3	4.162	600
13.1	6.752	692		22.6	3.941	643
14.1	6.300	632		22.9	3.876	688
14.4	6.140	422		23.6	3.777	1144
14.9	5.942	705		24.1	3.700	1267
15.4	5.757	491		24.9	3.570	1221
15.8	5.619	841		25.6	3.474	512
16.8	5.267	1630		26.4	3.374	442
17.7	4.999	492		27.1	3.292	778
18.0	4.934	572

In some embodiments, Form B oxalate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 118.

In some embodiments, Form B oxalate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 120, trace 120A.

In some embodiments, Form B oxalate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 120, trace 120B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.9	22.637	252		19.3	4.611	588
7.7	11.476	3253		19.6	4.536	785
9.8	9.056	235		19.9	4.469	2055
11.5	7.669	2247		20.2	4.403	953
13.4	6.626	700		20.7	4.298	387
13.7	6.460	508		21.0	4.224	1239
14.1	6.278	617		22.1	4.031	1292
15.4	5.759	4592		22.9	3.885	718
15.8	5.616	967		23.1	3.843	1060
16.1	5.507	2377		23.4	3.806	1147
16.9	5.253	631		24.1	3.698	1058
17.2	5.159	572		25.0	3.565	3369
17.6	5.040	1272		25.3	3.524	2734
18.1	4.890	1144		26.2	3.405	3543
18.8	4.710	1676		27.1	3.294	912

In some embodiments, Form A maleate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 121.

In some embodiments, Form A maleate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 122, trace 122A.

In some embodiments, Form A maleate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 122, trace 122B.

In some embodiments of a complex form of Compound 1, X is pamoic acid. In some such embodiments, a complex form of Compound 1 is a pamoate salt. In some embodiments, a pamoate salt of Compound 1 is a crystalline pamoate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A pamoate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.1	14.53	3876		19.4	4.58	2254
8.2	10.73	565		20.8	4.26	3684
10.2	8.67	312		21.5	4.13	4769
10.7	8.26	1402		22.2	4.01	568
11.4	7.76	188		22.9	3.89	514
12.1	7.29	583		23.3	3.82	605
13.3	6.67	502		24.3	3.66	491
13.9	6.37	1477		25.1	3.54	5643
15.4	5.76	1473		26.5	3.36	876
16.0	5.55	684		28.3	3.15	378
16.8	5.28	1937		29.3	3.05	319
18.0	4.94	2406		31.2	2.87	1051

In some embodiments, Form A pamoate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 123.

In some embodiments, Form A pamoate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 124, trace 124A.

In some embodiments, Form A pamoate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 124, trace 124B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.8	18.419	175		18.5	4.785	1405
6.7	13.252	527		19.1	4.642	923
7.5	11.865	271		19.8	4.483	964
8.4	10.520	554		21.0	4.223	875
9.7	9.087	1313		22.0	4.033	749
10.8	8.208	571		22.5	3.955	874
11.9	7.415	618		23.4	3.796	1148
13.5	6.568	831		23.9	3.727	2074
14.4	6.166	2022		24.3	3.663	1425
14.9	5.947	1065		25.1	3.543	834
15.3	5.777	817		26.2	3.404	916
16.0	5.531	1562		27.3	3.266	432
16.4	5.402	1295		28.0	3.191	379
17.8	4.992	881		29.8	3.000	388

In some embodiments, Form A 1-hydroxy-2-naphthoate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 125.

In some embodiments, Form A 1-hydroxy-2-naphthoate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 126.

In some embodiments of a complex form of Compound 1, X is malonic acid. In some such embodiments, a complex form of Compound 1 is a malonate salt. In some embodiments, a malonate salt of Compound 1 is a crystalline malonate salt. In some embodiments, a 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, 13.2, 13.7, and 15.6 ± 0.2 degrees 2θ. In some such embodiments, a complex form of Compound 1 is Form A malonate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.8	11.328	4581		20.0	4.430	828
11.7	7.553	2996		20.4	4.345	1281
12.4	7.135	164		21.1	4.214	630
13.2	6.724	402		22.4	3.975	615
13.7	6.449	660		23.2	3.829	573
15.6	5.665	4794		23.6	3.771	1883
16.1	5.495	1251		24.5	3.639	335
16.9	5.243	392		25.7	3.468	2844
17.6	5.042	1225		25.9	3.442	1892
17.7	5.000	1078		27.0	3.301	2136
18.9	4.699	826		27.7	3.220	262
19.4	4.585	575		32.3	2.768	380
19.6	4.530	816

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

In some embodiments, Form A malonate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 128, trace 128A.

In some embodiments, Form A malonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 128, trace 128B.

In some embodiments, a 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, a complex form of Compound 1 is Form B malonate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.6	15.89485	429		17.8	4.97879	1193
7.3	12.03475	262		18.1	4.89167	686
10.0	8.81941	265		18.5	4.78865	680
10.9	8.13506	385		19.0	4.66963	692
11.2	7.92972	1609		19.6	4.52597	653
12.3	7.17635	859		20.2	4.40622	471
13.1	6.75674	231		20.7	4.30059	1610
13.6	6.50525	518		21.6	4.12176	1024
14.1	6.27959	364		21.9	4.06022	1161
14.5	6.11586	1845		22.5	3.95638	878
15.9	5.57251	404		23.7	3.75666	1057
16.3	5.42237	622		24.7	3.60383	705
16.8	5.27905	1852		25.1	3.55218	354
17.5	5.06269	516		26.7	3.33519	1173

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

In some embodiments, Form B malonate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 130, trace 130A.

In some embodiments, Form B malonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 130, trace 130B.

In some embodiments, a 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, a complex form of Compound 1 is Form C malonate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.8	11.308	391
11.7	7.548	188
15.7	5.655	303
17.7	5.007	582
25.7	3.464	80

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

In some embodiments, Form C malonate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 132.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.841	61		19.8	4.476	154
9.7	9.089	88		21.0	4.222	129
11.1	7.942	137		22.1	4.027	47
14.9	5.950	334		23.9	3.718	58
15.6	5.696	77		25.1	3.541	214
16.1	5.497	54		25.9	3.444	310
16.6	5.350	115		27.8	3.213	124
18.7	4.754	78		32.6	2.746	50

In some embodiments, Form A L-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 133.

In some embodiments, Form A L-tartrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 134, trace 134A.

In some embodiments, Form A L-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 134, trace 134B.

In some embodiments, a 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, a complex form of Compound 1 is Form B L-tartrate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	11.878	529		18.6	4.759	409
9.7	9.099	295		19.3	4.595	483
11.2	7.929	724		19.6	4.538	722
11.7	7.577	446		21.0	4.221	418
14.4	6.135	333		22.0	4.040	214
14.9	5.949	1770		24.1	3.699	392
15.6	5.690	676		25.2	3.537	523
16.1	5.498	557		25.9	3.446	684
16.6	5.348	504		27.7	3.225	241
17.7	5.002	240		29.2	3.061	153

In some embodiments, Form B L-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 135.

In some embodiments, Form B L-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 136.

In some embodiments, a 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, a complex form of Compound 1 is Form C L-tartrate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	11.868	717		19.3	4.599	620
9.7	9.099	447		19.6	4.539	967
11.2	7.911	889		19.8	4.485	532
12.5	7.092	152		21.0	4.226	703
13.4	6.599	232		22.1	4.022	347
14.4	6.144	445		24.0	3.703	370
14.9	5.936	1849		25.1	3.542	698
15.5	5.702	655		25.8	3.447	943
16.1	5.496	783		26.7	3.333	301
16.6	5.348	796		27.4	3.255	239
17.7	5.004	257		27.8	3.211	348
18.2	4.864	214		29.1	3.064	205
18.7	4.737	366

In some embodiments, Form C L-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 137.

In some embodiments, Form C L-tartrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 138, trace 138A.

In some embodiments, Form C L-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 138, trace 138B.

In some embodiments, a 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, a complex form of Compound 1 is Form D L-tartrate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.7	18.677	597		17.6	5.047	250
7.4	11.927	906		18.3	4.853	1788
9.5	9.351	1215		18.6	4.766	269
11.1	8.004	2952		19.0	4.674	766
11.7	7.580	299		19.3	4.602	487
12.4	7.149	169		20.9	4.247	2066
13.1	6.736	739		21.9	4.063	252
13.5	6.577	758		22.2	4.013	671
14.2	6.232	449		22.9	3.886	166
14.9	5.963	985		24.0	3.710	798
15.3	5.776	364		25.3	3.525	302
15.9	5.567	286		25.7	3.463	799
16.5	5.378	318		26.3	3.384	422
16.8	5.287	904		27.0	3.307	559

In some embodiments, Form D L-tartrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 139.

In some embodiments, Form D L-tartrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 140, trace 140A.

In some embodiments, Form D L-tartrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 140, trace 140B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.2	14.322	288		18.7	4.748	1079
6.7	13.147	922		19.0	4.660	3958
11.2	7.904	494		19.7	4.497	653
12.3	7.210	2223		20.2	4.400	830
12.7	6.948	279		20.6	4.304	3817
13.4	6.597	1359		22.8	3.906	2496
14.2	6.251	921		23.5	3.778	235
14.3	6.175	1080		25.0	3.566	1431
14.6	6.052	213		26.0	3.428	2806
15.4	5.771	5313		26.3	3.384	435
16.0	5.542	2435		26.9	3.309	335
17.3	5.135	450		27.3	3.264	331
18.0	4.916	2002		30.0	2.977	647
18.4	4.816	368

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

In some embodiments, Form A fumarate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 142, trace 142A.

In some embodiments, Form A fumarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 142, trace 142B.

In some embodiments, a 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, a complex form of Compound 1 is Form B fumarate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.1	14.387	104		18.0	4.922	303
7.0	12.585	210		19.0	4.666	929
12.3	7.224	270		20.2	4.392	164
13.4	6.609	267		20.6	4.307	789
14.1	6.283	365		22.2	4.002	233
14.6	6.060	345		22.7	3.910	490
15.3	5.779	1036		25.0	3.567	284
16.0	5.554	313		26.0	3.430	567
17.6	5.025	221		28.3	3.151	86

In some embodiments, Form B fumarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 143.

In some embodiments, Form B fumarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 144.

In some embodiments, a 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, a complex form of Compound 1 is Form C fumarate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.6	11.673	2345
11.4	7.779	2628
14.5	6.091	143
15.2	5.834	5995
16.1	5.500	539
19.0	4.667	1865
21.5	4.141	543
22.9	3.889	437
24.6	3.613	919
26.4	3.371	494
29.0	3.075	112
30.6	2.917	456

In some embodiments, Form C fumarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 145.

In some embodiments, Form C fumarate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 146, trace 146A.

In some embodiments, Form C fumarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 146, trace 146B.

In some embodiments, a 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, a complex form of Compound 1 is Form D fumarate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
11.2	7.866	51
14.0	6.345	103
17.6	5.045	277
23.3	3.813	117
23.9	3.716	124
25.1	3.554	138
27.7	3.226	46

In some embodiments, Form D fumarate salt of Compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 147.

In some embodiments, Form D fumarate salt of Compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 148, trace 148A.

In some embodiments, Form D fumarate salt of Compound 1 is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 148, trace 148B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.778	1525		20.1	4.424	230
11.3	7.840	1296		21.0	4.237	455
13.5	6.578	387		22.4	3.974	526
14.7	6.026	310		23.0	3.871	530
15.1	5.879	7091		23.7	3.752	207
15.9	5.566	881		24.3	3.659	315
16.2	5.487	589		25.2	3.536	1524
16.5	5.371	344		25.8	3.447	995
18.3	4.839	309		26.4	3.381	863
18.9	4.702	2152		26.9	3.315	318
19.2	4.635	1040		27.5	3.246	513
19.4	4.585	515		28.2	3.159	180
19.8	4.488	244		28.5	3.128	665

In some embodiments, Form A citrate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 149.

In some embodiments, Form A citrate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 150, trace 150A.

In some embodiments, Form A citrate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 150, trace 150B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.860	463		19.9	4.460	823
8.2	10.774	1477		20.7	4.299	1713
9.9	8.924	315		20.9	4.251	570
11.2	7.913	786		21.5	4.142	422
12.3	7.170	6567		21.9	4.054	431
13.2	6.683	359		22.6	3.931	792
14.9	5.933	697		23.1	3.845	3717
15.3	5.804	888		23.5	3.787	427
16.0	5.550	1525		24.0	3.704	1829
16.5	5.375	819		25.2	3.530	441
16.9	5.250	555		25.7	3.466	848
17.6	5.053	997		26.5	3.360	711
18.6	4.767	1540		27.6	3.228	1991
19.5	4.546	352

In some embodiments, Form A L-lactate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 151.

In some embodiments, Form A L-lactate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 152, trace 152A.

In some embodiments, Form A L-lactate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 152, trace 152B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.9	9.914	286		17.9	4.948	1616
10.0	8.854	137		18.3	4.854	387
11.6	7.659	501		19.4	4.574	206
11.9	7.418	1151		20.1	4.411	366
13.5	6.550	426		20.4	4.347	526
14.1	6.260	421		21.1	4.217	145
14.8	5.978	409		21.4	4.144	223
15.1	5.886	798		21.8	4.081	314
15.4	5.761	515		22.7	3.917	512
15.9	5.587	1033		23.5	3.786	1061
17.0	5.205	449		24.3	3.667	712
17.4	5.093	646		25.2	3.539	689
17.6	5.045	838

In some embodiments, Form A acetate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 153.

In some embodiments, Form A acetate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 154, trace 154A.

In some embodiments, Form A acetate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 154, trace 154B.

In some embodiments, a 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, a complex form of Compound 1 is Form B acetate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.0	12.563	817		19.1	4.635	6456
9.3	9.525	583		19.8	4.478	1264
10.3	8.582	2147		20.2	4.397	519
11.6	7.653	12433		21.2	4.191	991
11.9	7.410	684		21.4	4.146	600
12.8	6.898	1315		22.4	3.971	14373
14.9	5.930	1289		23.7	3.754	3862
15.6	5.675	5401		24.2	3.678	541
16.4	5.391	2394		25.0	3.557	481
16.8	5.293	883		25.5	3.499	511
17.1	5.175	1136		26.3	3.386	863
17.6	5.042	6016		27.1	3.293	8148
18.6	4.780	868		39.0	2.311	599

In some embodiments, Form B acetate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 155.

In some embodiments, Form B acetate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 156, trace 156A.

In some embodiments, Form B acetate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 156, trace 156B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.2	10.812	249		20.0	4.444	1603
8.6	10.293	405		20.5	4.334	735
8.8	10.013	177		21.3	4.163	486
9.7	9.138	608		21.6	4.111	757
10.5	8.391	381		22.0	4.036	452
11.7	7.568	228		22.3	3.987	230
12.4	7.147	544		22.8	3.906	741
14.0	6.344	1608		23.2	3.830	854
14.3	6.197	579		23.5	3.782	1711
14.5	6.088	592		23.9	3.719	424
15.3	5.809	2343		24.7	3.602	708
15.6	5.666	1062		25.0	3.569	649
16.4	5.396	6650		25.6	3.485	1538
17.2	5.143	1430		25.7	3.461	1433
17.7	5.010	26155		26.5	3.362	939
18.6	4.768	330		26.7	3.339	944
19.3	4.594	670		27.5	3.238	416
19.7	4.507	787

In some embodiments, Form A propionate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 157.

In some embodiments, Form A propionate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 158, trace 158A.

In some embodiments, Form A propionate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 158, trace 158B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.3	10.716	1369		20.7	4.287	1046
9.9	8.927	173		21.0	4.227	369
11.3	7.856	200		21.4	4.148	267
12.4	7.142	5277		21.9	4.055	254
13.3	6.661	197		22.8	3.900	589
15.3	5.804	384		23.2	3.831	3140
15.9	5.557	989		24.2	3.675	1588
16.5	5.359	579		25.7	3.463	655
17.0	5.222	311		26.7	3.338	559
17.6	5.044	534		27.8	3.206	1626
17.8	4.974	320		28.3	3.149	257
18.8	4.727	806		28.8	3.101	236
19.9	4.457	419		29.1	3.066	826
20.2	4.403	249

In some embodiments, Form A DL-lactate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 159.

In some embodiments, Form A DL-lactate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 160, trace 160A.

In some embodiments, Form A DL-lactate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 160, trace 160B.

In some embodiments of a complex form of Compound 1, X is D-gluconic acid. In some such embodiments, a complex form of Compound 1 is a D-gluconate salt. In some embodiments, a D-gluconate salt of Compound 1 is a crystalline D-gluconate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A D-gluconate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.1	12.396	285		19.0	4.671	222
11.0	8.066	362		19.6	4.532	384
11.7	7.568	201		22.0	4.040	229
13.3	6.637	174		23.3	3.819	517
13.7	6.452	248		24.0	3.714	309
14.7	6.032	1555		25.0	3.558	305
15.1	5.871	353		25.7	3.464	307
16.1	5.495	615		26.7	3.338	183
16.5	5.377	314		27.4	3.258	187
17.2	5.158	184		32.5	2.755	110
18.3	4.848	227

In some embodiments, Form A D-gluconate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 161.

In some embodiments, Form A D-gluconate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 162.

In some embodiments of a complex form of Compound 1, X is DL-malic acid. In some such embodiments, a complex form of Compound 1 is a DL-malate salt. In some embodiments, a DL-malate salt of Compound 1 is a crystalline DL-malate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A DL-malate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.765	441		19.2	4.615	419
9.7	9.157	335		19.4	4.574	403
11.3	7.831	540		20.0	4.431	412
12.5	7.107	196		21.0	4.231	966
13.1	6.739	100		22.2	3.997	279
13.7	6.462	197		23.1	3.854	163
14.5	6.124	198		23.6	3.773	134
15.1	5.872	1636		23.9	3.725	222
16.3	5.423	569		24.3	3.656	388
16.8	5.291	460		25.1	3.542	97
17.4	5.100	166		25.8	3.459	677
18.1	4.898	179		26.3	3.388	689
18.9	4.696	284

In some embodiments, Form A DL-malate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 163.

In some embodiments, Form A DL-malate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 164, trace 164A.

In some embodiments, Form A DL-malate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 164, trace 164B.

In some embodiments, a 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, a complex form of Compound 1 is Form B DL-malate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.6	19.118	217		19.3	4.596	311
8.3	10.670	275		20.5	4.337	309
9.3	9.537	333		22.2	4.010	500
11.7	7.572	431		24.7	3.608	609
12.3	7.195	307		25.5	3.497	383
13.0	6.787	497		25.8	3.458	495
13.9	6.357	1996		26.7	3.342	544
16.0	5.548	302		28.1	3.179	466
16.4	5.392	960		29.1	3.064	129
16.6	5.327	725		30.9	2.894	221
17.4	5.089	369		33.7	2.656	215
17.9	4.942	419		34.2	2.619	352
18.6	4.769	804		37.7	2.384	268

In some embodiments, Form B DL-malate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 165.

In some embodiments, Form B DL-malate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 166, trace 166A.

In some embodiments, Form B DL-malate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 166, trace 166B.

In some embodiments of a complex form of Compound 1, X is glycolic acid. In some such embodiments, a complex form of Compound 1 is a glycolate salt. In some embodiments, a glycolate salt of Compound 1 is a crystalline glycolate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A glycolate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.4	10.465	1157		20.2	4.397	1352
8.6	10.263	1316		21.2	4.186	989
9.9	8.938	447		22.1	4.027	878
10.6	8.385	739		22.3	3.981	675
11.6	7.604	453		22.8	3.904	567
12.7	6.948	3441		23.1	3.852	502
13.2	6.688	493		23.6	3.771	3089
14.3	6.195	724		24.0	3.703	482
15.1	5.850	1011		24.6	3.621	1508
15.4	5.758	837		25.1	3.548	392
16.1	5.504	2829		25.5	3.494	366
16.9	5.251	1447		26.0	3.424	725
17.3	5.137	2668		27.4	3.258	865
18.0	4.940	2050		28.1	3.179	364
18.7	4.748	2165		28.4	3.148	716
19.3	4.594	631		28.7	3.109	389
19.9	4.459	1007

In some embodiments, Form A glycolate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 167.

In some embodiments, Form A glycolate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 168, trace 168A.

In some embodiments, Form A glycolate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 168, trace 168B.

In some embodiments of a complex form of Compound 1, X is glutaric acid. In some such embodiments, a complex form of Compound 1 is a glutarate salt. In some embodiments, a glutarate salt of Compound 1 is a crystalline glutarate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A glutarate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	11.903	2596		18.9	4.700	1339
9.5	9.277	325		19.1	4.639	816
11.1	7.939	4027		19.7	4.495	376
12.3	7.211	469		20.4	4.357	434
13.3	6.653	248		20.6	4.305	377
13.7	6.475	516		22.1	4.014	857
14.0	6.345	353		22.7	3.921	501
14.9	5.955	8673		23.4	3.807	627
16.1	5.505	2090		23.6	3.763	511
16.8	5.292	985		24.1	3.694	331
17.2	5.142	588		24.9	3.582	1602
17.7	5.012	311		26.6	3.354	888
18.6	4.765	1380		30.0	2.977	304

In some embodiments, Form A glutarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 169.

In some embodiments, Form A glutarate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 170, trace 170A.

In some embodiments, Form A glutarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 170, trace 170B.

In some embodiments, a 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, a complex form of Compound 1 is Form B glutarate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.8	18.575	499		18.4	4.813	465
5.8	15.232	432		18.7	4.744	442
9.5	9.313	511		19.0	4.663	379
11.0	8.065	889		19.7	4.496	1362
11.3	7.841	3148		20.1	4.417	1908
12.4	7.130	261		21.2	4.182	375
14.3	6.210	896		22.6	3.932	725
14.8	5.993	2426		23.2	3.828	577
15.2	5.815	458		24.4	3.653	380
15.6	5.693	661		25.2	3.528	1172
16.5	5.364	494		26.1	3.413	469
16.8	5.268	450		26.7	3.337	1354
18.2	4.888	922

In some embodiments, Form B glutarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 171.

In some embodiments, Form B glutarate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 172, trace 172A.

In some embodiments, Form B glutarate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 172, trace 172B.

In some embodiments of a complex form of Compound 1, X is L-malic acid. In some such embodiments, a complex form of Compound 1 is an L-malate salt. In some embodiments, an L-malate salt of Compound 1 is a crystalline L-malate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A L-malate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.773	1874		20.1	4.409	1420
9.6	9.176	610		20.8	4.265	647
11.3	7.846	2689		21.2	4.191	3040
12.5	7.106	565		22.3	3.991	1373
13.8	6.397	509		23.1	3.843	760
14.3	6.174	678		23.7	3.748	447
15.1	5.884	7051		24.1	3.700	355
15.3	5.780	1865		24.4	3.642	1651
16.2	5.469	1734		25.6	3.480	1951
16.7	5.319	1172		26.0	3.429	457
17.5	5.069	884		26.4	3.380	1872
18.2	4.861	751		27.2	3.283	860
18.9	4.706	1594		33.0	2.714	394
19.4	4.583	1767

In some embodiments, Form A L-malate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 173.

In some embodiments, Form A L-malate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 174, trace 174A.

In some embodiments, Form A L-malate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 174, trace 174B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.7	13.201	1499		18.4	4.823	1633
8.3	10.655	279		18.9	4.686	873
9.9	8.914	1772		20.0	4.431	2624
10.8	8.166	694		20.9	4.253	832
12.6	7.030	1234		21.1	4.206	620
13.4	6.618	326		22.4	3.972	444
15.0	5.903	2105		24.2	3.685	394
15.2	5.826	1936		24.7	3.599	1496
15.7	5.649	1281		26.3	3.395	815
16.0	5.541	1262		27.2	3.276	202
16.6	5.342	1003		29.1	3.070	149
17.2	5.144	302		31.4	2.853	258
18.2	4.869	1267		32.2	2.780	232

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

In some embodiments, Form A camphorate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 176, trace 176A.

In some embodiments, Form A camphorate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 176, trace 176B.

In some embodiments, a 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, a complex form of Compound 1 is Form B camphorate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
6.9	12.864	1434		19.3	4.591	436
8.4	10.555	453		20.0	4.432	771
9.9	8.945	1573		20.5	4.325	2213
10.3	8.591	431		20.8	4.274	1114
10.8	8.188	630		21.5	4.138	469
11.5	7.724	1177		22.1	4.025	655
12.6	7.053	620		22.5	3.945	693
13.3	6.655	678		23.3	3.823	344
15.3	5.782	3100		24.0	3.703	346
16.1	5.492	2041		24.3	3.664	356
16.8	5.279	1982		25.1	3.549	886
17.1	5.178	678		25.3	3.522	736
18.5	4.791	1001		26.1	3.410	785
18.9	4.695	1659

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

In some embodiments, Form B camphorate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 178, trace 178A.

In some embodiments, Form B camphorate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 178, trace 178B.

In some embodiments, a 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, a complex form of Compound 1 is Form C camphorate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.9	18.217	1285		18.2	4.862	368
8.7	10.197	382		19.2	4.614	597
9.7	9.092	769		19.5	4.546	3693
10.3	8.620	1117		19.9	4.455	1177
11.0	8.050	500		20.7	4.285	916
11.3	7.799	914		21.3	4.172	1047
12.5	7.082	1555		21.8	4.079	736
13.6	6.527	6278		22.1	4.023	1257
14.0	6.324	983		22.5	3.956	570
14.2	6.256	976		22.8	3.893	1137
14.4	6.165	397		25.0	3.561	422
15.5	5.720	5070		25.3	3.516	1059
16.2	5.457	3226		26.7	3.335	711
16.9	5.235	915		27.4	3.260	515
17.4	5.098	439		31.3	2.860	359
17.9	4.960	2207		34.5	2.598	420

In some embodiments, Form C camphorate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 179.

In some embodiments, Form C camphorate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 180, trace 180A.

In some embodiments, Form C camphorate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 180, trace 180B.

In some embodiments, a 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, a complex form of Compound 1 is Form D camphorate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.7	11.453	285		17.6	5.030	958
8.6	10.319	285		18.0	4.936	534
9.6	9.203	2215		19.3	4.608	1453
10.2	8.682	366		19.9	4.468	645
10.9	8.138	217		20.2	4.401	1122
12.1	7.344	2323		21.3	4.174	242
12.6	7.016	446		21.8	4.079	426
13.5	6.563	1055		22.3	3.979	228
13.9	6.363	527		23.5	3.792	423
14.7	6.017	414		24.2	3.682	834
15.3	5.782	3024		24.7	3.601	1476
15.8	5.605	1010		29.5	3.032	238
17.2	5.152	1002

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

In some embodiments, Form D camphorate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 182, trace 182A.

In some embodiments, Form D camphorate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 182, trace 182B.

In some embodiments of a complex form of Compound 1, X is DL-mandelic acid. In some such embodiments, a complex form of Compound 1 is a DL-mandelate salt. In some embodiments, a DL-mandelate salt of Compound 1 is a crystalline DL-mandelate salt. In some embodiments, a 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, a complex form of Compound 1 is Form A DL-mandelate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	11.901	1119		20.8	4.267	532
9.9	8.947	326		21.6	4.123	1109
11.1	7.936	2496		22.0	4.034	1012
12.2	7.277	929		22.5	3.948	1332
13.4	6.613	698		23.0	3.874	704
13.8	6.429	1711		23.4	3.809	2454
14.4	6.139	596		23.6	3.764	1532
14.9	5.951	5941		24.3	3.665	1444
15.2	5.823	781		24.8	3.591	554
16.3	5.452	3008		25.3	3.519	770
16.6	5.341	1880		26.0	3.431	1175
17.4	5.108	2723		26.2	3.407	875
18.6	4.758	2375		27.0	3.302	355
19.2	4.618	2360		27.8	3.208	1430
19.8	4.489	926		30.0	2.975	752
20.0	4.437	1071

In some embodiments, Form A DL-mandelate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 183.

In some embodiments, Form A DL-mandelate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 184, trace 184A.

In some embodiments, Form A DL-mandelate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 184, trace 184B.

In some embodiments, a 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, a complex form of Compound 1 is Form B DL-mandelate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.5	11.762	366		19.5	4.541	310
9.2	9.640	450		20.5	4.335	210
11.3	7.826	3039		21.3	4.179	791
13.3	6.639	469		22.7	3.913	1499
15.1	5.869	1722		23.8	3.746	629
15.9	5.567	1276		24.3	3.663	187
16.8	5.278	882		25.4	3.510	1661
18.4	4.815	951		26.1	3.413	533
18.6	4.764	862		26.4	3.375	372
18.9	4.695	495		27.7	3.222	334
19.3	4.607	413		27.9	3.193	312

In some embodiments, Form B DL-mandelate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 185.

In some embodiments, Form B DL-mandelate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 186, trace 186A.

In some embodiments, Form B DL-mandelate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 186, trace 186B.

In some embodiments, a 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, a complex form of Compound 1 is Form C DL-mandelate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.4	10.512	517		17.4	5.100	674
9.4	9.370	493		18.5	4.788	886
9.7	9.135	935		18.9	4.699	919
9.9	8.942	1064		19.2	4.634	741
10.9	8.084	900		19.5	4.556	406
11.9	7.408	368		20.4	4.358	325
13.5	6.579	787		21.7	4.100	591
14.0	6.311	1605		22.2	4.009	1142
14.6	6.055	1509		22.4	3.972	1460
15.1	5.850	524		22.7	3.913	438
15.6	5.687	427		23.1	3.850	555
15.9	5.591	708		23.6	3.769	2395
16.1	5.494	705		24.8	3.586	378
17.0	5.201	1515		26.1	3.411	1233

In some embodiments, Form C DL-mandelate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 187.

In some embodiments, Form C DL-mandelate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 188, trace 188A.

In some embodiments, Form C DL-mandelate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 188, trace 188B.

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

In some embodiments, Form A saccharin co-crystal is characterized by the following peaks in its X-ray powder diffraction pattern:

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.9	22.496	666		20.8	4.268	578
7.9	11.241	1912		21.3	4.180	235
11.8	7.495	3968		21.8	4.073	1268
12.1	7.325	285		23.5	3.787	294
13.4	6.585	454		23.9	3.720	237
15.0	5.921	1083		24.3	3.667	1453
15.8	5.623	4460		25.2	3.533	1364
16.7	5.293	691		25.5	3.496	2233
17.6	5.035	796		26.4	3.371	203
18.2	4.879	506		28.7	3.107	387
18.9	4.696	1354		29.3	3.048	312
19.7	4.498	1876		32.4	2.765	262
20.0	4.441	507

In some embodiments, Form A saccharin co-crystal is characterized by the FT-Raman spectrum depicted in FIG. 189.

In some embodiments, Form A saccharin co-crystal is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 190.

In some embodiments, Form A saccharin co-crystal is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 191, trace 191A.

In some embodiments, Form A saccharin co-crystal is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 191, trace 191B.

In some embodiments, Form A saccharin co-crystal is characterized by the ¹H NMRspectrum depicted in FIG. 192.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.3	26.862	150		17.9	4.955	8701
7.8	11.398	462		19.9	4.456	355
8.9	9.913	1721		20.3	4.375	444
10.4	8.523	344		20.9	4.256	219
11.4	7.769	213		21.2	4.199	455
11.8	7.497	121		21.7	4.102	376
12.9	6.877	260		21.9	4.067	398
13.4	6.607	238		22.6	3.929	516
14.0	6.326	1131		22.9	3.884	270
14.4	6.146	354		23.5	3.790	174
15.6	5.696	1107		24.0	3.707	305
15.9	5.587	339		25.6	3.481	800
16.8	5.264	1541		26.7	3.342	236
17.1	5.171	1315		29.4	3.038	217

In some embodiments, Form A nicotinic acid salt is characterized by the FT-Raman spectrum depicted in FIG. 193.

In some embodiments, Form A nicotinic acid salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 194.

In some embodiments, Form A nicotinic acid salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 195, trace 195A.

In some embodiments, Form A nicotinic acid salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 195, trace 195B.

In some embodiments, Form A nicotinic acid salt is characterized by the ¹H NMR spectrum depicted in FIG. 196.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.2	10.726	543		20.2	4.402	1051
9.9	8.927	244		20.7	4.299	570
12.0	7.358	402		21.0	4.230	472
12.4	7.158	3954		22.0	4.049	815
13.6	6.523	318		23.6	3.766	1242
15.3	5.775	824		24.1	3.688	431
16.0	5.535	463		24.5	3.635	1751
16.5	5.364	546		25.5	3.495	967
16.8	5.282	226		26.3	3.394	834
17.0	5.201	493		26.5	3.363	412
17.9	4.951	1106		26.9	3.316	544
18.2	4.877	1198		27.4	3.257	267
19.4	4.572	276

In some embodiments, Form B nicotinic acid salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 197.

In some embodiments, Form B nicotinic acid salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 198, trace 198A.

In some embodiments, Form B nicotinic acid salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 198, trace 198B.

In some embodiments, a 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, a complex form of Compound 1 is Form C nicotinate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.8	23.326	1156		18.7	4.733	795
7.5	11.718	2429		19.5	4.557	412
9.7	9.083	270		20.0	4.443	605
11.3	7.863	1547		20.7	4.296	262
12.0	7.362	206		21.8	4.076	308
13.4	6.617	216		22.6	3.933	411
13.9	6.370	202		23.4	3.801	371
15.0	5.902	3609		24.7	3.605	1015
16.1	5.522	794		25.0	3.560	1181
16.6	5.328	316		26.1	3.411	1023
17.4	5.110	563		27.4	3.258	219

In some embodiments, Form C nicotinic acid salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 199.

In some embodiments, Form C nicotinic acid salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 200, trace 200A.

In some embodiments, Form C nicotinic acid salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 200, trace 200B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.7	23.583	2591		21.6	4.106	405
7.5	11.791	2261		22.6	3.928	300
11.3	7.862	5996		24.5	3.638	1127
14.4	6.149	445		24.9	3.571	1401
15.0	5.897	8991		25.8	3.448	1303
16.5	5.360	128		26.4	3.374	103
17.7	5.025	241		27.0	3.308	138
18.8	4.718	1661		28.0	3.182	171
19.4	4.577	256		29.2	3.055	170
19.7	4.512	496		31.6	2.832	238
20.9	4.255	115		32.7	2.736	176

In some embodiments, Form A ascorbate salt is characterized by the FT-Raman spectrum depicted in FIG. 201.

In some embodiments, Form A ascorbate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 202.

In some embodiments, Form A ascorbate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 203, trace 203A.

In some embodiments, Form A ascorbate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 203, trace 203B.

In some embodiments, Form A ascorbate salt is characterized by the ¹H NMR spectrum depicted in FIG. 204.

In some embodiments, a 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, a complex form of Compound 1 is Form B ascorbate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.4	11.866	336		18.5	4.793	306
9.8	8.989	138		19.4	4.578	714
11.2	7.918	621		21.1	4.215	343
13.3	6.643	235		22.3	3.994	137
14.9	5.950	1565		23.4	3.797	250
15.7	5.642	381		24.0	3.711	387
16.1	5.507	689		24.7	3.603	446
16.6	5.350	380		25.4	3.510	567
17.9	4.943	233

In some embodiments, Form B ascorbate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 234.

In some embodiments, Form B ascorbate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 235, trace 235A.

In some embodiments, Form B ascorbate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 235, trace 235B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.8	23.137	642		18.1	4.903	195
7.6	11.560	2031		18.6	4.777	430
9.6	9.178	232		19.2	4.615	801
11.5	7.699	3638		19.6	4.538	325
13.3	6.669	129		21.0	4.239	193
14.4	6.160	227		21.8	4.080	504
14.8	5.971	330		23.9	3.724	224
15.4	5.771	3518		24.7	3.599	905
15.9	5.570	319		25.2	3.540	750
16.2	5.477	250		25.8	3.451	1157
17.0	5.205	119		27.1	3.294	125
17.6	5.049	227

In some embodiments, Form A gallate salt is characterized by the FT-Raman spectrum depicted in FIG. 205.

In some embodiments, Form A gallate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 206.

In some embodiments, Form A gallate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 207, trace 207A.

In some embodiments, Form A gallate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 207, trace 207B.

In some embodiments, Form A gallate salt is characterized by the ¹H NMR spectrum depicted in FIG. 208.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.8	23.137	642		18.1	4.903	195
7.6	11.560	2031		18.6	4.777	430
9.6	9.178	232		19.2	4.615	801
11.5	7.699	3638		19.6	4.538	325
13.3	6.669	129		21.0	4.239	193
14.4	6.160	227		21.8	4.080	504
14.8	5.971	330		23.9	3.724	224
15.4	5.771	3518		24.7	3.599	905
15.9	5.570	319		25.2	3.540	750
16.2	5.477	250		25.8	3.451	1157
17.0	5.205	119		27.1	3.294	125
17.6	5.049	227

In some embodiments, Form A salicylate salt is characterized by the FT-Raman spectrum depicted in FIG. 209.

In some embodiments, Form A salicylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 210.

In some embodiments, Form A salicylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 211, trace 211A.

In some embodiments, Form A salicylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 211, trace 211B.

In some embodiments, Form A salicylate salt is characterized by the ¹H NMR spectrum depicted in FIG. 212.

In some embodiments, a 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, a complex form of Compound 1 is Form B salicylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.1	17.232	1729		19.5	4.563	1056
7.0	12.673	489		19.7	4.499	754
7.6	11.569	377		20.2	4.395	1701
10.2	8.689	1626		20.5	4.333	599
10.9	8.091	2879		21.4	4.158	573
11.3	7.851	853		22.3	3.987	659
11.8	7.498	803		22.5	3.944	933
12.1	7.324	1284		23.5	3.788	1628
13.5	6.582	916		24.2	3.682	1847
13.9	6.362	5189		24.4	3.644	3120
14.4	6.145	1726		24.9	3.575	2806
14.8	5.986	1826		25.5	3.497	2266
15.2	5.814	560		25.8	3.452	2388
15.9	5.581	4446		26.1	3.420	1692
16.2	5.467	5887		26.5	3.365	720
16.5	5.364	3222		26.9	3.311	1803
16.9	5.236	1242		27.5	3.249	541
17.3	5.117	2339		27.8	3.209	799
17.6	5.025	1882		28.8	3.099	846
17.9	4.957	2126		29.4	3.043	616
18.2	4.862	2224		29.6	3.018	563
18.5	4.800	1202		29.9	2.985	539

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

In some embodiments, Form B salicylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 242, trace 242A.

In some embodiments, Form B salicylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 242, trace 242B.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.7	18.655	1952		20.0	4.445	1869
8.8	10.085	4964		20.9	4.259	4993
9.4	9.393	1731		21.3	4.174	796
10.0	8.882	2251		21.8	4.083	992
11.9	7.414	550		22.3	3.991	1178
12.9	6.877	1522		22.6	3.935	2874
13.4	6.608	477		23.3	3.814	593
13.8	6.398	1248		23.6	3.765	1551
14.6	6.085	1052		24.3	3.662	689
15.6	5.689	2119		24.8	3.594	4698
15.8	5.619	1697		25.9	3.437	973
17.0	5.211	535		26.5	3.369	697
17.6	5.053	4692		26.9	3.314	628
17.9	4.947	2829		27.6	3.231	849
18.2	4.875	685		29.9	2.986	896
18.7	4.752	1911		30.6	2.923	459
18.9	4.691	1119		32.3	2.774	596

In some embodiments, Form A orotate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 213.

In some embodiments, Form A orotate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 214, trace 214A.

In some embodiments, Form A orotate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 214, trace 214B.

In some embodiments, a 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, a complex form of Compound 1 is Form D orotate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
4.8	18.504	1897		20.0	4.441	1897
7.6	11.582	251		20.7	4.297	840
8.6	10.241	1674		21.1	4.203	2559
9.5	9.332	1235		22.2	4.013	1809
10.0	8.842	1160		22.8	3.898	461
11.8	7.472	406		23.8	3.740	1177
13.0	6.789	891		24.5	3.631	2398
13.4	6.585	741		26.2	3.401	920
14.0	6.338	741		27.6	3.237	406
15.5	5.701	1496		28.1	3.179	345
16.4	5.408	629		28.9	3.087	422
17.3	5.139	2086		30.0	2.978	325
17.9	4.960	2069		31.8	2.811	273
18.6	4.769	1355		35.0	2.562	86
19.2	4.630	1987

In some embodiments, Form D orotate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 217.

In some embodiments, Form D orotate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 218, trace 218A.

In some embodiments, Form D orotate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 218, trace 218B.

In some embodiments, a 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, a complex form of Compound 1 is Form F orotate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.5	25.010	646		15.2	5.821	307
4.4	20.183	764		15.7	5.640	445
5.0	17.790	2831		16.3	5.437	360
6.2	14.222	553		17.1	5.174	311
7.1	12.508	172		17.7	5.014	720
7.4	11.903	285		18.3	4.854	193
7.9	11.155	195		18.7	4.747	127
8.7	10.186	569		19.5	4.544	216
9.1	9.728	159		19.9	4.457	312
9.9	8.902	779		21.5	4.136	220
10.5	8.425	312		22.6	3.942	147
12.4	7.164	1405		23.3	3.813	122
14.4	6.151	358		24.3	3.664	149
14.9	5.945	1661

In some embodiments, Form F orotate salt is characterized by the FT-Raman spectrum depicted in FIG. 222.

In some embodiments, Form F orotate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 223.

In some embodiments, Form F orotate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 224, trace 224A.

In some embodiments, Form F orotate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 224, trace 224B.

In some embodiments, Form F orotate salt is characterized by the ¹H NMR spectrum depicted in FIG. 225.

In some embodiments, a 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, a complex form of Compound 1 is Form H orotate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
5.3	16.565	4288		19.9	4.467	281
7.9	11.163	394		20.3	4.370	1684
9.0	9.836	2846		20.9	4.256	402
10.7	8.303	548		21.3	4.171	568
11.4	7.768	503		22.4	3.970	685
11.9	7.440	1127		22.9	3.891	297
13.9	6.364	1616		23.9	3.723	775
14.9	5.958	368		24.7	3.611	798
15.4	5.737	843		25.1	3.547	319
16.1	5.504	630		25.9	3.437	304
16.8	5.273	1243		26.8	3.324	303
17.8	4.993	326		27.8	3.209	910
18.6	4.781	441		31.2	2.871	194

In some embodiments, Form H orotate salt is characterized by the FT-Raman spectrum depicted in FIG. 226.

In some embodiments, Form H orotate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 227.

In some embodiments, Form H orotate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 228, trace 228A.

In some embodiments, Form H orotate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 228, trace 228B.

In some embodiments, Form H orotate salt is characterized by the ¹H NMR spectrum depicted in FIG. 229.

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

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.6	11.603	5471		19.7	4.509	1985
9.4	9.378	1061		20.4	4.360	888
10.3	8.588	1592		20.7	4.296	2084
11.4	7.736	6082		20.9	4.256	4376
12.1	7.301	876		22.0	4.048	1835
12.4	7.111	966		22.4	3.973	1088
13.5	6.575	2288		22.8	3.900	5590
13.7	6.453	908		23.4	3.805	3229
14.2	6.253	2775		24.0	3.715	10155
15.3	5.806	13560		25.4	3.512	7991
15.8	5.619	925		25.8	3.449	9706
16.1	5.512	8968		26.2	3.400	2772
16.8	5.278	1645		27.3	3.271	5630
17.3	5.124	1781		28.3	3.154	694
18.1	4.905	1155		29.5	3.024	759
18.3	4.853	862		30.0	2.978	879
18.8	4.727	1013		35.1	2.559	742
19.1	4.639	6875

In some embodiments, a 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, a complex form of Compound 1 is Form B acetylsalicylate salt.

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

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
3.6	24.798	1917		15.7	5.645	704
5.0	17.698	1054		15.9	5.568	711
5.6	15.849	1538		16.7	5.315	609
7.0	12.558	1794		17.3	5.138	2598
7.9	11.234	727		17.6	5.046	447
9.0	9.870	794		18.1	4.902	1005
9.9	8.901	1850		18.9	4.683	1589
10.5	8.399	1925		19.4	4.570	1256
12.7	6.983	703		19.8	4.491	1042
12.9	6.839	605		21.5	4.143	576
13.4	6.621	2571		22.6	3.942	1160
14.1	6.290	987		23.3	3.825	1164
15.1	5.863	1298		23.6	3.774	1698

In some embodiments, Form B acetylsalicylate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in FIG. 239.

In some embodiments, Form B acetylsalicylate salt is characterized by the thermogravimetric analysis (TGA) pattern depicted in FIG. 240, trace 240A.

In some embodiments, Form B acetylsalicylate salt is characterized by the differential scanning calorimetry (DSC) pattern depicted in FIG. 240, trace 240B.

Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

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 compositions of this disclosure is such that it is effective to measurably inhibit JAK2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.

Compounds and compositions, according to method of the present invention, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein (i.e., a JAK2-mediated disease or disorder). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compound 1, or a crystalline form or complex thereof, is preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of Compound 1, or a crystalline form or complex thereof, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of Compound 1, or a crystalline form or complex thereof, then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered Compound 1, or a crystalline form or complex thereof, is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, 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 entrapping Compound 1, or a crystalline form or complex thereof, in liposomes or microemulsions that are compatible with body tissues.

In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, Compound 1, or a crystalline form or complex thereof, is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and/or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, 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. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Compound 1, or a crystalline form or complex thereof, can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms Compound 1, or a crystalline form or complex thereof, may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, 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.

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 a crystalline form or complex thereof, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing Compound 1, or a crystalline form or complex thereof, with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing Compound 1, or a crystalline form or complex thereof, with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a 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.

Pharmaceutically acceptable compositions of this 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, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing Compound 1, or a crystalline form or complex thereof, suspended or dissolved in one or more carriers. Carriers for topical administration of Compound 1, or a crystalline form or complex thereof, include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing Compound 1, or a crystalline form or complex thereof, 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of this 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, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Dosage forms for topical or transdermal administration of Compound 1, or a crystalline form or complex thereof, include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Compound 1, or a crystalline form or complex thereof, is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of Compound 1, or a crystalline form or complex thereof, to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of Compound 1, or a crystalline form or complex thereof, across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing Compound 1, or a crystalline form or complex thereof, in a polymer matrix or gel.

In some embodiments, compositions described herein comprise an amount of Compound 1, or a crystalline form or complex thereof, that is the molar equivalent to 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., 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) comprises 117.30 mg of a dihydrochloride monohydrate form of Compound 1 (MW = 614.22).

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.

In some embodiments, the binder is a microcrystalline cellulose. In some such embodiments, the microcrystalline cellulose is silicified microcrystalline cellulose.

In some embodiments, the binder is sodium stearyl fumarate.

In some embodiments, the composition comprises:

Component                        Amount
Compound 1 (free base)           100 mg
silicified microcrystalline cellulose (high density 90 µm) 178.45 mg
sodium stearyl fumarate          3.0 mg
TOTAL                            281.45 mg

In certain embodiments, the composition comprises:

Component                        Amount
Compound 1 2HCl•H2O (calculated based on the parent free base) 117.30 mg (100 mg parent free base)
silicified microcrystalline cellulose (high density 90 µm) 178.45 mg
sodium stearyl fumarate          3.0 mg
TOTAL                            298.75 mg

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes. Examples of kinases that are inhibited by the compounds and compositions described herein and against which the methods described herein are useful include JAK2, or a mutant thereof.

The activity of Compound 1, or a crystalline form or complex thereof, utilized as an inhibitor of a JAK2 kinase, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated JAK2 kinase, or a mutant thereof.

According to one embodiment, the invention relates to a method of inhibiting protein kinase activity in a biological sample comprising the step of contacting said biological sample with Compound 1, or a crystalline form or complex thereof, or a composition thereof.

According to another embodiment, the invention relates to a method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with Compound 1, or a crystalline form or complex thereof, or a composition thereof.

According to another embodiment, the invention relates to a method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient Compound 1, or a crystalline form or complex thereof, or a composition thereof. In other embodiments, the present disclosure provides a method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to said patient Compound 1, or a crystalline form or complex thereof, or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

Compound 1, or a crystalline form or complex thereof, is useful in treating a variety of disorders, including, but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy and other angiogenic-associated disorders including solid tumors and other types of cancer, eye disease, inflammation, psoriasis, and a viral infection. The kinds of cancer that can be treated include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

Some examples of the diseases and disorders that can be treated also include ocular neovasculariaztion, infantile haemangiomas; organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 diabetes and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic, dermatitits, autoimmune thryroid disorders, ulerative colitis, Crohn’s disease, metastatic melanoma, Kaposi’s sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritis,, scleroderma, chronic thyroiditis, Graves’ disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia graivs, multiple scleroiss, inflammatory bowel disease, graft vs host disease, neurodegenerative diseases including motor neuron disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral scelerosis, Huntington’s disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, and platelet aggregation.

Examples of some additional diseases and disorders 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, Vaicella-Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.

In some embodiments, Compound 1, or a crystalline form or complex thereof, is useful in treating a treating 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.

In some embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with a JAK2 inhibitor. In some such embodiments, a provided method comprises administering Compound 1, or a crystalline form or complex thereof, to a patient previously treated with ruxolitinib (JAKAFI®).

In some embodiments, a provided method comprises 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 is suffering from or has been diagnosed with a myeloproliferative disorder that is refractory or resistant to ruxolitinib.

In some embodiments, the patient has relapsed during or following ruxolitinib therapy.

In some embodiments, the patient is intolerant to ruxolitinib. In some embodiments, patient intolerance to ruxolitinib is evidenced by a hematological toxicity (e.g., anemia, thrombocytopenia, etc.) or a non-hematological toxicity.

In some embodiments, the patient has had an inadequate response to or is intolerant to hydroxyurea.

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.

In some embodiments, a 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 a 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.

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.

In some embodiments, a myeloproliferative disorder is selected from intermediate risk myelofibrosis and high risk myelofibrosis.

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 1 (also referred to as intermediate-1 risk). In some embodiments, the myelofibrosis is intermediate risk 2 (also referred to as intermediate-2 risk).

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.

In some embodiments, the present disclosure provides an article of manufacture comprising a packaging material and a pharmaceutical composition contained within the packaging material. In some embodiments, the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of one or more disorders identified above.

Additional Embodiments

Embodiment 1. A crystalline form of Compound 1:

Embodiment 2. The crystalline form of embodiment 1, wherein the form is unsolvated.

Embodiment 3. The crystalline form of embodiment 2, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.6, 19.5, 24.3, and 25.6 ± 0.2 degrees 2θ.

Embodiment 4. The crystalline form of embodiment 2, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.8	10.102	1414		20.4	4.360	4156
9.7	9.120	88376		21.0	4.229	4358
10.5	8.463	2192		22.7	3.914	1551
13.6	6.516	1881		23.0	3.874	2648
14.6	6.082	50409		23.5	3.781	1611
16.0	5.543	3640		23.9	3.730	9006
16.4	5.413	2620		24.3	3.660	13329
17.7	5.014	3311		24.6	3.614	1849
18.5	4.797	5807		25.6	3.479	7883
19.1	4.637	1316		28.0	3.192	1510
19.5	4.563	6885		28.6	3.119	1592
19.8	4.492	1686		29.4	3.043	2105
20.1	4.415	1686

Embodiment 5. The crystalline form of embodiment 1, wherein the form is solvated.

Embodiment 6. The crystalline form of embodiment 5, wherein the form is a 2-methyltetrahydrofuran solvate.

Embodiment 7. The crystalline form of embodiment 6, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.5, 18.3, 18.9, 20.1, and 23.8 ± 0.2 degrees 2θ.

Embodiment 8. The crystalline form of embodiment 6, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

Position °2θ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.6	11.633	715		23.8	3.734	25579
10.2	8.690	521		25.5	3.498	1600
11.9	7.430	2468		26.0	3.433	1425
12.5	7.096	3531		27.6	3.231	1295
12.7	6.963	2843		28.3	3.149	1147
14.1	6.265	2984		28.9	3.090	556
14.5	6.096	1620		30.4	2.937	356
16.1	5.494	2249		31.7	2.824	477
18.3	4.836	6390		34.2	2.620	224
18.9	4.699	5752		35.5	2.530	569
20.1	4.411	6304		36.0	2.497	405
21.4	4.147	1605		36.9	2.434	141
23.1	3.853	1981

Embodiment 9. The crystalline form of embodiment 1, wherein the form is a hydrate.

Embodiment 10. The crystalline form of embodiment 9, wherein the form is a monohydrate.

Embodiment 11. The crystalline form of embodiment 10, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.7, 15.2, 17.3, 18.0, and 19.4 ± 0.2 degrees 2θ.

Embodiment 12. The crystalline form of embodiment 10, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
8.7	10.184	23473		22.1	4.017	7400
10.6	8.332	6912		22.4	3.974	6455
14.4	6.172	8862		22.8	3.894	6416
15.2	5.825	11716		23.2	3.841	3537
15.5	5.719	3493		23.5	3.783	7215
16.3	5.439	5672		24.4	3.647	4592
16.6	5.329	5294		25.0	3.559	4787
16.9	5.244	7167		25.2	3.540	4028
17.3	5.120	51890		26.1	3.414	4525
18.0	4.917	15095		26.6	3.356	4349
19.4	4.578	10908		27.4	3.255	5512
20.2	4.388	8419		27.6	3.231	4683
21.8	4.078	5043

Embodiment 13. The crystalline form of embodiment 9, wherein the form is a tetrahydrate.

Embodiment 14. The crystalline form of embodiment 13, wherein the form 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.

Embodiment 15. The crystalline form of embodiment 13, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]		Position °2θ ± 0.2 degrees	d-spacing [Å]	Height [cts]
7.7	11.475	1223		20.0	4.435	3039
11.8	7.529	1943		20.3	4.380	4906
12.0	7.372	2255		20.8	4.267	1987
12.4	7.142	4460		21.3	4.163	1495
12.9	6.874	1805		21.9	4.066	999
13.4	6.619	1735		22.7	3.925	836
14.1	6.282	2143		23.6	3.770	22852
14.5	6.122	1529		24.8	3.585	1474
15.4	5.772	1552		25.8	3.453	907
16.4	5.397	3326		26.2	3.405	1278
18.5	4.800	7100		27.0	3.306	1347
19.3	4.591	4008		28.5	3.133	823
19.7	4.497	2119

Embodiment 16. A sample comprising the crystalline form of any one of embodiments 1-15, wherein the sample is substantially free of impurities.

Embodiment 17. The sample of embodiment 16, wherein the sample comprises at least about 90% by weight of Compound 1.

Embodiment 18. The sample of embodiment 16, wherein the sample comprises at least about 95% by weight of Compound 1.

Embodiment 19. The sample of embodiment 16, wherein the sample comprises at least about 99% by weight of Compound 1.

Embodiment 20. The sample of embodiment 16, wherein the sample comprises no more than about 5.0 percent of total organic impurities.

Embodiment 21. The sample of embodiment 16, wherein the sample comprises no more than about 3.0 percent of total organic impurities.

Embodiment 22. The sample of embodiment 16, wherein the sample comprises no more than about 1.5 percent of total organic impurities.

Embodiment 23. The sample of embodiment 16, wherein the sample comprises no more than about 1.0 percent of total organic impurities.

Embodiment 24. The sample of embodiment 16, wherein the sample comprises no more than about 0.5 percent of total organic impurities.

Embodiment 25. A complex comprising Compound 1:

and a co-former X; wherein the complex is crystalline and 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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

Embodiment 26. A complex comprising Compound 1:

and a co-former X; wherein:

• 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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

Embodiment 27. The complex of embodiment 25, wherein X is hydrobromic acid.

Embodiment 28. The complex of embodiment 25, wherein X is sulfuric acid.

Embodiment 29. The complex of embodiment 25, wherein X is toluenesulfonic acid.

Embodiment 30. The complex of embodiment 25, wherein X is methanesulfonic acid.

Embodiment 31. The complex of embodiment 25 or embodiment 26, wherein X is 2-naphthalenesulfonic acid.

Embodiment 32. The complex of embodiment 25, wherein X is phosphoric acid.

Embodiment 33. The complex of embodiment 25, wherein X is DL-tartaric acid.

Embodiment 34. The complex of embodiment 25 or embodiment 26, wherein X is succinic acid.

Embodiment 35. The complex of embodiment 25 or embodiment 26, wherein X is gentisic acid.

Embodiment 36. The complex of embodiment 25 or embodiment 26, wherein X is hippuric acid.

Embodiment 37. The complex of embodiment 25 or embodiment 26, wherein X is adipic acid.

Embodiment 38. The complex of embodiment 25 or embodiment 26, wherein X is galactaric acid.

Embodiment 39. The complex of embodiment 25 or embodiment 26, wherein X is 1,5-naphthalenedisulfonic acid.

Embodiment 40. The complex of embodiment 25 or embodiment 26, wherein X is (S)-camphorsulfonic acid.

Embodiment 41. The complex of embodiment 25 or embodiment 26, wherein X is 1,2-ethanedisulfonic acid.

Embodiment 42. The complex of embodiment 25 or embodiment 26, wherein X is ethanesulfonic acid.

Embodiment 43. The complex of embodiment 25 or embodiment 26, wherein X is benzenesulfonic acid.

Embodiment 44. The complex of embodiment 25, wherein X is oxalic acid.

Embodiment 45. The complex of embodiment 25 or embodiment 26, wherein X is maleic acid.

Embodiment 46. The complex of embodiment 25 or embodiment 26, wherein X is pamoic acid.

Embodiment 47. The complex of embodiment 25 or embodiment 26, wherein X is 1-hydroxy-2-naphthoic acid.

Embodiment 48. The complex of embodiment 25 or embodiment 26, wherein X is malonic acid.

Embodiment 49. The complex of embodiment 25, wherein X is L-tartaric acid.

Embodiment 50. The complex of embodiment 25 or embodiment 26, wherein X is fumaric acid.

Embodiment 51. The complex of embodiment 25, wherein X is citric acid.

Embodiment 52. The complex of embodiment 25 or embodiment 26, wherein X is L-lactic acid.

Embodiment 53. The complex of embodiment 25, wherein X is acetic acid.

Embodiment 54. The complex of embodiment 25 or embodiment 26, wherein X is propionic acid.

Embodiment 55. The complex of embodiment 25 or embodiment 26, wherein X is DL-lactic acid.

Embodiment 56. The complex of embodiment 25 or embodiment 26, wherein X is D-gluconic acid.

Embodiment 57. The complex of embodiment 25 or embodiment 26, wherein X is DL-malic acid.

Embodiment 58. The complex of embodiment 25 or embodiment 26, wherein X is glycolic acid.

Embodiment 59. The complex of embodiment 25 or embodiment 26, wherein X is glutaric acid.

Embodiment 60. The complex of embodiment 25 or embodiment 26, wherein X is L-malic acid.

Embodiment 61. The complex of embodiment 25 or embodiment 26, wherein X is camphoric acid.

Embodiment 62. The complex of embodiment 25, wherein X is DL-mandelic acid.

Embodiment 63. The complex of embodiment 25 or embodiment 26, wherein X is saccharin.

Embodiment 64. The complex of embodiment 25 or embodiment 26, wherein X is nicotinic acid.

Embodiment 65. The complex of embodiment 25 or embodiment 26, wherein X is ascorbic acid.

Embodiment 66. The complex of embodiment 25 or embodiment 26, wherein X is gallic acid.

Embodiment 67. The complex of embodiment 25 or embodiment 26, wherein X is salicylic acid.

Embodiment 68. The complex of embodiment 25 or embodiment 26, wherein X is orotic acid.

Embodiment 69. The complex of embodiment 25 or embodiment 26, wherein X is acetylsalicylic acid.

Embodiment 70. A sample comprising the complex of any one of embodiments 25-69, wherein the sample is substantially free of impurities.

Embodiment 71. The sample of embodiment 70, wherein the sample comprises at least about 90% by weight of the complex.

Embodiment 72. The sample of embodiment 70, wherein the sample comprises at least about 95% by weight of the complex.

Embodiment 73. The sample of embodiment 70, wherein the sample comprises at least about 99% by weight of the complex.

Embodiment 74. The sample of embodiment 70, wherein the sample comprises no more than about 5.0 percent of total organic impurities.

Embodiment 75. The sample of embodiment 70, wherein the sample comprises no more than about 3.0 percent of total organic impurities.

Embodiment 76. The sample of embodiment 70, wherein the sample comprises no more than about 1.5 percent of total organic impurities.

Embodiment 77. The sample of embodiment 70, wherein the sample comprises no more than about 1.0 percent of total organic impurities.

Embodiment 78. The sample of embodiment 70, wherein the sample comprises no more than about 0.5 percent of total organic impurities.

Embodiment 79. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a crystalline form of any one of embodiments 1-15, or a composition thereof.

Embodiment 80. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient a crystalline form of any one of embodiments 1-15, or a composition thereof.

Embodiment 81. A method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to the patient a crystalline form of any one of embodiments 1-15, or pharmaceutically acceptable composition thereof.

Embodiment 82. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a complex of any one of embodiments 25-69, or a composition thereof.

Embodiment 83. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient a complex of any one of embodiments 25-69, or a composition thereof.

Embodiment 84. A method for treating a JAK2-mediated disease or disorder, 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.

Embodiment 85. The complex of embodiment 27, wherein the complex comprises one equivalent of hydrobromic acid.

Embodiment 86. The complex of embodiment 27, wherein the complex comprises two equivalents of hydrobromic acid.

Embodiment 87. The complex of embodiment 28, wherein the complex comprises 0.5 equivalents of sulfuric acid.

Embodiment 88. The complex of embodiment 29, wherein the complex comprises one equivalent of toluenesulfonic acid.

Embodiment 89. The complex of embodiment 30, wherein the complex comprises 1.2 equivalents of methanesulfonic acid.

Embodiment 90. The complex of embodiment 31, wherein the complex comprises 1.5 equivalents of 2-naphthalenesulfonic acid.

Embodiment 91. The complex of embodiment 32, wherein the complex comprises one equivalent of phosphoric acid.

Embodiment 92. The complex of embodiment 33, wherein the complex comprises one equivalent of DL-tartaric acid.

Embodiment 93. The complex of embodiment 34, wherein the complex comprises one equivalent of succinic acid.

Embodiment 94. The complex of embodiment 35, wherein the complex comprises one equivalent of gentisic acid.

Embodiment 95. The complex of embodiment 36, wherein the complex comprises one equivalent of hippuric acid.

Embodiment 96. The complex of embodiment 37, wherein the complex comprises 0.9 equivalents of adipic acid.

Embodiment 97. The complex of embodiment 38, wherein the complex comprises one equivalent of galactaric acid.

Embodiment 98. The complex of embodiment 63, wherein the complex comprises one equivalent of saccharin.

Embodiment 99. The complex of embodiment 64, wherein the complex comprises one equivalent of nicotinic acid.

Embodiment 100. The complex of embodiment 65, wherein the complex comprises one equivalent of ascorbic acid.

Embodiment 101. The complex of embodiment 66, wherein the complex comprises one equivalent of gallic acid.

Embodiment 102. The complex of embodiment 68, wherein the complex comprises one equivalent of orotic acid.

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.

Embodiment 104. The complex of embodiment 28, wherein the complex is a heterosolvate.

Embodiment 105. The complex of embodiment 104, wherein the heterosolvate is water:tetrahydrofuran.

Embodiment 106. The complex of any one of embodiments 28, 32, and 91, wherein the complex is a solvate.

Embodiment 107. The complex of embodiment 106, wherein the solvate is an acetone solvate.

Embodiment 108. The complex of embodiment 106, wherein the solvate is a methanol solvate.

Exemplification

Instrumentation

FT-Raman Spectroscopy. Raman spectra were collected with a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) equipped with 1064 nm Nd:YVO₄ excitation laser, InGaAs and liquid-N₂ cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm^-1 resolution, 64 scans, using Happ-Genzel apodization function and 2-level zero-filling.

Powder X-Ray Diffraction (PXRD or XRPD). PXRD (or XRPD) diffractograms were acquired on PANalytical X′Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.02°2θ and X′celerator™ RTMS (Real Time Multi-Strip) detector. Configuration on the incidental beam side: fixed divergence slit (0.25°), 0.04 rad Soller slits, 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. Samples were mounted flat on zero-background Si wafers.

Differential Scanning Calorimetry (DSC). DSC was conducted with a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N₂ purge. DSC thermograms were obtained at 15° C./min in crimped Al pans.

Thermogravimetric Analysis (TGA). TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N₂ purge at 15° C./min in Pt or Al pans.

Thermogravimetric Analysis with IR Off-Gas Detection (TGA-IR). TGA-IR was conducted with a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGA-IR module with a gas flow cell and DTGS detector. TGA was conducted with 60 mL/min N₂ flow and heating rate of 15° C./min in Pt or Al pans. IR spectra were collected at 4 cm^-1 resolution and 32 scans at each time point.

High-performance Liquid Chromatography (HPLC). HPLC analyses were conducted with an HP1100 system equipped with a G1131 Quad pump, G1367A autosampler, and G1315B diode array detector. Column: Luna C18(2) (50 × 2.0 mm, 3 µm). Mobile phase: 100% water (0.05%TFA) to 95% ACN (0.05% TFA) over 8 min and 2 min re-equilibration. Flow rate: 1 mL/min. Detection: 254 nm.

Proton Nuclear Magnetic Resonance (¹H NMR). Solution for ¹H NMR was prepared by dissolving the solids in DMSO-d6. The spectra were collected using Agilent DD2 500 MHz spectrometer with TMS reference.

Ion Chromatography (IC). Ion chromatography was performed on a Dionex ICS-3000. Column: Dionex IonPac AS12A 4x200mm; Detection: Suppressed conductivity, ASRS 300 with suppressor current at 22 mA; Eluent (2.7 mM Na₂CO₃/0.3 mM NaHCO₃) at 1.5 mL/min.

Example 1. Compound 1 Free Base (Form C)

Compound 1 dihydrochloride (44.5 g) was dissolved in water (498 mL). Aqueous sodium hydroxide (2.0 eq; 5N; 28.9 mL) was slowly added, followed by acetonitrile (80 mL) and crystalline seeds of Compound 1 Form C (400 mg). The suspension was stirred at RT for 2 hours. The crystalline solids were isolated via vacuum filtration, washed with water (2 × 100 mL) and MTBE (2 × 50 mL), and air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. with nitrogen bleed for 24 hours. The yield of crystalline free base was 97.5% (37 g).

Compound 1 Form C is a white crystalline powder and was characterized by XRPD (FIG. 5), TGA (FIG. 6A), DSC (FIG. 6B) and DVS (FIG. 7). Thermal data shows that the free base is a monohydrate form 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.

Solubility of Compound 1 free base (Form C) was estimated by visual assessment of dissolution in various solvents at RT and 40° C. Aliquots of solvents were added to 10 mg of free base at RT until complete dissolution or until a maximum volume of 1.8 mL was added. Suspensions not dissolved at RT were heated to 40° C. and checked for dissolution. Following visual solubility assessment, additional Form C was added to the samples which dissolved to yield thin suspensions. The suspensions were stirred at RT for 18 h, and the solids were isolated by vacuum-filtration. The solids were analyzed by PXRD and compared to the parent groups identified during the concurrent salt screening.

Example 2. Primary Salt Screen of Fedratinib

Fedratinib has two basic sites (pK_a = 9.3, 6.4) for salt formation. Fifty-three counterions and stoichiometric combinations were selected. Table 1 provides a summary of the additives, pK_a values, method of dosing and equivalents dosed for each additive.

Additives Utilized in the Screening Studies
No.	Additive	Dosing Method	pKa	Equivalents Dosed
1	HBr	3 M solution in water	<-6	1, 2
2	Naphthalene-1,5-disulfonic acid	1.5 M solution in water	-3.4, -2.6	0.5, 1
3	Sulfuric acid	2.5 M solution in water	-3, 1.9	0.5, 1
4	Camphor-10-sulfonic acid	3 M solution in water	-2.2	1, 2
5	Ethane-1,2-disulfonic acid	3 M solution in water	-2.1, -1.5	0.5, 1
6	Ethanesulfonic acid	3 M solution in water	-2.1	1, 2
7	p-Toluenesulfonic acid	3 M solution in water	-1.3	1, 2
8	Methanesulfonic acid	3 M solution in water	-1.2	1, 2
9	Naphthalene-2-sulfonic acid	3 M solution in THF	0.2	1, 2
10	Benzenesulfonic acid	3 M solution in water	0.7	1, 2
11	Oxalic acid	0.5 M solution in water	1.3	1
12	Maleic acid	3 M solution in water	1.9, 6.2	1
13	Phosphoric acid	3 M solution in water	2, 7.1, 12.3	1
14	Glutamic acid	Dosed as solid	2.2, 4.3, 9.7	1
15	Pamoic acid	Dosed as solid	2.5, 3.1	1
16	1-Hydroxy-2-naphthoic acid	Dosed as solid	2.7	1
17	Malonic acid	3 M solution in water	2.8, 5.7	1
18	Gentisic acid	Dosed as solid	2.9	1
19	L-Tartaric acid	3 M solution in water	3, 4.4	1
20	DL-Tartaric acid	1.5 M solution in water	3, 4.4	1
21	Fumaric acid	0.2 M solution in EtOH	3, 4.4	1
22	Citric acid	3 M solution in water	3.1, 4.8, 6.4	1
23	Galactaric (Mucic) acid	Dosed as solid	3.1, 3.6	1
24	Glycolic acid	Dosed as solid	3.3	1
25	L-Mandelic acid	1 M solution in water	3.4	1
26	DL-Mandelic acid	Dosed as solid	3.4	1
27	L-Malic acid	Dosed as solid	3.5, 5.1	1
28	DL-Malic acid	Dosed as solid	3.5, 5.1	1
29	Hippuric acid	Dosed as solid	3.6	1
30	D-Gluconic acid	3.14 M solution in water	3.8	1
31	L-Aspartic acid	Dosed as solid	3.9	1
32	L-Lactic acid	3 M solution in water	3.9	1
33	DL-Lactic acid	12.1 M solution in water	3.9	1
33	Benzoic acid	Dosed as solid	4.2	1
34	Succinic acid	1 M solution in MeOH	4.2, 5.6	1
35	Glutaric acid	Dosed as solid	4.3, 5.3	1
36	Adipic acid	Dosed as solid	4.4, 5.4	1
37	Acetic acid	3 M solution in water	4.8	1
38	Camphoric acid	Dosed as solid	4.7, 5.8	1
39	Propionic acid	3 M solution in water	4.9	1
40	Choline Hydroxide	4.6 M solution in water	>11	1
41	Potassium Hydroxide	1 M solution in water	~14	1
42	Sodium Hydroxide	5 M solution in water	~14	1

Multiple modes of crystallization were utilized for the salt screening studies and are as follows:

• 1. Temperature-cycled ripening of solutions/suspensions between 40° C. and 5° C. for two days.
• 2. Fast evaporation of solvents under reduced pressure.
• 3. Cooling of solutions at 5° C. for up to two days.
• 4. Slow evaporation of solvents at RT for up to seven days.

All samples were examined for crystallinity by polarized light microscopy (PLM) at the end of each crystallization mode. If an experiment yielded a birefringent hit, the solids were isolated by vacuum filtration, air-dried for up to two hours with vacuum pull at room temperature. The solids were analyzed by FT-Raman spectroscopy and/or PXRD.

FT-Raman spectra/PXRD pattern of samples prepared using the same additive were compared to determine whether they were the same crystal form. Representative samples from each unique group were subjected to further characterization using PXRD, DSC, TGA and TGA-IR analyses (as appropriate).

The results from the salt screening study are summarized in Table 2. Salt screening experiments led to crystalline salt hits from 36 of the 42 unique additives. All remaining experiments yielded non-crystalline products (gums/amorphous glassy material) and were not isolated.

Results from Salt Screening of Fedratinib
No.	Additive (Eq.)	Solvents
MTBE	MIBK	EtOAc	THF	Acetone	IPA	CH3CN	MeOH
1	HBr (1 eq)	A	A	A	A	A	A	A	A
2	HBr (2 eq)	B	1	B	1	B	B	B	B
3	Naphthalenedisulfonic acid (0.5 eq)	A	A	A	G/O	A	A, 2	B	C, 2
4	Naphthalenedisulfonic acid (1 eq)	A	1	1	G/O	A, 2	B, 2	G/O	C
5	Sulfuric acid (0.5 eq)	FB	FB	FB	B	A	FB	FB	FB
6	Sulfuric acid (1 eq)	A	A	A	B	B	B	C	B
7	S-Camphor-10-sulfonic acid (1 eq)	G/O	G/O	G/O	G/O	G/O	G/O	G/O	G/O
8	S-Camphor-10-sulfonic acid (2 eq)	G/O	A	B	G/O	A	G/O	G/O	G/O
9	1,2-Ethanedisulfonic acid (0.5 eq)	FB	FB	FB	C, 2	B	FB	FB	A
10	1,2-Ethanedisulfonic acid (1 eq)	G/O	C	G/O	G/O	B	D	A	A
11	Ethanesulfonic acid (1 eq)	G/O	FB	FB	A	G/O	FB	G/O	G/O
12	Ethanesulfonic acid (2 eq)	B	FB	B	B	B	A	B	A
13	Toluenesulfonic acid (1 eq)	A, 2	A	A	A	A	A	A	A
14	Toluenesulfonic acid (2 eq)	G/O	G/O	G/O	G/O	G/O	B	G/O	G/O
15	Methanesulfonic acid (1 eq)	1	1	1	1	A	B	G/O	G/O
16	Methanesulfonic acid (2 eq)	G/O	C	G/O	G/O	C	C	G/O	G/O
17	2-Naphthalenesulfonic acid (1 eq)	A, 2	A	A	A	A	A	A	A
18	2-Naphthalenesulfonic acid (2 eq)	A	A	A	A	A	A	A	A
19	Benzenesulfonic acid (1 eq)	G/O	G/O	A	B	G/O	C	D	G/O
20	Benzenesulfonic acid (2 eq)	G/O	G/O	G/O	G/O	G/O	G/O	G/O	G/O
21	Oxalic acid (1 eq)	B	B	A	A	A	A	A	A
22	Maleic acid (1 eq)	A	A	A	A, 2	G/O	A	G/O	G/O
23	Phosphoric acid (1 eq)	A	A	A	C	B	B	B	D
24	Glutamic acid (1 eq)	FB	FB	FB	CI	CI	CI	CI	CI
25	Pamoic acid (1 eq)	A, 2	A	A	A	A	A	A	A
26	1-Hydroxy-2-napthoic acid (1 eq)	CI	FB	CI	G/O	G/O	A	G/O	G/O
27	Malonic acid (1 eq)	A	A	A	A	G/O	B	C	G/O
28	L-Tartaric acid (1 eq)	A	B	C	C	B	C	D	G/O
29	DL-Tartaric acid (1 eq)	B	A	A	A	A	A	A	A
30	Fumaric acid (1 eq)	A	B	B	E	A	A, B	C	D
31	Citric acid (1 eq)	A	A, FB	A, FB	A	A	A, FB	G/O	G/O
32	L-Mandelic acid (1 eq)	FB	FB	FB	G/O	G/O	FB	FB	FB
33	L-Lactic acid (1 eq)	A	A	A	G/O	G/O	A	A	G/O
34	Succinic acid (1 eq)	A	A	A	1	1	A	1	G/O
35	Acetic acid (1 eq)	B	A	A	B	A	FB	A	G/O
36	Propionic acid (1 eq)	A	FB	FB	FB	A	FB	FB	A
37	NaOH (1 eq)	FB	FB	FB	FB	G/O	FB	G/O	FB
38	KOH (1 eq)	FB	FB	FB	FB	FB	FB	FB	FB
39	DL-Lactic acid (1 eq)	G/O	A	A	G/O	G/O	G/O	G/O	G/O
40	D-Gluconic acid (1 eq)	G/O	G/O	1	G/O	A, 1	A, 1	G/O	G/O
41	Choline (1 eq)	G/O	G/O	G/O	G/O	G/O	G/O	G/O	FB
42	DL-Malic acid (1 eq)	FB	FB	A	A	A	B	A	G/O
43	Glycolic acid (1 eq)	A	A	A	G/O	G/O	A	A	G/O
44	Gentisic acid (1 eq)	G/O	A	A	G/O	A	A	A	A
45	Glutaric acid (1 eq)	A	B	A	G/O	G/O	A	A	G/O
46	L-Malic acid (1 eq)	FB	A, B	A	G/O	A	A	A	G/O
47	Hippuric acid (1 eq)	A	A	A	G/O	A	A	A	G/O
48	L-Aspartic acid (1 eq)	G/O	FB, CI	FB, CI	CI	CI	FB	FB	FB
49	Benzoic acid (1 eq)	FB	G/O	G/O	G/O	G/O	FB, CI	FB	G/O
50	Adipic acid (1 eq)	A	A	A	G/O	A, B	A	A, FB	G/O
51	Camphoric acid (1 eq)	A	B	C	G/O	G/O	FB	D	G/O
52	Galactaric acid (1 eq)	FB	A	A	CI	A	A	A	G/O
53	DL-Mandelic acid (1 eq)	FB	A	B	G/O	G/O	C	B	G/O

Legend

Letters represent Raman/PXRD groupings for each counterion

    New Complex Form(s) Identified (A, B, etc.)
FB  Free base
CI  Counterion
G/O Gum/Oil
1   Discolored/Hygroscopic
2   Poorly Crystalline

Example 3. Secondary Salt Screen of Fedratinib

Of the 36 salt hits, the following 13 salts were scaled up to 200 mg scale: HBr (Forms A and B), sulfate (Form A), tosylate (Form A), mesylate (Form A), 2-naphthalenesulfonate (Forms 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).

Example 3.1. Hydrobromide Salt

Two crystalline forms of hydrobromide salt were identified from salt screening experiments and designated Form A and Form B. Form A was identified using one equivalent of HBr, while Form B was identified using two equivalents of HBr. Both Forms A and B had promising thermal properties and were selected for scale up.

Preparation of Form A. THF (6.3 mL) was combined with crystalline free base Form C (315 mg) and aqueous HBr acid (1.0 equivalent; 3 M in water; 200 µL). Crystalline seeds of Form A hydrobromide salt (~1 mg) were added. The suspension was stirred at RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 1 hour. The yield of crystalline Form A was 89.9% (327 mg).

Form A was crystalline by FT-Raman (FIG. 10) and PXRD (FIG. 11), and the material was birefringent with tiny irregular particles by PLM. DSC analysis showed two large endotherms at 215 and 231° C. (FIG. 12, trace 12B), while TGA analysis showed a weight loss of 0.4% up to 100° C. (FIG. 12, trace 12A). Form A was determined to be a 1.1 : 1.0 (counterion : parent) salt by ion-chromatography. The slight excess of HBr could be due to a trace of Form B (di-HBr salt).

Preparation of Form B. 2-Propanol (6.0 mL) was combined with crystalline free base Form C (300 mg) and aqueous HBr acid (2.0 equivalent; 3 M in water; 381 µL). Crystalline seeds of HBr salt (~1 mg) were added. The suspension was stirred at RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 1 hour. The yield of crystalline Form B was 83.8% (329 mg).

Form B was crystalline by FT-Raman (FIG. 13) and PXRD (FIG. 14), and the material was birefringent with tiny needles by PLM. DSC analysis showed a small broad endotherm at 72° C. and large sharp endotherm at 233° C. (FIG. 15, trace 15B), while TGA-IR analysis showed a weight loss of 2.4% water with trace IPA up to 100° C. (FIG. 15, trace 15A). DVS analysis showed 0.9% moisture uptake between 5-95% RH (FIG. 16). PXRD pattern of the post DVS sample did not show any change in crystal form (FIG. 17). Form B was determined to be a 2.0 : 1.0 (counterion : parent) salt by ion-chromatography.

Example 3.2. Sulfate Salt

At least three crystalline forms of the sulfate salt were identified from salt screening experiments and designated Forms A, B and C. Form A was characterized by FT-Raman (FIG. 18), PXRD (FIG. 19), TGA-IR (FIG. 20, trace 20A), and DSC (FIG. 20, trace 20B). Form B was characterized by FT-Raman (FIG. 21), PXRD (FIG. 22), TGA-IR (FIG. 23, trace 23A), and DSC (FIG. 23, trace 23B). Form C was characterized by FT-Raman (FIG. 24), PXRD (FIG. 25), and DSC (FIG. 26).

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 experiment.

Preparation of Form D. Acetone (7.4 mL) was combined with crystalline free base Form C (372 mg) and aqueous sulfuric acid (0.5 equivalent; 2.5 M; 142 µL). Crystalline seeds of sulfate salt (~1 mg) were added. The suspension was stirred at RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline sulfate salt was 77.4% (315 mg).

Form D was crystalline by FT-Raman (FIG. 27) and PXRD (FIG. 28) but did not match Form A. DSC analysis showed multiple complex endotherms (FIG. 29, trace 29B), while TGA-IR analysis showed a weight loss of 1.0% water followed by 6.7% acetone up to 160° C. (FIG. 29, trace 29A). Thermal data suggests that Form D is an acetone solvate. Form D was determined to be a 0.5 : 1.0 (counterion : parent) sulfate salt by ion-chromatography.

Example 3.3. Tosylate Salt

Two crystalline forms were identified from salt screening experiments and designated Form A and Form B. Form A was identified using one equivalent of p-toluenesulfonic acid, while Form B was identified using two equivalents of p-toluenesulfonic acid. Form A was characterized by PXRD (FIG. 30), TGA-IR (FIG. 31, trace 31A), and DSC (FIG. 31, trace 31B). Form B was characterized by PXRD (FIG. 32), TGA-IR (FIG. 33, trace 33A), and DSC (FIG. 33, trace 33B).

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 experiment.

Preparation of Form C. Acetone (5.3 mL) was combined with crystalline free base Form C (265 mg) and aqueous tosic acid (1.0 equivalent; 3 M; 168 µL). Crystalline seeds of tosylate salt (Form A, ~1 mg) were added. The suspension was stirred at RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline tosylate salt was 86.7% (305 mg).

The tosylate salt was crystalline by FT-Raman (FIG. 34) and PXRD (FIG. 35) but did not match Form A. DSC analysis (FIG. 36, trace 36B) showed a sharp, higher temperature endotherm at 241° C., while TGA analysis (FIG. 36, trace 36A) showed a 0.1% weight loss up to 100° C. Thermal data suggests that Form C is a nonsolvated and more stable form than Form A. DVS analysis (FIG. 37) showed 1.2% moisture uptake between 5-95% RH. PXRD pattern of the post DVS sample did not show any change in crystal form (FIG. 38). Form C was determined to be a 1.0 : 1.0 (counterion : parent) tosylate salt by ¹H NMR (FIG. 39).

Example 3.4. Mesylate Salt

Three crystalline forms were identified from salt screening experiments and designated Forms A, B and C. Forms A and B were identified using one equivalent of methanesulfonic acid, while Form C was identified using two equivalents of methanesulfonic acid. Form B was characterized by PXRD (FIG. 44) and DSC (FIG. 46, trace 46B). Form C was characterized by PXRD (FIG. 45) and DSC (FIG. 46, trace 46C). Form A had the most promising thermal properties and was selected for scale up.

Preparation of Form A. Acetone (6.0 mL) was combined with crystalline free base Form C (298 mg) and aqueous mesic acid (1.0 equivalent; 3 M; 189 µL). Crystalline seeds of the mesylate salt (Form A, ~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 RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline mesylate salt was 91.3% (322 mg).

The mesylate salt was crystalline by FT-Raman (FIG. 40) and PXRD (FIG. 41) and was mostly consistent with Form A. DSC analysis (FIG. 42, trace 42B) showed a sharp endotherm at 207° C., while TGA analysis (FIG. 42, trace 42A) showed a 0.3% weight loss up to 100° C. Form A was determined to be a 1.2 : 1.0 (counterion : parent) mesylate salt by ¹H NMR (FIG. 43). The ¹H NMR data suggests that the trace extra peaks in PXRD for Form A could be due to a di-mesylate salt impurity and that controlling stoichiometry may be difficult.

Example 3.5. 2-Naphthalenesulfonate Salt

One crystalline form (Form A) of 2-naphthalenesulfonate salt was identified from salt screening experiments, using either one or two equivalents of 2-naphthalenesulfonic acid. Form A had promising thermal properties and was selected for scale up.

Preparation of Form A. Acetone (5.0 mL) was combined with crystalline free base Form C (252 mg) and 2-naphthalenesulfonic acid (1.0 equivalent; 3 M in THF; 160 µL). Crystalline seeds of 2-naphthalenesulfonate salt (Form A, ~1 mg) were added. The suspension was stirred at RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline 2-naphthalenesulfonate salt was 86.8% (349 mg).

The 2-naphthalenesulfonate salt was crystalline by FT-Raman (FIG. 47) and PXRD (FIG. 48). Form A was found to be a mixture with Group B (an acetone solvate) (FIG. 49). Thermal data was very complex and showed a step-wise loss of 0.9% water up to 75° C. followed by a loss of 2.6% acetone from 75-175° C. (FIG. 50). Form A was determined to be a 1.5 : 1.0 (counterion : parent) 2-naphthalenesulfonate salt and has 0.5 equivalents of acetone by ¹H NMR (FIG. 51). The thermal and ¹H NMR data suggests that an acetone solvate impurity (Form B) is present and that controlling stoichiometry may be difficult.

Example 3.6. Phosphate Salt

Four crystalline forms of the phosphate salt were identified from salt screening experiments and designated Forms A, B, C and D. Form A was characterized by PXRD (FIG. 52) and DSC (FIG. 56, trace 56A). Form B was characterized by PXRD (FIG. 53) and DSC (FIG. 56, trace 56B). Form C was characterized by PXRD (FIG. 54) and DSC (FIG. 56, trace 56C). Form D was characterized by PXRD (FIG. 55) and DSC (FIG. 56, trace 56D).

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 experiment.

Preparation of Form E. Methanol (7.0 mL) was combined with crystalline free base Form C (350 mg) and aqueous phosphoric acid (1.0 equivalent; 3 M; 222 µL). Crystalline seeds of the phosphate salt (Form D, ~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 RT (~25° C.) for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 1 hour and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline phosphate salt was 81.4% (338 mg).

The phosphate salt was crystalline by FT-Raman (FIG. 57) and PXRD (FIG. 58) but did not match the targeted form, Form D. DSC analysis showed multiple complex endotherms (FIG. 59, trace 59B), while TGA-IR analysis showed a weight loss of 3.8% water and methanol up to 125° C. (FIG. 59, trace 59A). Thermal data suggests that Form E is a methanol solvate. Form E was determined to be a 1.0 : 1.0 (counterion : parent) phosphate salt by ion-chromatography.

Example 3.7. DL-Tartrate Salt

Crystalline DL-tartrate salt hits were isolated from all eight salt formation experiments. These eight hits were sorted into two groups based on FT-Raman spectral match (designated as Form A and Form B). Form A was isolated from seven of the eight experiments and scaled-up on 200 mg scale. Form B was characterized by PXRD (FIG. 65), TGA (FIG. 66, trace 66A) and DSC (FIG. 66, trace 66B).

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 solid). Crystalline seeds of DL-tartrate salt (~1 mg) was added. The suspension was heated to 50° C., stirred at 50° C. for 15 minutes, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline DL-tartrate salt was 66.8% (171 mg).

Form A was crystalline by FT-Raman (FIG. 60) and PXRD (FIG. 61). DSC data showed a small, broad endotherm with onset at 25.4° C. followed by a second sharp endotherm at 194.4° C. (FIG. 62, trace 62B). TGA data showed ~3 %wt loss between 30-85° C. (FIG. 62, trace 62A). TGA-IR analysis of evolving gases showed loss of water suggesting that Form A of DL-tartrate salt is a hydrate. DVS analysis (FIG. 63) showed ~2.2% moisture uptake between 5-95% RH. PXRD pattern of the post DVS sample did not show any change in crystal form. The stoichiometry of DL-tartrate salt showed 1.0 : 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 64).

Example 3.8. Succinate Salt

Crystalline succinate salt hits were isolated from four of the eight salt formation experiments. FT-Raman spectra of all four hits were consistent with each other indicative of a single crystal form (designated as Form A). Form A was characterized by PXRD (FIG. 67), TGA (FIG. 68, trace 68A) and DSC (FIG. 68, trace 68B). An attempt to prepare Form A of succinate salt on a 200 mg scale was unsuccessful and yielded a new crystal form (designated as Form B).

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, dosed as solid). Crystalline seeds of succinate salt (~1 mg) was added. The suspension was heated to 40° C., stirred at 40° C. for five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. To the suspension MeOH (0.75 mL) was added. The suspension was heated to 50° C., stirred at 50° C. for five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline succinate salt was 76.2% (199.3 mg).

Form B was crystalline by FT-Raman (FIG. 69) and PXRD (FIG. 70). DSC data (FIG. 71, trace 71B) showed a single endotherm at 153.2° C. TGA data (FIG. 71, trace 71A) showed ~0.8 %wt loss between 30-165° C. suggesting that Form B is likely a non-solvated form. The stoichiometry of succinate salt showed 1.0 : 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 72).

Example 3.9. Gentisate Salt

Crystalline gentisate salt hits were isolated from six of the eight salt formation experiments. The remaining experiments yielded gum/oil. FT-Raman spectra of all six hits were consistent with each other indicative of a single crystal form (designated as Form A). Form A was scaled-up on 200 mg scale.

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 solid). Crystalline seeds of gentisate salt (~1 mg) was added. The suspension was heated to 40° C., stirred at 40° C. for five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline gentisate salt was 79.3% (237.2 mg).

Form A was crystalline by FT-Raman (FIG. 73) and PXRD (FIG. 74). DSC data showed a single endotherm at 200.2° C. (FIG. 75, trace 75B). TGA data showed ~0.8 %wt loss between 30-196° C. suggesting that Form A gentisate salt is likely a non-solvated form (FIG. 75, trace 75A). The stoichiometry of gentisate salt showed 1.0 : 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 76).

Example 3.10. Hippurate Salt

Crystalline hippurate salt hits were isolated from six of the eight salt formation experiments. The remaining experiments yielded gum/oil. FT-Raman spectra of all six hits were consistent with each other indicative of a single crystal form (designated as Form A). Form A of hippurate salt was scaled-up on 200 mg scale.

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 solid). Crystalline seeds of hippurate salt (~1 mg) was added. The suspension was heated to 40° C., stirred at 40° C. for five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline hippurate salt was 73.7% (217 mg).

Form A was crystalline by FT-Raman (FIG. 77) and PXRD (FIG. 78). DSC data showed a single endotherm at 170.1° C. (FIG. 79, trace 79B). TGA data showed ~0.1 %wt. loss between 30-157° C. suggesting that Form A of hippurate salt is a non-solvated form (FIG. 79, trace 79A). The stoichiometry of hippurate salt showed 1.0 : 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 80).

Example 3.11. Adipate Salt

Crystalline adipate salt hits were isolated from six of the eight salt formation experiments. FT-Raman spectra of five of the six crystalline hits were consistent with each other indicative of a single crystal form (designated as Form A) while the FT-Raman spectrum of the sample isolated from acetone suggest a mixture of forms. Form A was characterized by PXRD (FIG. 81), TGA (FIG. 82, trace 82A) and DSC (FIG. 82, trace 82B). An attempt to prepare Form A on a 200 mg scale was unsuccessful and yielded a new crystal form (designated as Form C).

Preparation of Group C. EtOAc (7.5 mL) was combined with crystalline free base Form C (210.27 mg) and adipic acid (1.0 equivalent, dosed as solid). Crystalline seeds of adipate salt (~1 mg) was added. The suspension was heated to 40° C., stirred at 40° C. for five hours, cooled slowly (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 five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline adipate salt was 76.2% (205.2 mg).

Form C was crystalline by FT-Raman (FIG. 83) and PXRD (FIG. 84). DSC data showed a small endotherm with onset at 93.2° C. followed two sharp endotherms at 132.6° C. and 171.2° C. (FIG. 85, trace 85B). TGA data showed ~0.9 %wt loss between 30-180° C. (FIG. 85, trace 85A). The stoichiometry of adipate salt showed 0.9 : 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 86).

Example 3.12. Galactarate Salt

Crystalline galactarate salt hits were isolated from five of the eight salt formation experiments. The remaining experiments yielded gum/oil, free-base or counterion. FT-Raman spectra of all five salt hits were consistent with each other indicative of a single crystal form (designated as Form A). Form A of galactarate salt was scaled-up on 200 mg scale.

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 solid). Crystalline seeds of galactarate salt (~1 mg) was added. The suspension was heated to 40° C., stirred at 40° C. for five hours, cooled slowly (0.1° C./min) to 25° C. and stirred at 25° C. for 16 hours. The crystalline solids were isolated via vacuum filtration, air-dried under vacuum for 2 hours and dried in a vacuum oven at 40° C. for 4 hours. The yield of crystalline galactarate salt was 86.9 (237.5 mg).

Form A was crystalline by FT-Raman (FIG. 87) and PXRD (FIG. 88). DSC data showed a single endotherm at 184.4° C. (FIG. 89, trace 89B). TGA data showed ~0.7 %wt. loss between 30-157° C. suggesting that Form A of galactarate salt is a non-solvated form (FIG. 89, trace 89A). The stoichiometry of galactarate salt showed 1.0: 1.0 (counterion : parent) by ¹H NMR analysis (FIG. 90).

Example 3.13. Crystalline Salt Hits

In addition to the crystalline salts discussed in Examples 3.1-3.12, the salt screening study also yielded salts from a variety of additives. The characterization data of these salt hits are provided in Table 3.

Crystalline Hits from Screen
Salt	Form	FT-Raman	PXRD	DSC	TGA
Napadisylate	A	-	FIG. 91	FIG. 94 (94A)	-
B	-	FIG. 92	FIG. 94 (94B)	-
C	-	FIG. 93	FIG. 94 (94C)	-
(S)-Camphorsulfonate	A	FIG. 95	FIG. 96	FIG. 97 (97B)	FIG. 97 (97A)
B	FIG. 98	FIG. 99	FIG. 100 (100B)	FIG. 100 (100A)
Edisylate	A	-	FIG. 101	FIG. 105B	FIG. 105 (105A)
	B	-	FIG. 102	FIG. 106 (106B)	-
C	-	FIG. 103	FIG. 106 (106A)	-
D	-	FIG. 104	FIG. 106 (106C)	-
Esylate	A	-	FIG. 107	FIG. 109 (109B)	FIG. 109 (109A)
B	-	FIG. 108	FIG. 110 (110B)	FIG. 110 (110A)
Besylate	A	-	FIG. 111	FIG. 115 (115A)	-
B	-	FIG. 112	FIG. 115 (115B)	-
C	-	FIG. 113	FIG. 115 (115C)	-
D	-	FIG. 114	FIG. 116 (116B)	FIG. 116 (116A)
Oxalate	A	-	FIG. 117	FIG. 119 (119B)	FIG. 119 (119A)
B	-	FIG. 118	FIG. 120 (120B)	FIG. 120 (120A)
Maleate	A	-	FIG. 121	FIG. 122 (122B)	FIG. 122 (122A)
Pamoate	A	-	FIG. 123	FIG. 124 (124B)	FIG. 124 (124A)
1-Hydroxy-2-naphthoate	A	-	FIG. 125	FIG. 126	-
Malonate	A	-	FIG. 127	FIG. 128 (128B)	FIG. 128 (128A)
B	-	FIG. 129	FIG. 130 (130B)	FIG. 130 (130A)
C	-	FIG. 131	FIG. 132	-
L-Tartrate	A	-	FIG. 133	FIG. 134 (134B)	FIG. 134 (134A)
B	-	FIG. 135	FIG. 136	-
C	-	FIG. 137	FIG. 138 (138B)	FIG. 138 (138A)
D	-	FIG. 139	FIG. 140 (140B)	FIG. 140 (140A)
Fumarate	A	-	FIG. 141	FIG. 142 (142B)	FIG. 142 (142A)
B	-	FIG. 143	FIG. 144
C	-	FIG. 145	FIG. 146 (146B)	FIG. 146 (146A)
D	-	FIG. 147	FIG. 148 (148B)	FIG. 148 (148A)
Citrate	A	-	FIG. 149	FIG. 150 (150B)	FIG. 150 (150A)
L-Lactate	A	-	FIG. 151	FIG. 152 (152B)	FIG. 152 (152A)
Acetate	A	-	FIG. 153	FIG. 154 (154B)	FIG. 154 (154A)
B	-	FIG. 155	FIG. 156 (156B)	FIG. 156 (156A)
Propionate	A	-	FIG. 157	FIG. 158 (158B)	FIG. 158 (158A)
DL-Lactate	A	-	FIG. 159	FIG. 160 (160B)	FIG. 160 (160A)
D-Gluconate	A	-	FIG. 161	FIG. 162
DL-Malate	A	-	FIG. 163	FIG. 164 (164B)	FIG. 164 (164A)
B	-	FIG. 165	FIG. 166 (166B)	FIG. 166 (166A)
Glycolate	A	-	FIG. 167	FIG. 168 (168B)	FIG. 168 (168A)
Glutarate	A	-	FIG. 169	FIG. 170 (170B)	FIG. 170 (170A)
B	-	FIG. 171	FIG. 172 (172B)	FIG. 172 (172A)
L-Malate	A	-	FIG. 173	FIG. 174 (174B)	FIG. 174 (174A)
Camphorate	A	-	FIG. 175	FIG. 176 (176B)	FIG. 176 (176A)
B	-	FIG. 177	FIG. 178 (178B)	FIG. 178 (178A)
C	-	FIG. 179	FIG. 180 (180B)	FIG. 180 (180A)
D	-	FIG. 181	FIG. 182 (182B)	FIG. 182 (182A)
DL-Mandelate	A	-	FIG. 183	FIG. 184 (184B)	FIG. 184 (184A)
B	-	FIG. 185	FIG. 186 (186B)	FIG. 186 (186A)
C	-	FIG. 187	FIG. 188 (188B)	FIG. 188 (188A)

Example 4. Primary Co-Crystal Screen of Fedratinib

A total of 24 co-crystal formers (CCF) were selected based on hydrogen-bonding propensities, molecular diversity, and pharmaceutical acceptability. One equivalent of CCF was dosed in all screening experiments. Table 4 presents the set of CCFs utilized.

Co-crystal Formers Utilized in the Screen
#	CCFs	Molar Equivalent
1	Urea	1
2	Caffeine	1
3	Nicotinamide	1
4	Isonicotinamide	1
5	L-Prolinamide	1
6	Vanillin	1
7	Methyl paraben	1
8	Propyl paraben	1
9	Butylated hydroxyanisole	1
10	Pyrogallol	1
11	Chrysin	1
12	Resveratrol	1
13	Quercetin dihydrate	1
14	Saccharin	1
15	Aspartame	1
16	Xylitol	1
17	Sucralose	1
18	D-Mannitol	1
19	L-Ascorbic acid	1
20	Nicotinic acid	1
21	Gallic acid	1
22	Orotic acid	1
23	Salicylic acid	1
24	Acetylsalicylic acid	1

A total of five neat solvents and two binary mixtures were utilized in the presented cocrystal screening experiments: THF, EtOAc, DCM, MIBK, MeOH, THF/cyclohexane (2:8 v/v), and IPA:water (9:1 v/v). The selection was based on diversity of molecular structure and properties of the solvent (e.g., polarity, chemical diversity), and solubility of free base Form C (“API”) from visual solubility assessment.

A total of ~240 co-crystal-screening experiments were conducted using 24 CCFs and a combination of i) solvent-drop grinding (SDG) - with four solvents, ii) slurry-ripening (SR) in six solvents, and iii) evaporation of solutions obtained in step ii.

Solvent-Drop Grinding (SDG). Several preliminary experiments were conducted to determine appropriate milling parameters for the SDG experiments. The results of these experiments are summarized in Table 5 (15 minutes of grinding at 15 Hz with one milling ball). The data indicated that 15 minutes of grinding at 15 Hz with one milling ball was appropriate for 100 mg API with 2-15 µL solvent. The specific (initial) solvent volumes selected for the four solvents were: THF - 5 µL; EtOAc, DCM, and MIBK - 15 µL.

Determination of Appropriate Solvent-Drop Grinding (SDG) Parameters
No.	Free Base (mg)	Solvent (µL)	Yield (mg)	Product Properties	PLM	Free Base Form by PXRD
1	98.8	none	41.6	much static; stuck to jar walls	birefringent	Form A
2	98.7	THF (2)	39.3	much static; stuck to jar walls	birefringent	Form A
3	98.8	EtOAc (5)	26.1	much static; stuck to jar walls	birefringent	Form A
4	99	DCM (5)	29.6	much static; stuck to jar walls	birefringent	Form A
5	101.2	MIBK (10)	65.2	less static; less stuck to jar walls; partial dissolution	birefringent	Form A
6	99.3	THF (5)	37.1	some static; stuck to jar walls; partial dissolution	birefringent	Form A
7	99.3	EtOAc (10)	48.3	some static; stuck to jar walls; maybe partial dissolution	birefringent	Form A
8	98.1	DCM (10)	43.7	much static; stuck to jar walls	birefringent	Form A
9	100.4	EtOAc (15)	56.3	less static; less stuck to jar walls; partial dissolution	birefringent	Form A
10	98.8	DCM (15)	52.5	less static; less stuck to jar walls; partial dissolution	birefringent	Form A

For the SDG experiments, the API (~100 mg), a stoichiometric amount of CCF (1 eq), and solvent THF, EtOAc, DCM, or MIBK were combined in a stainless steel milling jar (10 mL). Grinding was conducted on a Retsch Mill (Model MM301) at room temperature (~23° C.) with one milling ball (7 mm) at 15 Hz for 15 minutes. In cases where these parameters were observed or expected (based on properties of the CCF) to result in low yield or gumming, the milling time was reduced to 10 minutes or manual grinding via a mortar and pestle was used.

Slurry-Ripening (SR). Products from the SDG experiments were utilized and combined with the same four neat solvents used in the SDG experiments to conduct SR studies, except that THF:cyclohexane (2:8 v/v) was substituted for THF. For CCFs that yielded potential cocrystals (or salts) from SDG, saturated solutions of the CCFs were prepared in the specific solvents that yielded potential co-crystals or salts and used for SR experiments.

For two additional solvents (MeOH and IPA:water (9:1 v/v)), 1:1 (API:CCF) equivalent mixtures were prepared and combined with the two solvent systems.

The saturated solutions of CCFs were prepared by combining the CCF (estimated amount to achieve suspension) with 2 mL of solvent, then mixing at 23° C. for 16 hours. Suspensions were filtered through a 0.20 µm PTFE filter membrane to yield saturated solutions.

SR experiments were conducted in 2 mL vial s containing a tumble-stir disc and employed up to 1.9 mL 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 seven days, followed by mixing at 25° C. for five days. During this processing time, additional solvent was added to yield mixable suspensions with sufficient solids for isolation and analysis. Suspended solids were isolated by filtration and air-dried for 18 hours.

Evaporation (EV). Solutions that were obtained in slurry-ripening experiments were slowly evaporated (by loosening the vial cap) in a fume hood until dry. Products were examined first by PLM for birefringence, and further analyzed by PXRD if birefringent.

All solid outputs of the screen were analyzed by PXRD to assess co-crystal formation. Likely co-crystals were analyzed by additional techniques as appropriate and as sample quantity permitted (FT-Raman, DSC, TGA-IR, PLM, etc.).

The conducted experiments yielded potential co-crystals (pure or in mixture with parent and/or CCF) of Form C free base with isonicotinamide, pyrogallol, saccharin, and xylitol, and potential salts with L-ascorbic acid, nicotinic acid, gallic acid, orotic acid, salicylic acid, and acetylsalicylic acid. Most potential co-crystals (or salts) were obtained from SR/EV experiments. The PXRD patterns of salicylic acid Form A and acetylsalicylic acid Form A were observed to be identical. Proton NMR analysis confirmed that the acetylsalicylic acid salt Form A was consistent with salicylic acid salt Form A, as no acetyl group was observed. This may be due to hydrolysis of acetylsalicylic acid to salicylic acid during slurry-ripening.

Co-crystal formers that did not yield potential co-crystals included urea, caffeine, nicotinamide, L-prolinamide, vanillin, methyl paraben, propyl paraben, butylated hydroxyanisole, chrysin, resveratrol, quercetin, aspartame, sucralose, and D-mannitol. These co-crystal formers yielded amorphous materials, parent forms, CCF, or a combination thereof. The products obtained in the SDG and SR/EV experiments are shown in Table 6 and Table 7, respectively.

Co-crystal or Salt Screening Products Obtained from SDG Approach
#	CCF	THF	EtOAc	DCM	MIBK
1	Urea	C	CI	C	CI	C	CI	C	CI
2	Caffeine	C	CI	C	CI	C	CI	C	CI
3	Nicotinamide	C	CI	C	CI	C	CI	C	CI
4	Isonicotinamide	C	CI	C	CI	C	CI	C	CI
5	L-Prolinamide	C	CI	C	CI	C	CI	C	CI
6	Vanillin	C	CI	C	CI	C	CI	C	CI
7	Methyl paraben	C	CI	C	CI	C	CI	C	CI
8	Propyl paraben	C	CI	C	CI	C	CI	C	CI
9	Butylated hydroxyanisole	C	CI	C	CI	C	CI	C	CI
10	Pyrogallol	C	C	C	CI	C
11	Chrysin	C	CI	C	CI	C	CI	C	CI
12	Resveratrol	C	CI	C	CI	C	CI	C	CI
13	Quercetin dihydrate	C	CI	C	CI	C	CI	C	CI
14	Saccharin	C	CI	C	CI	C	CI	C	CI
15	Aspartame	C	CI	C	CI	C	CI	C	CI
16	Xylitol	C	CI	C	CI	C	CI	C	CI
17	Sucralose	C	CI	C	CI	C	CI	C	CI
18	D-Mannitol	C	CI	C	CI	C	CI	C	CI
19	L-Ascorbic acid	C	CI	C	CI	C	CI	C	CI
20	Nicotinic acid	C	CI	C	CI	C	CI	C	CI
21	Gallic acid	C	CI	C	CI	C	CI	C	CI
22	Orotic acid	C	CI	C	CI	C	CI	C	CI
23	Salicylic acid	C	CI	C	CI	NC	C	CI	C	CI
24	Acetylsalicylic acid	C	CI	C	CI	C	CI	C	CI	NC

LEGEND
NC New Complex Form Identified
FB Parent Free Base Form
CI Counterion
Notes: A, B - crystal forms identified

Co-crystal or Salt Screening Products Obtained from Slurry-Ripening or Evaporation Approach

#

CCF

THF/cyclohexane (2:8)

EtOAc

DCM

MIBK

MeOH

IPA/water (9:1)

1

Urea

C

CI

C

CI

C

CI

C

CI

A

C

CI

2

Caffeine

C

CI

C

CI

C

CI

C

CI

A

CI

C

CI

3

Nicotinamide

C

CI

C

CI

C,+*

CI

C

CI

A

C

CI

4

Isonicotinamide

C

CI

C

CI

C

CI

NC

C

CI

A

C

CI

5

L-Prolinamide

C

C

CI

C

CI

C

CI

C

C

6

Vanillin

C

C

C

CI

C

A

C

7

Methyl paraben

C

C

ND

C

A

C

8

Propyl paraben

C

C

CI

C,+

C

CI

A

C

CI

9

Butylated hydroxyanisole

C

C

C

C

A

C

10

Pyrogallol

A,C

NC

A,C

NC

A,C

NC

C

NC

A,C (ev)

NC

C

11

Chrysin

C

CI

C

CI

C

CI

C

CI

A

CI

C

CI

12

Resveratrol

C

CI

C

CI

C

CI

C

CI

A

C

CI

13

Quercetin dihydrate

C

CI

C

CI

C,+

CI

C

CI

A

CI

C

CI

14

Saccharin

NC(A)

NC(A)

NC(A)

NC(A)

NC(A)

NC(A)

15

Aspartame

C

CI

C

CI

ND

CI

C

CI

AM(ev)

C

CI

16

Xylitol

C

CI

C

CI

C,+

CI

NC

C

CI

A

C

#

CCF

THF/cyclohexane (2:8)

EtOAc

DCM

MIBK

MeOH

IPA/water (9:1)

17

Sucralose

C

CI

C

CI

C

CI

C

CI

A

C

18

D-Mannitol

C

CI

C

CI

C

CI

C

CI

A

CI

C

CI

19

L-Ascorbic acid

NC(A,B)

NC(B)

NC(A,B)

NC(B)

NC(A,B (ev))

NC(A)

20

Nicotinic acid

NC(A)

NC(B)

AM

NC(A)

NC(C (ev))

C

21

Gallic acid

NC(A)

C

NC(A,B)

C

NC(A)

NC(A,B)

22

Orotic acid

NC(A)

NC(B,E) *

NC(C,E)

NC(D)

NC€

NC(F)

23

Salicylic acid

NC(A)

NC(B)1

NC(A)

NC(A)

NC(A)

NC(A)

24

Acetylsalicylic acid

NC(A,B)

C

NC(A,B)

AM(ev)

NC(B)1

NC(A)

NC(A)

LEGEND:

Notes: A, B, etc. - crystal forms

NC(X)

New Complex Form(s) Identified (X = A, B, etc.)

+ - mixture, likely with unidentified forms of parent free base

FB

Parent Free Base Form

* - poorly crystalline

CI

Counterion

(ev) - from solution evaporation

AM

Amorphous Form

1 - presaturated with CCF (saturated)

ND - form undetermined

Attributes of Scaled-Up Co-Crystals or Salts
Complex Form Scaled Up	Equivalents of CCF (1H NMR)	DSC Endotherms (Onset, °C)	TGA %Wt Loss	Nature	Complex Forms Observed During Scale-Up
Saccharin Form A	1	183.8	0.1	non-solvated	A
(26-174° C.)
Nicotinic acid Form A	1	179.9	0.2	non-solvated	A-C
(29-168°)
Ascorbic acid Form A	1	46.0	5.4	hydrate	A, B
116.8
157.0	(29-140° C.)
(maybe 2 merged)
Gallic acid Form A	1	48.0	2.4	hydrate	A, B
193.5	(22-89° C.)
Salicylic acid Form A	1	34.9	2.5	hydrate	A, B
159.8	(26-96° C.)
Orotic acid Form F	1	56.5	10.8	hydrate	A-H
104.7	(24-129° C.)
135.2
Orotic acid Form H	1	34.3	3.2	hydrate
134.5
144.4	(23-95° C.)
165.8
203.4

Example 5 Scale Up of Co-Crystals

Of the potential co-crystal (or salt) hits, the following seven exhibited desirable physiochemical properties and were scaled up on a 250 mg scale: saccharin Form A, nicotinic acid Form A, ascorbic acid Form A, gallic acid Form A, salicylic acid Form A, and orotic acid Forms F and H. Results are described in detail below.

Example 5.1. Saccharin Co-Crystal

Saccharin co-crystal hits 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 subjected to detailed characterization.

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 yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for two hours and dried at 40° C. in a vacuum oven for 18 hours. The product weight was 287 mg of Form A (87% yield relative to the cocrystal).

Form A was determined to be a crystalline powder by FT-Raman (FIG. 189) and PXRD (FIG. 190). DSC analysis showed a melting endotherm with onset at 183.8° C. (ΔH = 104.2 J/g) (FIG. 191, trace 191B). TGA analysis showed 0.1% weight loss between 26-174° C., indicating a non-solvated form (FIG. 191, trace 191A). Proton NMR analysis of Form A indicated that Form A comprises 1 equivalent of saccharin (FIG. 192).

Example 5.2. Nicotinic Acid Salt

Nicotinic acid salt hits were obtained from three SR and one EV experiments. PXRD analysis of the samples indicated three forms, designated as Form A, Form B and Form C. Form A (non-solvated) was scaled up (250 mg scale) and subjected to detailed characterization. Form B was characterized by PXRD (FIG. 197), TGA (FIG. 198, trace 198A), and DSC (FIG. 198, trace 198B). Form C was characterized by PXRD (FIG. 199), TGA (FIG. 200, trace 200A), and DSC (FIG. 200, trace 200B).

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 yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for two hours and dried at 40° C. in a vacuum oven for 18 hours. The product weight was 247 mg of nicotinic acid salt Form A (79% yield relative to the salt).

Form A was determined to be a crystalline powder by FT-Raman (FIG. 193) and PXRD (FIG. 194). DSC analysis showed a melting endotherm with onset at 179.9° C. (ΔH = 120.4 J/g) (FIG. 195, trace 195B). TGA analysis showed 0.2% weight loss between 29-168° C., indicating a non-solvated form (FIG. 195, trace 195A). Proton NMR analysis of Form A indicated that Form A comprises 1 equivalent of nicotinic acid (FIG. 196).

Example 5.3. L-Ascorbic Acid Salt

Ascorbic acid salt hits were obtained from six SR experiments. PXRD analysis of the samples indicated two forms, designated as Form A and Form B. Form A (hydrate) was scaled up (250 mg scale) and subjected to detailed characterization.

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 yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for four hours and left open in a fume hood for 18 hours. The product weight was 294 mg of ascorbic acid salt Form A (83% yield relative to the salt).

Form A was determined to be a crystalline powder by FT-Raman (FIG. 201) and PXRD (FIG. 202). DSC analysis showed a dehydration endotherm with onset 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 (possibly two merged) with onset at 157.0° C. (ΔH = 71.4 J/g) (FIG. 203, trace 203B). TGA analysis showed 5.4% weight (2.2 eq) loss of water between 29-140° C., indicating a hydrated form (FIG. 203, trace 203A). Proton NMR analysis of Form A indicated that Form A comprises 1 equivalent of L-ascorbic acid (FIG. 204).

Example 5.4. Gallic Acid Salt

Gallic acid salt hits were obtained from four SR experiments. PXRD analysis of the samples indicated two forms, designated as Form A and Form B. Form A was obtained in pure form while Form B was obtained only in mixture with Form A. Form A (hydrate) of the gallic acid salt was scaled up (250 mg scale) and subjected to detailed characterization.

Preparation of Form A (Hydrate). Form C free base (245.0 mg) was combined with gallic acid (77.0 mg; 1 eq) and solvent (MeOH, 4.0 mL), and mixed at 40° C. for 30 minutes yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for four hours and left open in a fume hood for 18 hours. The product weight was 256 mg of gallic acid salt Form A (77% yield relative to the salt).

Form A was determined to be a crystalline powder by FT-Raman (FIG. 205) and PXRD (FIG. 206). DSC analysis showed a dehydration endotherm with onset at 48.5° C. (ΔH = 79.8 J/g) followed by a melting endotherm with onset at 193.5° C. (ΔH = 176.1 J/g) (FIG. 207, trace 207B). TGA analysis showed 2.4% weight (1.0 eq) loss of water between 22-89° C., indicating a hydrated form (FIG. 207, trace 207A). Proton NMR analysis of Form A indicated that Form B comprises 1 equivalent of gallic acid (FIG. 208).

Example 5.5. Salicylic Acid Salt

Salicylic acid salt hits were obtained from one SDG experiment and six SR experiments; however, the hit from SDG was a mixture of a potential salt, parent, and CCF. PXRD analysis of the six SR hits indicated two forms, designated as Form A and Form B. Most hits (⅚) were consistent with Form A. Form A (hydrate) of the salicylic acid salt was scaled up (250 mg scale) and subjected to detailed characterization.

Preparation of Form A (Hydrate). Form C free base (253.8 mg) was combined with salicylic acid (64.7 mg; 1 eq) and solvent (IPA/water 9:1, 4.5 mL), and mixed at 40° C. for 30 minutes yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for 18 hours. The product weight was 272 mg of salicylic acid salt Form A (83% yield relative to the salt).

Form A was determined to be a crystalline powder by FT-Raman (FIG. 209) and PXRD (FIG. 210). DSC analysis showed a dehydration endotherm with onset at 34.9° C. (ΔH = 71.0 J/g) followed by a melting endotherm with onset at 159.8° C. (ΔH = 83.8 J/g) (FIG. 211, trace 211B). TGA analysis showed 2.5% weight (1.0 eq) loss of water between 26-96° C., indicating a hydrated form (FIG. 211, trace 211A). Proton NMR analysis of Form A indicated that Form A comprises 1 equivalent of salicylic acid (FIG. 212).

Example 5.6. Orotic Acid Salt

Orotic acid salt hits were obtained from six SR experiments. PXRD analysis of the hits indicated six forms, designated as Form A, Form B, Form C, Form D, Form E and Form F. Scale-up experiments (250 mg) were conducted for Forms E and F (hydrates), and the other groups were deprioritized due to solvation or because they were mixtures of two groups as shown in Table 7. The Form E scale-up experiment was unsuccessful and produced two new groups: Form G and Form H. Form G is a MeOH/water solvate that desolvates under ambient conditions to Form H, a hydrate. Form A was characterized by PXRD (FIG. 213), TGA (FIG. 214, trace 214A) and DSC (FIG. 214, trace 214B). The mixture of Form B and Form E was characterized by PXRD (FIG. 215). The mixture of Form C and Form E was characterized by PXRD (FIG. 216). Form D was characterized by PXRD (FIG. 217), TGA (FIG. 218, trace 218A) and DSC (FIG. 218, trace 218B). Form E was characterized by PXRD (FIG. 219), TGA (FIG. 220, trace 220A) and DSC (FIG. 220, trace 220B). Form G was characterized by PXRD (FIG. 221). Form F and Form H (hydrates) of the orotic acid salt were scaled up (250 mg) and subjected to detailed characterization.

Preparation of Form F (Hydrate). Form C free base (250.0 mg) was combined with orotic acid (77.0 mg; 1 eq) and solvent (IPA/water 9:1, 10.0 mL), and mixed at 40° C. for 30 minutes yielding a suspension. Seeds (~5 mg) were added, and the suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 60 hours yielding a moderately thick slurry. The solids were isolated by vacuum-filtration for 22 hours. The product weight was 297 mg of orotic acid salt Form F (82% yield relative to the co-crystal).

Form F was determined to be a crystalline powder by FT-Raman (FIG. 222) and PXRD (FIG. 223). DSC analysis showed two dehydration endotherms with onsets at 56.5° C. (ΔH = 86.1 J/g) and 104.7° C. (ΔH = 15.4 J/g), respectively, immediately followed by a melting endotherm with onset at 135.2° C. (ΔH = 12.3 J/g) (FIG. 224, trace 224B). TGA analysis showed 10.8% weight (4.5 eq) loss of water between 24 °-129° C., indicating a hydrated form (FIG. 224, trace 224A). Proton NMR analysis of Form F indicated that Form F comprises 1 equivalent of orotic acid (FIG. 225).

PXRD analysis of the sample post heating indicated significant loss of crystallinity but no change in form.

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 yielding a near clear solution. Seeds (Group E, ~5 mg) were added, and the suspension became very thick, so additional solvent was added (MeOH, 1.5 mL). The suspension was mixed at 40° C. for two hours, slow-cooled to 20° C., and mixed at 20° C. for 18 hours yielding a moderately thick slurry. PXRD indicated a new form, and DSC/TGA-IR indicated a MeOH/water solvate, which was designated Form G. The batch solids were isolated by vacuum-filtration for 18 hours. The product weight was 178 mg. PXRD indicated yet a new form, and DSC/TGA-IR indicated a hydrate, which was designated Form H (53% yield relative to the salt).

Form H was determined to be a crystalline powder by FT-Raman (FIG. 226) and PXRD (FIG. 227). DSC analysis showed a broad dehydration endotherm with onset 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 with onset at 165.8° C. (ΔH = 44.6 J/g), and a broad endotherm with onset at 203.4° C. (ΔH = 11.1 J/g) (FIG. 228, trace 228B). TGA analysis showed 3.2% weight (1.2 eq) loss of water between 23-95° C., indicating a hydrated form (FIG. 228, trace 228A). Proton NMR analysis of Form H indicated that Form H comprises 1 equivalent of orotic acid (FIG. 229).

PXRD analysis of the post-heated sample indicated some loss of crystallinity and a loss of several major peaks.

Example 5.7. Other Co-Crystal or Salt Hits

Acetylsalicylic acid salt Form A was scaled up, however the PXRD pattern was observed to be identical to that of salicylic acid salt Form A. Proton NMR analysis confirmed that the acetylsalicylic acid salt Form A was consistent with salicylic acid salt Form A, as no acetyl group was observed. This may be due to hydrolysis of acetylsalicylic acid to salicylic acid during slurry-ripening.

In addition to the scaled up co-crystals (or salts), several other potential co-crystals were obtained from screening. These hits were not completely characterized and/or scaled up due to:

• limited sample amounts,
• undesirable physiochemical properties (poor crystallinity/poor thermal properties)
• being identified as a mixture with parent and/or CCF.

Representative samples of these co-crystal (or salt) hits are summarized in Table 9.

Attributes of Other Co-Crystal or Salt Hits Identified in Screening
Crystal Form	Potential Co-crystal or Salt	DSC Endotherms (Onset, °C)	Comments	PXRD	DSC	TGA
Form A	Isonicotinamide	Not obtained	Mixture with Free Base Form C and CCF	FIG. 230	—	—
Form A	Pyrogallol	33.8 (broad)	Mixture with Free Base Forms A+C; DCM/water solvate	FIG. 231	FIG. 232B	FIG. 232A
134.7 (broad)
Form A	Xylitol	Not obtained	Mixture with Free Base Form C and other forms, CCF	FIG. 233	—	—
Form B	Ascorbic acid	40.9 (broad)	Moderately crystalline; Hydrate	FIG. 234	FIG. 235B	FIG. 235A
132.0 (broad)
Form B	Gallic acid	Not obtained	Mixture with Gallate Form A	FIG. 236	—	—
Form A	Orotic acid	61.1 (broad)	THF/cyclohexane/water solvate	FIG. 213	FIG. 214B	FIG. 214A
158.0 (broad)
178.9 (sharp)
Form B	Not obtained	Mixture with Orotate Form E	FIG. 215	—	—
Form C	Not obtained	Mixture with Orotate Form E	FIG. 216	—	—
Form D	166.6 (broad)	MIBK/water solvate	FIG. 217	FIG. 218B	FIG. 218A
182.3 (small)
Form E	41.3 (broad)	Hydrate; may be difficult to reproduce	FIG. 219	FIG. 220B	FIG. 220A
78.0 (broad)
163.9 (broad)
Form G	38.1 (broad)	MeOH/water solvate	FIG. 221	—	—
143.5 (small)
167.2 (broad)
203.3 (broad)
Form B	Salicylic acid	116.9 (broad)	EtOAc solvate	FIG. 237	FIG. 238B	FIG. 238A
140.2 (broad)
Form B	Acetylsalicylic acid	101.2 (broad)	MIBK solvate	FIG. 239	FIG. 240B	FIG. 240A

Example 6. Aqueous Solubility of Certain Complexes

The solid/salt forms (~20-30 mg) were transferred to clear glass vials (4 ml). To each vial containing solid forms, the water (~0.2 -2 ml) was separately added. The volume of water added and the weight of the solid/salt form was appropriately adjusted to yield excess undissolved solid/salt form. The vials containing the solid/salt form/water mixture were transferred on to the rack that were kept at rotation and the samples were equilibrated with agitation at ambient temperature for 24 hr. At the end of the equilibration process, visual observations of the suspensions were made and the samples were withdrawn and centrifuged (14,000 rpm for 3 min) in a Costar SPIN-X polypropylene centrifuge tube (2.0 ml) filter (0.22 mm Nylon filter) to separate any un-dissolved drug. The clear filtrate was assayed for drug content to determine solubility of the active in the solution following appropriate dilution where necessary in acetonitrile/water (50:50). A standard curve in the concentration range of 0.126 mg/ml to 0.001 mg/ml was prepared using the free base. The samples and standards were assayed for drug content using the HPLC. Results are set forth in Table 10:

Solubility of Certain Forms of Compound 1
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
Nicotinic Acid Form A    4.0
Saccharin Form A         0.1
Ascorbic Acid Form A     5.4
Gallic Acid Form A       0.2
Orotic Acid Form F       0.9
Orotic Acid Form H       0.6
Salicylic Acid Form A    0.05

Claims

1. A crystalline form of Compound 1:

2. The crystalline form of claim 1, wherein the form is unsolvated.

3. The crystalline form of claim 2, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.7, 14.6, 19.5, 24.3, and 25.6 ± 0.2 degrees 2θ.

4. The crystalline form of claim 2, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

5. The crystalline form of claim 1, wherein the form is solvated.

6. The crystalline form of claim 5, wherein the form is a 2-methyltetrahydrofuran solvate.

7. The crystalline form of claim 6, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 12.5, 18.3, 18.9, 20.1, and 23.8 ± 0.2 degrees 2θ.

8. The crystalline form of claim 6, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

9. The crystalline form of claim 1, wherein the form is a hydrate.

10. The crystalline form of claim 9, wherein the form is a monohydrate.

11. The crystalline form of claim 10, wherein the form is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 8.7, 15.2, 17.3, 18.0, and 19.4 ± 0.2 degrees 2θ.

12. The crystalline form of claim 10, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

13. The crystalline form of claim 9, wherein the form is a tetrahydrate.

14. The crystalline form of claim 13, wherein the form 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.

15. The crystalline form of claim 13, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

16. A sample comprising the crystalline form of claim 1, wherein the sample is substantially free of impurities.

17. A complex comprising Compound 1: and a co-former X; wherein the complex is crystalline and 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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, choline, potassium hydroxide, and sodium hydroxide.

18. A complex comprising Compound 1: and a co-former X; wherein: 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, nicotinic acid, ascorbic acid, gallic acid, salicylic acid, orotic acid, acetylsalicylic acid, and choline.

19. A sample comprising the complex of claim 17, wherein the sample is substantially free of impurities.

20. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a crystalline form of claim 1, or a composition thereof.

21. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient a crystalline form of claim 1, or a composition thereof.

22. A method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to the patient a crystalline form of claim 1, or pharmaceutically acceptable composition thereof.

23. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a complex of claim 17, or a composition thereof.

24. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient a complex of claim 17, or a composition thereof.

25. A method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to the patient a complex of claim 17, or a pharmaceutically acceptable composition thereof.

26. A sample comprising the complex of claim 18, wherein the sample is substantially free of impurities.

27. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a biological sample comprising the step of contacting said biological sample with a complex of claim 18, or a composition thereof.

28. A method of inhibiting activity of a JAK2 kinase, or a mutant thereof, in a patient comprising the step of administering to said patient a complex of claim 18, or a composition thereof.

29. A method for treating a JAK2-mediated disease or disorder, in a patient in need thereof, comprising the step of administering to the patient a complex of claim 18, or a pharmaceutically acceptable composition thereof.