Crystalline forms of a JAK2 inhibitor

文档序号：440383 发布日期：2021-12-24 浏览：10次中文

阅读说明：本技术 Jak2抑制剂的结晶形式 (Crystalline forms of a JAK2 inhibitor ) 是由黄亷丰 N·邹 W·吴邹道忠于 2020-02-11 设计创作，主要内容包括：本公开提供了JAK2抑制剂的结晶形式、其组合物以及治疗JAK2介导的病症的方法。(The present disclosure provides crystalline forms of a JAK2 inhibitor, compositions thereof, and methods of treating JAK 2-mediated disorders.)

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 2 Θ.

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-methyl-tetrahydrofuran 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 2-theta.

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 2 Θ.

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 2 Θ.

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 any one of claims 1-15, 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, benzoic acid, L-mandelic acid, L-malic acid, L-aspartic acid, benzoic acid, saccharin, nicotinic acid, succinic acid, felodioic acid, maleic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, L-tartaric acid, L-malic acid, benzoic acid, L-malic acid, benzoic acid, nicotinic acid, L-tartaric acid, L-tartaric acid, L-tartaric acid, citric acid, tartaric acid, L-tartaric acid, and/or a salt, citric acid, succinic acid, tartaric acid, succinic acid, tartaric 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 or claim 18, wherein the sample is substantially free of impurities.

20. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the crystalline form of any one of claims 1-15 or a composition thereof.

21. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient the crystalline form of any one of claims 1-15 or a composition thereof.

22. A method of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient the crystalline form of any one of claims 1-15, or a pharmaceutically acceptable composition thereof.

23. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the complex of claim 17 or claim 18, or a composition thereof.

24. A method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient the complex of claim 17 or claim 18, or a composition thereof.

25. A method of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient the complex of claim 17 or claim 18, or a pharmaceutically acceptable composition thereof.

Technical Field

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

Background

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

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

In general, protein kinases mediate intracellular signaling by affecting phosphoryl transfer from nucleoside triphosphates to protein receptors involved in signaling pathways. These phosphorylation events act as molecular on/off switches that can modulate or regulate the biological function of the target protein. 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 such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), and growth factors such as granulocyte macrophage colony stimulating factor (GM-CSF) and Fibroblast Growth Factor (FGF). Extracellular stimuli can affect one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis control, and cell cycle regulation.

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

Disclosure of 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:

In some embodiments, compound 1 or a crystalline form or complex thereof can be used to treat a myeloproliferative disorder. In some embodiments, the myeloproliferative disorder is selected from the group consisting of myelofibrosis, polycythemia vera, and essential thrombocythemia. In some embodiments, the myelofibrosis is selected from primary myelofibrosis or secondary myelofibrosis. In some embodiments, the secondary myelofibrosis is selected from the group consisting of post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

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

According to another embodiment, the disclosure relates to a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, comprising the step of administering to the patient compound 1 or a crystalline form or complex thereof or a composition thereof. In other embodiments, the present disclosure provides a method of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient compound 1 or a crystalline form or complex thereof or a composition thereof.

Drawings

Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of form a of compound 1.

Figure 2A depicts the thermogravimetric analysis (TGA) pattern of form a of compound 1. Figure 2B depicts a Differential Scanning Calorimetry (DSC) pattern of form a of compound 1.

Figure 2C depicts the Dynamic Vapor Sorption (DVS) isotherm of form a of compound 1.

Figure 3 depicts the XRPD pattern of form B of compound 1.

Figure 4A depicts the TGA pattern of form B of compound 1. Figure 4B depicts the DSC pattern of form B of compound 1.

Figure 5 depicts the XRPD pattern of form C of compound 1.

Figure 6A depicts the TGA pattern of form C of compound 1. Figure 6B depicts the DSC pattern of form C of compound 1.

Figure 7 depicts DVS isotherms for form C of compound 1.

Figure 8 depicts the XRPD pattern of form D of compound 1.

Figure 9A depicts a TGA pattern of form D of compound 1. Figure 9B depicts the DSC pattern of form D of compound 1.

Figure 10 depicts the FT-raman spectrum of form a hydrobromide salt of compound 1.

Figure 11 depicts the XRPD pattern of form a hydrobromide salt of compound 1.

Figure 12 depicts a TGA pattern (12A) for form a hydrobromide salt of compound 1 and a DSC pattern (12B) for form a hydrobromide salt of compound 1.

Figure 13 depicts the FT-raman spectrum of form B hydrobromide salt of compound 1.

Figure 14 depicts the XRPD pattern of form B hydrobromide salt of compound 1.

Figure 15 depicts a TGA pattern (15A) for form B hydrobromide of compound 1 and a DSC pattern (15B) for form B hydrobromide of compound 1.

Figure 16 depicts the Dynamic Vapor Sorption (DVS) isotherm of form B hydrobromide salt of compound 1.

Figure 17 depicts the XRPD pattern of form B hydrobromide salt of compound 1 after DVS.

Figure 18 depicts the FT-raman spectrum of form a sulfate salt of compound 1.

Figure 19 depicts the XRPD pattern of form a sulfate salt of compound 1.

Fig. 20 depicts a TGA pattern (20A) for form a sulfate salt of compound 1 and a DSC pattern (20B) for form a sulfate salt of compound 1.

Figure 21 depicts the FT-raman spectrum of form B sulfate salt of compound 1.

Figure 22 depicts the XRPD pattern of form B sulfate salt of compound 1.

Figure 23 depicts a TGA pattern (23A) for form B sulfate salt of compound 1 and a DSC pattern (23B) for form B sulfate salt of compound 1.

Figure 24 depicts the FT-raman spectrum of form C sulfate salt of compound 1.

Figure 25 depicts the XRPD pattern of form C sulfate salt of compound 1.

Figure 26 depicts the DSC pattern of form C sulfate salt of compound 1.

Figure 27 depicts the FT-raman spectrum of form D sulfate salt of compound 1.

Figure 28 depicts the XRPD pattern of form D sulfate salt of compound 1.

Fig. 29 depicts a TGA pattern (29A) for form D sulfate salt of compound 1 and a DSC pattern (29B) for form D sulfate salt of compound 1.

Figure 30 depicts the XRPD pattern of form a tosylate salt of compound 1.

Figure 31 depicts a TGA pattern (31A) for form a tosylate salt of compound 1 and a DSC pattern (31B) for form a tosylate salt of compound 1.

Figure 32 depicts the XRPD pattern of form B tosylate salt of compound 1.

Figure 33 depicts a TGA pattern (33A) for form B tosylate salt of compound 1 and a DSC pattern (33B) for form B tosylate salt of compound 1.

Figure 34 depicts the FT-raman spectrum of form C tosylate salt of compound 1.

Figure 35 depicts the XRPD pattern of form C tosylate salt of compound 1.

Figure 36 depicts a TGA pattern (36A) for form C tosylate salt of compound 1 and a DSC pattern (36B) for form C tosylate salt of compound 1.

Figure 37 depicts DVS isotherms for form C tosylate salt of compound 1.

Figure 38 depicts the XRPD pattern of form C tosylate salt of compound 1 after DVS.

FIG. 39 depicts form C tosylate salt of Compound 1¹H-NMR spectrum.

Figure 40 depicts the FT-raman spectrum of form a mesylate salt of compound 1.

Figure 41 depicts the XRPD pattern of form a mesylate salt of compound 1.

Figure 42 depicts a TGA pattern (42A) for a dried sample of form a mesylate salt of compound 1 and a DSC pattern (42B) for a dried sample of form a mesylate salt of compound 1.

FIG. 43 depicts form A mesylate salt of Compound 1¹H-NMR spectrum.

Figure 44 depicts the XRPD pattern of form B mesylate salt of compound 1.

Figure 45 depicts the XRPD pattern of form C mesylate salt of compound 1.

Figure 46 depicts the DSC pattern of form a mesylate of compound 1 (46A), form B mesylate of compound 1 (46B), and form C mesylate of compound 1 (46C).

Figure 47 depicts an FT-raman spectrum of form A2-naphthalenesulfonate salt of compound 1.

Figure 48 depicts the XRPD pattern of form A2-naphthalenesulfonate salt of compound 1.

Figure 49 depicts the XRPD pattern of a mixture of form a and form B2-naphthalenesulfonate salt of compound 1.

Figure 50 depicts a TGA pattern (50A) for form A2-naphthalenesulfonate of compound 1 and a DSC pattern (50B) for form A2-naphthalenesulfonate of compound 1.

FIG. 51 depicts a mixture of form A and form B2-naphthalenesulfonates of Compound 1¹H NMR。

Figure 52 depicts the XRPD pattern of form a phosphate of compound 1.

Figure 53 depicts the XRPD pattern of form B phosphate of compound 1.

Figure 54 depicts the XRPD pattern of form C phosphate of compound 1.

Figure 55 depicts the XRPD pattern of form D phosphate of compound 1.

Figure 56 depicts a DSC pattern for form a phosphate of compound 1 (56A), form B phosphate of compound 1 (56B), form C phosphate of compound 1 (56C), and form D phosphate of compound 1 (56D).

Figure 57 depicts the FT-raman spectrum of form E phosphate of compound 1.

Figure 58 depicts the XRPD pattern of form E phosphate of compound 1.

Fig. 59 depicts a TGA pattern (59A) for form E phosphate of compound 1 and a DSC pattern (59B) for form E phosphate of compound 1.

Figure 60 depicts the FT-raman spectrum of form a DL-tartrate of compound 1.

Figure 61 depicts the XRPD pattern of form a DL-tartrate salt of compound 1.

Figure 62 depicts a TGA pattern (62A) for form a DL-tartrate salt of compound 1 and a DSC pattern (62B) for form a DL-tartrate salt of compound 1.

Figure 63 depicts DVS isotherms of form a DL-tartrate of compound 1.

FIG. 64 depicts form A DL-tartrate of Compound 1¹H-NMR spectrum.

Figure 65 depicts the XRPD pattern of form B DL-tartrate salt of compound 1.

Figure 66 depicts a TGA pattern (66A) for form B DL-tartrate salt of compound 1 and a DSC pattern (66B) for form B DL-tartrate salt of compound 1.

Figure 67 depicts the XRPD pattern of form a succinate salt of compound 1.

Fig. 68 depicts a TGA pattern (68A) for form a succinate salt of compound 1 and a DSC pattern (68B) for form a succinate salt of compound 1.

Figure 69 depicts an FT-raman spectrum of form B succinate of compound 1.

Figure 70 depicts the XRPD pattern of form B succinate salt of compound 1.

Figure 71 depicts a TGA pattern (71A) for form B succinate salt of compound 1 and a DSC pattern (71B) for form B succinate salt of compound 1.

FIG. 72 depicts form B succinate salt of Compound 1¹H-NMR spectrum.

Figure 73 depicts an FT-raman spectrum of form a gentisate salt of compound 1.

Figure 74 depicts the XRPD pattern of form a gentisate salt of compound 1.

Figure 75 depicts a TGA pattern (75A) for form a gentisate of compound 1 and a DSC pattern (75B) for form a gentisate of compound 1.

Figure 76 depicts form a gentisate salt of compound 1¹H-NMR spectrum.

Figure 77 depicts the FT-raman spectrum of form a hippurate of compound 1.

Figure 78 depicts the XRPD pattern of form a hippurate of compound 1.

Figure 79 depicts a TGA pattern (79A) for form a hippurate of compound 1 and a DSC pattern (79B) for form a hippurate of compound 1.

FIG. 80 depicts form A hippurate of Compound 1¹H-NMR spectrum.

Figure 81 depicts the XRPD pattern of form a adipate of compound 1.

Figure 82 depicts the TGA pattern (82A) of form a adipate of compound 1 and the DSC pattern (82B) of form a adipate of compound 1.

Figure 83 depicts the FT-raman spectrum of form C adipate of compound 1.

Figure 84 depicts the XRPD pattern of form C adipate of compound 1.

Figure 85 depicts the TGA pattern (85A) for form C adipate of compound 1 and the DSC pattern (85B) for form C adipate of compound 1.

FIG. 86 depicts form C adipate of Compound 1¹H-NMR spectrum.

Figure 87 depicts an FT-raman spectrum of form a galactarate salt of compound 1.

Figure 88 depicts the XRPD pattern of form a galactarate salt of compound 1.

Figure 89 depicts a TGA pattern (89A) for form a galactarate salt of compound 1 and a DSC pattern (89B) for form a galactarate salt of compound 1.

FIG. 90 depicts form A galactaric acid salt of Compound 1¹H-NMR spectrum.

Figure 91 depicts the XRPD pattern of form a napadisylate salt of compound 1.

Figure 92 depicts the XRPD pattern of form B napadisylate salt of compound 1.

Figure 93 depicts the XRPD pattern of form C napadisylate of compound 1.

Figure 94 depicts a DSC pattern for form a napadisylate of compound 1 (94A), form B napadisylate of compound 1 (94B), and form C napadisylate of compound 1 (94C).

Figure 95 depicts the FT-raman spectrum of form a(s) -camphorsulfonate of compound 1.

Figure 96 depicts the XRPD pattern of form a(s) -camphorsulfonic acid salt of compound 1.

Fig. 97 depicts a TGA pattern (97A) for form a(s) -camphorsulfonate of compound 1 and a DSC pattern (97B) for form a(s) -camphorsulfonate of compound 1.

Figure 98 depicts the FT-raman spectrum of form b(s) -camphorsulfonate of compound 1.

Figure 99 depicts the XRPD pattern of form b(s) -camphorsulfonic acid salt of compound 1.

Figure 100 depicts a TGA pattern (100A) for form B(s) -camphorsulfonate of compound 1 and a DSC pattern (100B) for form B(s) -camphorsulfonate of compound 1.

Figure 101 depicts the XRPD pattern of form a edisylate salt of compound 1.

Figure 102 depicts the XRPD pattern of form B edisylate salt of compound 1.

Figure 103 depicts the XRPD pattern of form C edisylate salt of compound 1.

Figure 104 depicts the XRPD pattern of form D edisylate salt of compound 1.

Figure 105 depicts a TGA pattern (105A) for form a edisylate salt of compound 1 and a DSC pattern (105B) for form a edisylate salt of compound 1.

Figure 106 depicts a DSC pattern for form C edisylate of compound 1 (106A), form B edisylate of compound 1 (106B), form D edisylate of compound 1 (106C), and form a edisylate of compound 1 (106D).

Figure 107 depicts the XRPD pattern of form a ethanesulfonate of compound 1.

Figure 108 depicts the XRPD pattern of form B ethanesulfonate of compound 1.

Figure 109 depicts a TGA pattern (109A) for form a ethanesulfonate of compound 1 and a DSC pattern (109B) for form a ethanesulfonate of compound 1.

Figure 110 depicts a TGA pattern (110A) for form B ethanesulfonate of compound 1 and a DSC pattern (110B) for form B ethanesulfonate of compound 1.

Figure 111 depicts the XRPD pattern of form a benzenesulfonate salt of compound 1.

Figure 112 depicts the XRPD pattern of form B besylate of compound 1.

Figure 113 depicts the XRPD pattern of form C benzenesulfonate salt of compound 1.

Figure 114 depicts the XRPD pattern of form D besylate of compound 1.

Figure 115 depicts the DSC pattern of form a benzenesulfonate salt of compound 1 (115A), form B benzenesulfonate salt of compound 1 (115B), form C benzenesulfonate salt of compound 1 (115C), and form D benzenesulfonate salt of compound 1 (115D).

Figure 116 depicts a TGA pattern (116A) for form D benzenesulfonate salt of compound 1 and a DSC pattern (116B) for form D benzenesulfonate salt of compound 1.

Figure 117 depicts the XRPD pattern of form a oxalate salt of compound 1.

Figure 118 depicts the XRPD pattern of form B oxalate salt of compound 1.

Figure 119 depicts a TGA pattern (119A) for form a oxalate salt of compound 1 and a DSC pattern (119B) for form a oxalate salt of compound 1.

Figure 120 depicts a TGA pattern (120A) for form B oxalate of compound 1 and a DSC pattern (120B) for form B oxalate of compound 1.

Figure 121 depicts the XRPD pattern of form a maleate salt of compound 1.

Figure 122 depicts a TGA pattern (122A) for form a maleate salt of compound 1 and a DSC pattern (122B) for form a maleate salt of compound 1.

Figure 123 depicts the XRPD pattern of form a pamoate salt of compound 1.

Figure 124 depicts a TGA pattern (124A) for form a pamoate salt of compound 1 and a DSC pattern (124B) for form a pamoate salt of compound 1.

Figure 125 depicts the XRPD pattern of form A1-hydroxy-2-naphthoate of compound 1.

FIG. 126 depicts a DSC profile of form A1-hydroxy-2-naphthoate of Compound 1.

Figure 127 depicts the XRPD pattern of form a malonate salt of compound 1.

Figure 128 depicts a TGA pattern (128A) for form a malonate of compound 1 and a DSC pattern (128B) for form a malonate of compound 1.

Figure 129 depicts the XRPD pattern of form B malonate salt of compound 1.

Figure 130 depicts a TGA pattern (130A) for form B malonate of compound 1 and a DSC pattern (130B) for form B malonate of compound 1.

Figure 131 depicts the XRPD pattern of form C malonate of compound 1.

Figure 132 depicts a DSC pattern for form C malonate of compound 1.

Figure 133 depicts the XRPD pattern of form A L-tartrate of compound 1.

Figure 134 depicts a TGA pattern (134A) for form A L-tartrate salt of compound 1 and a DSC pattern (134B) for form A L-tartrate salt of compound 1.

Figure 135 depicts the XRPD pattern of form B L-tartrate of compound 1.

Figure 136 depicts a DSC pattern of form B L-tartrate of compound 1.

Figure 137 depicts the XRPD pattern of form C L-tartrate of compound 1.

Figure 138 depicts a TGA pattern (138A) for form C L-tartrate salt of compound 1 and a DSC pattern (138B) for form C L-tartrate salt of compound 1.

Figure 139 depicts the XRPD pattern of form D L-tartrate of compound 1.

Figure 140 depicts a TGA pattern (140A) for form D L-tartrate salt of compound 1 and a DSC pattern (140B) for form D L-tartrate salt of compound 1.

Figure 141 depicts the XRPD pattern of form a fumarate salt of compound 1.

Figure 142 depicts a TGA pattern (142A) for form a fumarate salt of compound 1 and a DSC pattern (142B) for form a fumarate salt of compound 1.

Figure 143 depicts the XRPD pattern of form B fumarate salt of compound 1.

Figure 144 depicts a DSC pattern for form B fumarate salt of compound 1.

Figure 145 depicts the XRPD pattern of form C fumarate salt of compound 1.

Figure 146 depicts a TGA pattern (146A) for form C fumarate of compound 1 and a DSC pattern (146B) for form C fumarate of compound 1.

Figure 147 depicts the XRPD pattern of form D fumarate salt of compound 1.

Figure 148 depicts a TGA pattern (148A) for form D fumarate of compound 1 and a DSC pattern (148B) for form D fumarate of compound 1.

Figure 149 depicts the XRPD pattern of form a citrate salt of compound 1.

Figure 150 depicts a TGA pattern (150A) for form a citrate salt of compound 1 and a DSC pattern (150B) for form a citrate salt of compound 1.

Figure 151 depicts the XRPD pattern of form A L-lactate of compound 1.

Figure 152 depicts a TGA pattern (152A) for form A L-lactate of compound 1 and a DSC pattern (152B) for form A L-lactate of compound 1.

Figure 153 depicts the XRPD pattern of form a acetate salt of compound 1.

Figure 154 depicts a TGA pattern (154A) for form a acetate of compound 1 and a DSC pattern (154B) for form a acetate of compound 1.

Figure 155 depicts the XRPD pattern of form B acetate of compound 1.

Figure 156 depicts a TGA pattern (156A) for form B acetate of compound 1 and a DSC pattern (156B) for form B acetate of compound 1.

Figure 157 depicts the XRPD pattern of form a propionate of compound 1.

Fig. 158 depicts a TGA pattern (158A) for form a propionate of compound 1 and a DSC pattern (158B) for form a propionate of compound 1.

Figure 159 depicts the XRPD pattern of form a DL-lactate of compound 1.

Figure 160 depicts a TGA pattern (160A) for form a DL-lactate of compound 1 and a DSC pattern (160B) for form a DL-lactate of compound 1.

Figure 161 depicts the XRPD pattern of form A D-gluconate of compound 1.

Fig. 162 depicts the DSC pattern of form A D-gluconate of compound 1.

Figure 163 depicts the XRPD pattern of form a DL-malate salt of compound 1.

Figure 164 depicts a TGA pattern (164A) for form a DL-malate salt of compound 1 and a DSC pattern (164B) for form a DL-malate salt of compound 1.

Figure 165 depicts the XRPD pattern of form B DL-malate salt of compound 1.

Figure 166 depicts a TGA pattern (166A) for form B DL-malate salt of compound 1 and a DSC pattern (166B) for form B DL-malate salt of compound 1.

Figure 167 depicts the XRPD pattern of form a glycolate of compound 1.

Figure 168 depicts a TGA pattern (168A) for form a glycolate of compound 1 and a DSC pattern (168B) for form a glycolate of compound 1.

Figure 169 depicts the XRPD pattern of form a glutarate salt of compound 1.

Figure 170 depicts a TGA pattern (170A) for form a glutarate salt of compound 1 and a DSC pattern (170B) for form a glutarate salt of compound 1.

Figure 171 depicts the XRPD pattern of form B glutarate salt of compound 1.

Figure 172 depicts a TGA pattern (172A) for form B glutarate salt of compound 1 and a DSC pattern (172B) for form B glutarate salt of compound 1.

Figure 173 depicts the XRPD pattern of form A L-malate salt of compound 1.

Figure 174 depicts a TGA pattern (174A) for form A L-malate salt of compound 1 and a DSC pattern (174B) for form A L-malate salt of compound 1.

Figure 175 depicts the XRPD pattern of form a camphorate salt of compound 1.

Fig. 176 depicts a TGA pattern (176A) for form a camphorate salt of compound 1 and a DSC pattern (176B) for form a camphorate salt of compound 1.

Figure 177 depicts the XRPD pattern of form B camphorate salt of compound 1.

Fig. 178 depicts a TGA pattern (178A) for form B camphorate salt of compound 1 and a DSC pattern (178B) for form B camphorate salt of compound 1.

Fig. 179 depicts the XRPD pattern of form C camphorate salt of compound 1.

Fig. 180 depicts a TGA pattern (180A) for form C camphorate salt of compound 1 and a DSC pattern (180B) for form C camphorate salt of compound 1.

Figure 181 depicts the XRPD pattern of form D camphorate of compound 1.

Fig. 182 depicts a TGA pattern (182A) for form D camphorate salt of compound 1 and a DSC pattern (182B) for form D camphorate salt of compound 1.

Figure 183 depicts the XRPD pattern of form a DL-mandelate salt of compound 1.

Figure 184 depicts a TGA pattern (184A) for form a DL-mandelate salt of compound 1 and a DSC pattern (184B) for form a DL-mandelate salt of compound 1.

Figure 185 depicts the XRPD pattern of form B DL-mandelate salt of compound 1.

Figure 186 depicts a TGA pattern (186A) for form B DL-mandelate salt of compound 1 and a DSC pattern (186B) for form B DL-mandelate salt of compound 1.

Figure 187 depicts an XRPD pattern of form C DL-mandelate salt of compound 1.

Figure 188 depicts a TGA pattern (188A) for form C DL-mandelate salt of compound 1 and a DSC pattern (188B) for form C DL-mandelate salt of compound 1.

Figure 189 depicts an FT-raman spectrum of a form a saccharin co-crystal of compound 1.

Figure 190 depicts the XRPD pattern of form a saccharin co-crystal of compound 1.

Figure 191 depicts a TGA pattern of form a saccharin co-crystal of compound 1 (191A) and a DSC pattern of form a saccharin co-crystal of compound 1 (191B).

Figure 192 depicts form a saccharin co-crystal of compound 1¹H-NMR spectrum.

Figure 193 depicts the FT-raman spectrum of form a nicotinate salt of compound 1.

Figure 194 depicts the XRPD pattern of form a nicotinate salt of compound 1.

Figure 195 depicts a TGA pattern (195A) for form a nicotinate salt of compound 1 and a DSC pattern (195B) for form a nicotinate salt of compound 1.

Figure 196 depicts form a nicotinate salt of compound 1¹H-NMR spectrum.

Figure 197 depicts the XRPD pattern of form B nicotinate salt of compound 1.

Figure 198 depicts a TGA pattern of form B nicotinate salt of compound 1. Figure 198B depicts a DSC pattern of form B nicotinate salt of compound 1.

Figure 199 depicts the XRPD pattern of form C nicotinate salt of compound 1.

Figure 200 depicts a TGA pattern (200A) for form C nicotinate salt of compound 1 and a DSC pattern (200B) for form C nicotinate salt of compound 1.

Figure 201 depicts an FT-raman spectrum of form a ascorbate of compound 1.

Figure 202 depicts the XRPD pattern of form a ascorbate salt of compound 1.

Figure 203 depicts a TGA pattern (203A) for form a ascorbate salt of compound 1 and a DSC pattern (203B) for form a ascorbate salt of compound 1.

FIG. 204 depicts form A ascorbate of Compound 1¹H-NMR spectrum.

Figure 205 depicts an FT-raman spectrum of form a gallate salt of compound 1.

Figure 206 depicts the XRPD pattern of form a gallate salt of compound 1.

Figure 207 depicts a TGA pattern (207A) for form a gallate of compound 1 and a DSC pattern (207B) for form a gallate of compound 1.

FIG. 208 depicts the form A gallate of Compound 1¹H-NMR spectrum.

Figure 209 depicts the FT-raman spectrum of form a salicylate of compound 1.

Figure 210 depicts the XRPD pattern of form a salicylate of compound 1.

Figure 211 depicts a TGA pattern (211A) for form a salicylate of compound 1 and a DSC pattern (211B) for form a salicylate of compound 1.

FIG. 212 depicts form A salicylate of Compound 1¹H-NMR spectrum.

Figure 213 depicts the XRPD pattern of form a orotate salt of compound 1.

Figure 214 depicts a TGA pattern (214A) for form a orotate salt of compound 1 and a DSC pattern (214B) for form a orotate salt of compound 1.

Figure 215 depicts the XRPD pattern of a mixture of form B and form E orotate salts of compound 1.

Figure 216 depicts the XRPD pattern of a mixture of form C and form E orotate salts of compound 1.

Figure 217 depicts the XRPD pattern of form D orotate salt of compound 1.

Figure 218 depicts a TGA pattern (218A) for form D orotate salt of compound 1 and a DSC pattern (218B) for form D orotate salt of compound 1.

Figure 219 depicts the XRPD pattern of form E orotate salt of compound 1.

Figure 220 depicts a TGA pattern (220A) for form E orotate salt of compound 1 and a DSC pattern (220B) for form E orotate salt of compound 1.

Figure 221 depicts the XRPD pattern of form G orotate salt of compound 1.

Figure 222 depicts an FT-raman spectrum of form F orotate salt of compound 1.

Figure 223 depicts the XRPD pattern of form F orotate salt of compound 1.

Figure 224 depicts a TGA pattern (224A) for form F orotate salt of compound 1 and a DSC pattern (224B) for form F orotate salt of compound 1.

Figure 225 depicts the form F orotate salt of compound 1¹H-NMR spectrum.

Figure 226 depicts the FT-raman spectrum of form H orotate salt of compound 1.

Figure 227 depicts the XRPD pattern of form H orotate salt of compound 1.

Figure 228 depicts a TGA pattern (228A) for form H orotate salt of compound 1 and a DSC pattern (228B) for form H orotate salt of compound 1.

FIG. 229 depicts the orotate salt of form H of Compound 1¹H-NMR spectrum.

Figure 230 depicts XRPD patterns of a mixture of form a of compound 1, isonicotinamide co-crystal, and isonicotinamide co-former.

Figure 231 depicts the XRPD pattern of the form a pyrogallol cocrystal of compound 1, possibly mixed with one or more forms of the free base of compound 1.

Figure 232 depicts a TGA pattern (232A) for a mixture of form a pyrogallol cocrystals of compound 1, possibly mixed with one or more forms of compound 1 free base, and a DSC pattern (232B) for a mixture of form a pyrogallol cocrystals of compound 1, possibly mixed with one or more forms of compound 1 free base.

Figure 233 depicts an XRPD pattern of a form a xylitol co-crystal of compound 1, possibly mixed with one or more forms of the compound 1 free base and a xylitol co-former.

Figure 234 depicts the XRPD pattern of form B ascorbate salt of compound 1.

Figure 235 depicts a TGA pattern (235A) for form B ascorbate of compound 1 and a DSC pattern (235B) for form B ascorbate of compound 1.

Figure 236 depicts an XRPD pattern of a mixture of form a gallate of compound 1 and form B gallate of compound 1.

Figure 237 depicts the XRPD pattern of form B salicylate of compound 1.

Figure 238 depicts a TGA pattern (238A) for form B salicylate of compound 1 and a DSC pattern (238B) for form B salicylate of compound 1.

Figure 239 depicts the XRPD pattern of form B acetylsalicylate of compound 1.

Figure 240 depicts a TGA pattern (240A) for form B acetylsalicylate of compound 1 and a DSC pattern (240B) for form B acetylsalicylate of compound 1.

Detailed Description

General description of certain aspects of the invention

U.S. patent 7,528,143 issued on 5.5.2009, hereby incorporated by reference ("the' 143 patent") describes certain 2, 4-disubstituted pyrimidine compounds that are useful for treating myeloproliferative diseases, including polycythemia vera, essential thrombocythemia, and myelofibrosis (e.g., primary and secondary myelofibrosis, such as post-polycythemia vera and post-essential thrombocythemia myelofibrosis). Such compounds include compound 1:

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

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

Crystalline forms of compound 1

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

Thus, 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 does not contain significant amounts of foreign substances. 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 the crystalline form of compound 1. In certain embodiments, the sample comprises at least about 95% by weight of the crystalline form of compound 1. In other embodiments, the sample comprises at least about 99% by weight of the crystalline form of compound 1.

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

It has been found that compound 1 can exist in at least four different crystal forms or polymorphs.

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

in some embodiments, form a of compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 1.

In some embodiments, form a of compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in figure 2A.

In some embodiments, form a of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 2B.

In some embodiments, form a of compound 1 is characterized by a Dynamic Vapor Sorption (DVS) isotherm depicted in figure 2C.

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

in some embodiments, form B of compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 3.

In some embodiments, form B of compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in figure 4A.

In some embodiments, form B of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 4B.

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

in some embodiments, form C of compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 5.

In some embodiments, form C of compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in figure 6A.

In some embodiments, form C of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 6B.

In some embodiments, form C of compound 1 is characterized by a Dynamic Vapor Sorption (DVS) isotherm depicted in fig. 7.

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

in some embodiments, form D of compound 1 is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 8.

In some embodiments, form D of compound 1 is characterized by the thermogravimetric analysis (TGA) pattern depicted in figure 9A.

In some embodiments, form D of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 9B.

In some embodiments, it would be desirable to provide a form of compound 1 that confers features such as improved water solubility, stability, and ease of formulation as compared to compound 1. 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:

It will be appreciated that the complex comprising compound 1 and the co-former X may exist in pure or unsolvated form, hydrated form, solvated form, and/or hetero-solvated form. In some embodiments, the complex comprising compound 1 and the co-former X is in a pure or unsolvated crystalline form, and thus no water or solvent is incorporated into the crystalline structure. In some embodiments, the complex comprising compound 1 and the co-former X is in a hydrated or solvated form. In some embodiments, the complex comprising compound 1 and the co-former X is in a hydrate/solvate form (also referred to herein as a "heterosolvate"). In some embodiments, the present disclosure provides an anhydrous form of a complex comprising compound 1:

And a co-former X;

wherein:

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

and a co-former X;

wherein:

In some embodiments, the present disclosure provides solvate forms of a complex comprising compound 1:

and a co-former X;

wherein:

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

and a co-former X;

wherein:

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, for example, ionic interactions, dipole-dipole interactions, pi-stacking interactions, hydrogen bonding interactions, and the like.

It is to be understood that the term "complex" encompasses salt forms resulting from ionic interactions between compound 1 and an acid or base, as well as non-ionic associations between compound 1 and neutral species.

In some embodiments, the term "complex" is used herein to refer to a form comprising compound 1 associated with a co-former ion. Thus, in some such embodiments, the term "complex" is used herein to refer to a salt comprising compound 1 and an acid or base.

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

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

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

It will be appreciated that a complex comprising compound 1 and a co-former X may comprise 1 equivalent of X. Thus, in some embodiments, a complex described herein comprises compound 1 and 1 equivalent of X. In some embodiments, a complex described herein comprises compound 1 and 2 equivalents of X. In some embodiments, the complexes described herein comprise compound 1 and 3 equivalents of X. In some embodiments, a complex described herein comprises 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 compound 1 in the form of a complex, 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 excess co-former X, excess compound 1, residual solvent, or any other impurities that may result from the preparation and/or isolation of the complex form of compound 1. In certain embodiments, the sample comprises at least about 90% by weight of compound 1 in the form of a complex. In certain embodiments, the sample comprises at least about 95% by weight of compound 1 in complex form. In other embodiments, the sample comprises at least about 99% by weight of compound 1 in complex form.

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

The structures depicted for the complex form of compound 1 include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, having the structure of the invention but with hydrogen replaced by deuterium or tritium or with carbon replaced by deuterium¹³C or¹⁴C-enriched carbon-substituted compounds are within the scope of the invention.

In some embodiments, the complex form of compound 1 is crystalline, wherein X is selected from the group consisting of: hydrobromic acid, sulfuric acid, toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, phosphoric acid, DL-tartaric acid, succinic acid, gentisic acid, hippuric acid, adipic acid, galactaric acid, naphthalene-1, 5-disulfonic acid, (S) -camphor-10-sulfonic acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, benzenesulfonic acid, oxalic acid, maleic acid, pamoic acid, 1-hydroxy-2-naphthoic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, L-lactic acid, acetic acid, propionic acid, DL-lactic acid, D-gluconic acid, DL-malic acid, glutaric acid, camphoric acid, glycolic acid, L-malic acid, saccharin, 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 the complex form of compound 1, X is hydrobromic acid. In some such embodiments, the complex form of compound 1 is the hydrobromide salt. In some embodiments, the complex form of compound 1 comprises 1 equivalent of hydrobromic acid. In some embodiments, the hydrobromide salt of compound 1 is a crystalline hydrobromide salt. In some embodiments, the crystalline hydrobromide salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 9.3, 13.9, 16.6, 19.0 and 20.0 ± 0.2 degrees 2 Θ. In some such embodiments, the complex form of compound 1 is form a hydrobromide salt.

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

in some embodiments, the form a hydrobromide salt is characterized by an FT-raman spectrum depicted in figure 10.

In some embodiments, the form a hydrobromide salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 11.

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

In some embodiments, the form a hydrobromide salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 12B in figure 12.

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

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

in some embodiments, the form B hydrobromide salt is characterized by an FT-raman spectrum depicted in figure 13.

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

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

In some embodiments, form B is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 15B in figure 15.

In some embodiments, the form B hydrobromide salt is characterized by a Dynamic Vapor Sorption (DVS) isotherm depicted in figure 16.

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

In some embodiments, the sulfate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the sulfate salt of compound 1 is a crystalline hydrate form of the sulfate salt. In some embodiments, the crystalline hydrate form of the sulfate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a sulfate.

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

in some embodiments, form a sulfate is characterized by the FT-raman spectrum depicted in fig. 18.

In some embodiments, form a sulfate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 19.

In some embodiments, form a sulfate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 20A in figure 20.

In some embodiments, form a sulfate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 20B in figure 20.

In some embodiments, the sulfate salt of compound 1 is a heterosolvate. In some such embodiments, the heterosolvated form of the sulfate salt of compound 1 is water: a tetrahydrofuran heterosolvate. In some embodiments, the sulfate salt of compound 1 is water: the tetrahydrofuran heterosolvate form is the water of crystallization of the sulfate salt: tetrahydrofuran heterosolvate form. In some embodiments, the water of crystallization of the sulfate salt of compound 1: the tetrahydrofuran heterosolvate form 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B sulfate.

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

in some embodiments, form B sulfate is characterized by an FT-raman spectrum depicted in fig. 21.

In some embodiments, form B sulfate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in fig. 22.

In some embodiments, form B sulfate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 23A in figure 23.

In some embodiments, form B sulfate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 23B in figure 23.

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

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

in some embodiments, form C sulfate is characterized by an FT-raman spectrum depicted in figure 24.

In some embodiments, form C sulfate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 25.

In some embodiments, form C sulfate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 26.

In some embodiments, the complex form of compound 1 comprises 0.5 equivalents of sulfuric acid. In some embodiments, the sulfate salt of compound 1 is a solvate. In some embodiments, the solvate form of the sulfate salt of compound 1 is an acetone solvate. In some such embodiments, the solvate form of the sulfate salt of compound 1 is a diacetone solvate. In some embodiments, the diacetone solvate form of the sulfate salt of compound 1 is a crystalline diacetone solvate form of the sulfate salt. In some embodiments, the crystalline diacetone solvate form of the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form D sulfate.

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

in some embodiments, form D sulfate is characterized by an FT-raman spectrum depicted in fig. 27.

In some embodiments, form D sulfate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 28.

In some embodiments, form D sulfate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 29A in figure 29.

In some embodiments, form D sulfate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 29B in figure 29.

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

In some embodiments, the crystalline tosylate salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 4.3, 7.1, 8.6, 9.3, 17.2, and 17.8 ± 0.2 degrees 2 Θ. In some such embodiments, the 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:

in some embodiments, form a tosylate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 30.

In some embodiments, form a tosylate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 31A in figure 31.

In some embodiments, form a tosylate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 31B in figure 31.

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

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

in some embodiments, form B tosylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 32.

In some embodiments, form B tosylate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 33A in figure 33.

In some embodiments, form B tosylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 33B in figure 33.

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

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

in some embodiments, form C tosylate is characterized by an FT-raman spectrum depicted in figure 34.

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

In some embodiments, form C tosylate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 36A in figure 36.

In some embodiments, the form C tosylate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 36B in figure 36.

In some embodiments, form C tosylate is characterized by a dynamic vapor adsorption (DVS) isotherm depicted in figure 37.

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

In some embodiments, form C tosylate is characterized by what is depicted in figure 39¹H NMR。

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

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

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

in some embodiments, the form a mesylate salt is characterized by an FT-raman spectrum depicted in figure 40.

In some embodiments, the form a mesylate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 41.

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

In some embodiments, the form a mesylate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 42B in figure 42.

In some embodiments, the form a mesylate salt is characterized by what is depicted in figure 43¹H NMR。

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

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

in some embodiments, the form B mesylate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 44.

In some embodiments, the form B mesylate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 46B in figure 46.

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

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

in some embodiments, the form C mesylate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 45.

In some embodiments, the form C mesylate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 46C in figure 46.

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

In some embodiments, the complex form of compound 1 comprises 1.5 equivalents of 2-naphthalenesulfonic acid. In some embodiments, the 2-naphthalenesulfonate salt of compound 1 is a hemisolvate. In some such embodiments, the hemisolvate form of the 2-naphthalenesulfonate salt of compound 1 is a hemiacetone solvate. In some embodiments, the hemiacetone solvate form of the 2-naphthalenesulfonate of compound 1 is a crystalline hemiacetone solvate form of the 2-naphthalenesulfonate.

In some embodiments, the crystalline hemi-acetone solvate form of the 2-naphthalenesulfonate salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.6, 10.5, 10.9, 11.1, 12.6, 16.8, and 17.5 ± 0.2 degrees 2 Θ. In some such embodiments, the complex form of compound 1 is form A2-naphthalenesulfonate.

In some embodiments, form A2-naphthalenesulfonate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, form A2-naphthalenesulfonate is characterized by an FT-raman spectrum depicted in figure 47.

In some embodiments, the form A2-naphthalenesulfonate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in fig. 48.

In some embodiments, form A2-naphthalenesulfonate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 50A in figure 50.

In some embodiments, form A2-naphthalenesulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 50B in figure 50.

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

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

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

in some embodiments, form a phosphate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 52.

In some embodiments, form a phosphate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 56A in figure 56.

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

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

in some embodiments, form B phosphate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 53.

In some embodiments, form B phosphate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 56B in figure 56.

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

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

in some embodiments, form C phosphate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 54.

In some embodiments, form C phosphate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 56C in figure 56.

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

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

in some embodiments, form D phosphate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 55.

In some embodiments, form D phosphate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 56D in figure 56.

In some embodiments, the complex form of compound 1 comprises 1 equivalent of phosphoric acid. In some embodiments, the phosphate salt of compound 1 is a solvate. In some embodiments, the solvate form of the phosphate salt of compound 1 is a methanol solvate. In some embodiments, the methanol solvate form of the phosphate salt of compound 1 is a crystalline methanol solvate. In some embodiments, the crystalline methanol solvate form of the phosphate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form E phosphate.

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

in some embodiments, form E phosphate is characterized by an FT-raman spectrum depicted in figure 57.

In some embodiments, form E phosphate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 58.

In some embodiments, form E phosphate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 59A in figure 59.

In some embodiments, form E phosphate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 59B in figure 59.

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

In some embodiments, the DL-tartrate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the DL-tartrate salt of compound 1 is a crystalline hydrate form of the DL-tartrate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a DL-tartrate.

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

in some embodiments, form a DL-tartrate is characterized by a FT-raman spectrum depicted in figure 60.

In some embodiments, form a DL-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 61.

In some embodiments, form a DL-tartrate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 62A in figure 62.

In some embodiments, form a DL-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 62B in figure 62.

In some embodiments, form a DL-tartrate is characterized by a Dynamic Vapor Sorption (DVS) isotherm pattern depicted in figure 63.

In some embodiments, form a DL-tartrate is characterized by what is depicted in figure 64¹H NMR。

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

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

in some embodiments, form B DL-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 65.

In some embodiments, form B DL-tartrate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 66A in figure 66.

In some embodiments, form B DL-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 66B in figure 66.

In some embodiments of the complex form of compound 1, X is succinic acid. In some such embodiments, the complex form of compound 1 is succinate. In some embodiments, the succinate salt of compound 1 is a crystalline succinate salt. In some embodiments, the crystalline succinate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the 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:

In some embodiments, form a succinate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 67.

In some embodiments, form a succinate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 68A in figure 68.

In some embodiments, form a succinate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 68B in figure 68.

In some embodiments, the complex form of compound 1 comprises 1 equivalent of succinic acid. In some embodiments, the crystalline succinate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B succinate.

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

in some embodiments, form B succinate is characterized by the FT-raman spectrum depicted in figure 69.

In some embodiments, form B succinate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 70.

In some embodiments, form B succinate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 71A in figure 71.

In some embodiments, form B succinate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 71B in figure 71.

In some embodiments, form B succinate is characterized by what is depicted in figure 72¹H NMR。

In some embodiments of the complex form of compound 1, X is gentisic acid. In some such embodiments, the complex form of compound 1 is gentisate. In some embodiments, the complex form of compound 1 comprises 1 equivalent of gentisic acid. In some embodiments, the gentisate salt of compound 1 is a crystalline gentisate salt. In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a gentisate salt.

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

in some embodiments, form a gentisate is characterized by an FT-raman spectrum depicted in figure 73.

In some embodiments, form a gentisate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 74.

In some embodiments, form a gentisate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 75A in figure 75.

In some embodiments, form a gentisate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 75B in figure 75.

In some embodiments, form a gentisate is characterized by what is depicted in figure 76¹H NMR。

In some embodiments of the complex form of compound 1, X is hippuric acid. In some such embodiments, the complex form of compound 1 is hippurate. In some embodiments, the complex form of compound 1 comprises 1 equivalent of hippuric acid. In some embodiments, the hippurate salt of compound 1 is a crystalline hippurate salt. In some embodiments, the crystalline hippurate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a hippurate.

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

In some embodiments, form a hippurate is characterized by the FT-raman spectrum depicted in figure 77.

In some embodiments, form a hippurate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 78.

In some embodiments, form a hippurate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 79A in figure 79.

In some embodiments, form a hippurate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 79B in figure 79.

In some embodiments, form a hippurate is characterized by what is depicted in figure 80¹H NMR。

In some embodiments of the complex form of compound 1, X is adipic acid. In some such embodiments, the complex form of compound 1 is an adipate salt. In some embodiments, the complex form of compound 1 comprises 0.9 equivalents of adipic acid. In some embodiments, the adipate salt of compound 1 is a crystalline adipate salt. In some embodiments, the crystalline adipate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a adipate.

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

in some embodiments, form a adipate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 81.

In some embodiments, form a adipate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 82A in figure 82.

In some embodiments, form a adipate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 82B in figure 82.

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

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

in some embodiments, form C adipate is characterized by an FT-raman spectrum depicted in figure 83.

In some embodiments, form C adipate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 84.

In some embodiments, form C adipate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 85A in figure 85.

In some embodiments, form C adipate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 85B in figure 85.

In some embodiments, form C adipate is characterized by what is depicted in figure 86¹H NMR。

In some embodiments of the complex form of compound 1, X is galactaric acid. In some such embodiments, the complex form of compound 1 is a galactarate salt. In some embodiments, the complex form of compound 1 comprises 1 equivalent of galactaric acid. In some embodiments, the galactaric acid salt of compound 1 is a crystalline galactaric acid salt. In some embodiments, the crystalline galactaric acid salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the 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:

In some embodiments, form a galactarate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 87.

In some embodiments, form a galactaric acid salt is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 89A in figure 89.

In some embodiments, form a galactarate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 89B in figure 89.

In some embodiments, form a galactarate salt is characterized by the depiction in figure 90¹H NMR。

In some embodiments of the complex form of compound 1, X is 1, 5-naphthalenedisulfonic acid. In some such embodiments, the complex form of compound 1 is 1, 5-naphthalenedisulfonate (also referred to as "naphthalenedisulfonate"). In some embodiments, the napadisylate salt of compound 1 is a crystalline napadisylate salt. In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a napadisylate.

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

In some embodiments, form a napadisylate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in fig. 91.

In some embodiments, form a napadisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 94A in figure 94.

In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B napadisylate.

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

in some embodiments, form B napadisylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in fig. 92.

In some embodiments, form B napadisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 94B in figure 94.

In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form C napadisylate.

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

in some embodiments, form C napadisylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in fig. 93.

In some embodiments, form C napadisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 94C in figure 94.

In some embodiments of the complex form of compound 1, X is (S) -camphorsulfonic acid. In some such embodiments, the complex form of compound 1 is (S) -camphorsulfonate. In some embodiments, the (S) -camphorsulfonate of compound 1 is a crystalline (S) -camphorsulfonate. In some embodiments, the crystalline (S) -camphorsulfonic acid 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a(s) -camphorsulfonate.

In some embodiments, the form a(s) -camphorsulfonic acid salt is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, the form a(s) -camphorsulfonate is characterized by the FT-raman spectrum depicted in figure 95.

In some embodiments, the form a(s) -camphorsulfonic acid salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 96.

In some embodiments, the form a(s) -camphorsulfonic acid salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 97A in figure 97.

In some embodiments, the form a(s) -camphorsulfonic acid salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 97B in figure 97.

In some embodiments, the crystalline (S) -camphorsulfonic acid 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 2 Θ. In some such embodiments, the complex form of compound 1 is form b(s) -camphorsulfonate.

In some embodiments, form b(s) -camphorsulfonic acid salt is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, form b(s) -camphorsulfonate is characterized by the FT-raman spectrum depicted in figure 98.

In some embodiments, the form b(s) -camphorsulfonic acid salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 99.

In some embodiments, form b(s) -camphorsulfonate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 100A in diagram 100.

In some embodiments, form B(s) -camphorsulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 100B of figure 100.

In some embodiments of the complex form of compound 1, X is 1, 2-ethanedisulfonic acid. In some such embodiments, the complex form of compound 1 is 1, 2-ethanedisulfonate (also referred to as "ethanedisulfonate"). In some embodiments, the edisylate salt of compound 1 is a crystalline edisylate salt. In some embodiments, the edisylate salt is a hydrate. In some embodiments, the hydrate form of the edisylate salt of compound 1 is a crystalline hydrate form of the edisylate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the 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:

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 ethanedisulfonate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 105A in figure 105.

In some embodiments, form a ethanedisulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 105B in figure 105.

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

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

in some embodiments, form B edisylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 102.

In some embodiments, form B edisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 106B of figure 106.

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

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

in some embodiments, form C ethanedisulfonate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 103.

In some embodiments, form C edisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 106A of figure 106.

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

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

in some embodiments, form D edisylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 104.

In some embodiments, form D edisylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 106C of figure 106.

In some embodiments of the complex form of compound 1, X is ethanesulfonic acid. In some such embodiments, the complex form of compound 1 is ethanesulfonate. In some embodiments, the ethanesulfonate of compound 1 is a crystalline ethanesulfonate. In some embodiments, the crystalline ethanesulfonate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a ethanesulfonate.

In some embodiments, form a ethanesulfonate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, form a ethanesulfonate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 107.

In some embodiments, form a ethanesulfonate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 109A in figure 109.

In some embodiments, form a ethanesulfonate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 109B of figure 109.

In some embodiments, the crystalline ethanesulfonate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B ethanesulfonate.

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

in some embodiments, form B ethanesulfonate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 108.

In some embodiments, form B ethanesulfonate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 110A in figure 110.

In some embodiments, form B ethanesulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted by trace 110B in figure 110.

In some embodiments of the complex form of compound 1, X is benzenesulfonic acid. In some such embodiments, the complex form of compound 1 is a benzenesulfonate (also referred to as "besylate"). In some embodiments, the benzenesulfonate salt of compound 1 is a crystalline benzenesulfonate salt. In some embodiments, the crystalline benzenesulfonate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a benzenesulfonate salt.

In some embodiments, form a benzenesulfonate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, the form a benzenesulfonate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 111.

In some embodiments, form a benzenesulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 115A in figure 115.

In some embodiments, the crystalline benzenesulfonate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B benzenesulfonate.

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

in some embodiments, the form B besylate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 112.

In some embodiments, form B benzenesulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 115B in figure 115.

In some embodiments, the crystalline benzenesulfonate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form C benzenesulfonate.

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

in some embodiments, the form C benzenesulfonate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 113.

In some embodiments, the form C benzenesulfonate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 115C in figure 115.

In some embodiments, the benzenesulfonate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the benzenesulfonate salt of compound 1 is a crystalline hydrate form of the benzenesulfonate salt. In some embodiments, the crystalline hydrate form of the benzenesulfonate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form D benzenesulfonate.

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

in some embodiments, form D benzenesulfonate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 114.

In some embodiments, form D benzenesulfonate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 116A of figure 116.

In some embodiments, form D benzenesulfonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 116B in figure 116.

In some embodiments of the complex form of compound 1, X is oxalic acid. In some such embodiments, the complex form of compound 1 is an oxalate salt. In some embodiments, the oxalate salt of compound 1 is a crystalline oxalate salt. In some embodiments, the oxalate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the oxalate salt of compound 1 is a crystalline hydrate form of the oxalate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a oxalate salt.

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

in some embodiments, the form a oxalate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 117.

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

In some embodiments, the form a oxalate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 119B in figure 119.

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

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

in some embodiments, the form B oxalate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 118.

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

In some embodiments, form B oxalate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 120B in figure 120.

In some embodiments of the complex form of compound 1, X is maleic acid. In some such embodiments, the complex form of compound 1 is a maleate salt. In some embodiments, the maleate salt of compound 1 is a crystalline maleate salt. In some embodiments, the maleate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the maleate salt of compound 1 is a crystalline hydrate form of the maleate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the 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:

in some embodiments, form a maleate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 121.

In some embodiments, form a maleate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 122A in figure 122.

In some embodiments, form a maleate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 122B in figure 122.

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

In some embodiments, form a pamoate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 123.

In some embodiments, form a pamoate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 124A in figure 124.

In some embodiments, form a pamoate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 124B in figure 124.

In some embodiments of the complex form of compound 1, X is 1-hydroxy-2-naphthoic acid. In some such embodiments, the complex form of compound 1 is 1-hydroxy-2-naphthoate. In some embodiments, the 1-hydroxy-2-naphthoate salt of compound 1 is a crystalline 1-hydroxy-2-naphthoate salt. In some embodiments, the crystalline 1-hydroxy-2-naphthoate salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 6.7, 8.4, 9.7, 10.8, and 16.0 ± 0.2 degrees 2 Θ. In some such embodiments, the complex form of compound 1 is form A1-hydroxy-2-naphthoate.

In some embodiments, form A1-hydroxy-2-naphthoate is characterized by the following peaks in its X-ray powder diffraction pattern:

In some embodiments, form A1-hydroxy-2-naphthoate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 125.

In some embodiments, form A1-hydroxy-2-naphthoate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 126.

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

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

in some embodiments, form a malonate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 127.

In some embodiments, the form a malonate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 128A in figure 128.

In some embodiments, the form a malonate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 128B in figure 128.

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

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

in some embodiments, the form B malonate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 129.

In some embodiments, form B malonate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 130A in figure 130.

In some embodiments, form B malonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 130B in figure 130.

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

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

in some embodiments, the form C malonate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 131.

In some embodiments, form C malonate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 132.

In some embodiments of the complex form of compound 1, X is L-tartaric acid. In some such embodiments, the complex form of compound 1 is L-tartrate. In some embodiments, the L-tartrate salt of compound 1 is a crystalline L-tartrate salt. In some embodiments, the crystalline L-tartrate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form A L-tartrate.

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

in some embodiments, form A L-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 133.

In some embodiments, form A L-tartrate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 134A in figure 134.

In some embodiments, form A L-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 134B in figure 134.

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

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

in some embodiments, form B L-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 135.

In some embodiments, form B L-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern as depicted in figure 136.

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

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

in some embodiments, form C L-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 137.

In some embodiments, form C L-tartrate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 138A in figure 138.

In some embodiments, form C L-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 138B in figure 138.

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

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

in some embodiments, form D L-tartrate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 139.

In some embodiments, form D L-tartrate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 140A in figure 140.

In some embodiments, form D L-tartrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 140B of figure 140.

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

in some embodiments, form a fumarate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 141.

In some embodiments, form a fumarate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 142A in figure 142.

In some embodiments, form a fumarate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 142B in figure 142.

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

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

in some embodiments, form B fumarate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 143.

In some embodiments, form B fumarate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 144.

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

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

in some embodiments, form C fumarate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 145.

In some embodiments, form C fumarate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 146A in figure 146.

In some embodiments, form C fumarate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 146B in figure 146.

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

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

in some embodiments, form D fumarate salt of compound 1 is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 147.

In some embodiments, form D fumarate salt of compound 1 is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 148A in figure 148.

In some embodiments, form D fumarate salt of compound 1 is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 148B in figure 148.

In some embodiments of the complex form of compound 1, X is citric acid. In some such embodiments, the complex form of compound 1 is citrate. In some embodiments, the citrate salt of compound 1 is a crystalline citrate salt. In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a citrate.

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

in some embodiments, form a citrate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 149.

In some embodiments, form a citrate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 150A of figure 150.

In some embodiments, form a citrate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 150B in figure 150.

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

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

In some embodiments, form A L-lactate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 151.

In some embodiments, form A L-lactate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 152A in figure 152.

In some embodiments, form A L-lactate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 152B of figure 152.

In some embodiments of the complex form of compound 1, X is acetic acid. In some such embodiments, the complex form of compound 1 is an acetate salt. In some embodiments, the acetate salt of compound 1 is a crystalline acetate salt. In some embodiments, the crystalline acetate salt of compound 1 is characterized by one or more peaks 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a acetate salt.

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

in some embodiments, form a acetate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 153.

In some embodiments, form a acetate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 154A in figure 154.

In some embodiments, form a acetate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 154B in figure 154.

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

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

in some embodiments, form B acetate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 155.

In some embodiments, form B acetate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 156A in figure 156.

In some embodiments, form B acetate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 156B of figure 156.

In some embodiments of the complex form of compound 1, X is propionic acid. In some such embodiments, the complex form of compound 1 is a propionate. In some embodiments, the propionate of compound 1 is a crystalline propionate. In some embodiments, the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a propionate.

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

in some embodiments, form a propionate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 157.

In some embodiments, form a propionate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 158A in figure 158.

In some embodiments, form a propionate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 158B in figure 158.

In some embodiments of the complex form of compound 1, X is DL-lactic acid. In some such embodiments, the complex form of compound 1 is a DL-lactate. In some embodiments, the DL-lactate salt of compound 1 is a crystalline DL-lactate salt. In some embodiments, the crystalline DL-lactate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a DL-lactate.

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

In some embodiments, form a DL-lactate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 159.

In some embodiments, form a DL-lactate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 160A in graph 160.

In some embodiments, form a DL-lactate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 160B in figure 160.

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

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

in some embodiments, form A D-gluconate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 161.

In some embodiments, form A D-gluconate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in figure 162.

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

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

in some embodiments, form a DL-malate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 163.

In some embodiments, form a DL-malate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 164A in figure 164.

In some embodiments, form a DL-malate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 164B in figure 164.

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

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

in some embodiments, form B DL-malate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 165.

In some embodiments, form B DL-malate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 166A in figure 166.

In some embodiments, form B DL-malate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 166B in figure 166.

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

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

in some embodiments, form a glycolate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 167.

In some embodiments, form a glycolate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 168A in figure 168.

In some embodiments, form a glycolate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 168B in figure 168.

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

In some embodiments, form a glutarate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 169.

In some embodiments, form a glutarate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 170A in diagram 170.

In some embodiments, form a glutarate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 170B in figure 170.

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

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

in some embodiments, form B glutarate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 171.

In some embodiments, form B glutarate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 172A in figure 172.

In some embodiments, form B glutarate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 172B in figure 172.

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

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

in some embodiments, form A L-malate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 173.

In some embodiments, form A L-malate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 174A in figure 174.

In some embodiments, form A L-malate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted by trace 174B in figure 174.

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

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

in some embodiments, form a camphorate salt is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 175.

In some embodiments, form a camphorate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 176A in figure 176.

In some embodiments, form a camphorate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 176B of figure 176.

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

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

in some embodiments, form B camphorate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 177.

In some embodiments, form B camphorate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 178A of figure 178.

In some embodiments, form B camphorate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 178B of fig. 178.

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

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

in some embodiments, form C camphorate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in fig. 179.

In some embodiments, form C camphorate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 180A of figure 180.

In some embodiments, form C camphorate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 180B of figure 180.

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

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

in some embodiments, form D camphorate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 181.

In some embodiments, form D camphorate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 182A in figure 182.

In some embodiments, form D camphorate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 182B of figure 182.

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

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

In some embodiments, form a DL-mandelate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 183.

In some embodiments, form a DL-mandelate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 184A of figure 184.

In some embodiments, form a DL-mandelate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 184B in figure 184.

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

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

in some embodiments, form B DL-mandelate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 185.

In some embodiments, form B DL-mandelate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 186A of figure 186.

In some embodiments, form B DL-mandelate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 186B of figure 186.

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

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

in some embodiments, form C DL-mandelate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 187.

In some embodiments, form C DL-mandelate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 188A in figure 188.

In some embodiments, form C DL-mandelate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in fig. 188, trace 188B.

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

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

in some embodiments, the form a saccharin co-crystal is characterized by an FT-raman spectrum depicted in figure 189.

In some embodiments, the form a saccharin co-crystal is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 190.

In some embodiments, the form a saccharin co-crystal is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 191A in figure 191.

In some embodiments, the form a saccharin co-crystal is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 191B in figure 191.

In some embodiments, the form a saccharin co-crystal is characterized by the depiction in figure 192¹H NMR spectrum.

In some embodiments of the complex form of compound 1, X is nicotinic acid. In some such embodiments, the complex form of compound 1 is a nicotinate salt. In some embodiments, the nicotinate salt of compound 1 is a crystalline nicotinate salt. In some embodiments, the complex form of compound 1 comprises 1 equivalent of niacin. In some embodiments, the crystalline nicotinate salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from 7.8, 8.9, 14.0, 16.8, and 17.9 ± 0.2 degrees 2 Θ. In some such embodiments, the 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:

in some embodiments, form a nicotinate is characterized by an FT-raman spectrum depicted in figure 193.

In some embodiments, form a nicotinate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 194.

In some embodiments, form a nicotinate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 195A in figure 195.

In some embodiments, form a nicotinate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 195B in figure 195.

In some embodiments, form a nicotinate is characterized by what is depicted in figure 196¹H NMR spectrum.

In some embodiments, the nicotinate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the nicotinate salt of compound 1 is a crystalline hydrate form of the nicotinate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B nicotinate.

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

in some embodiments, form B nicotinate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 197.

In some embodiments, form B nicotinate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 198A in figure 198.

In some embodiments, form B nicotinate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 198B in figure 198.

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

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

in some embodiments, form C nicotinate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 199.

In some embodiments, form C nicotinate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 200A of diagram 200.

In some embodiments, form C nicotinate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 200B in figure 200.

In some embodiments of the complex form of compound 1, X is ascorbic acid. In some such embodiments, the complex form of compound 1 is ascorbate. In some embodiments, the ascorbate salt of compound 1 is a crystalline ascorbate salt. In some embodiments, the complex form of compound 1 comprises 1 equivalent of ascorbic acid. In some embodiments, the ascorbate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the ascorbate salt of compound 1 is a crystalline hydrate form of the ascorbate salt. In some embodiments, the crystalline hydrate form of the 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a ascorbate.

In some embodiments, form a ascorbate salt is characterized by the following peaks in its X-ray powder diffraction pattern:

In some embodiments, form a ascorbate is characterized by a FT-raman spectrum depicted in figure 201.

In some embodiments, form a ascorbate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 202.

In some embodiments, form a ascorbate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 203A in figure 203.

In some embodiments, form a ascorbate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 203B in figure 203.

In some embodiments, form a ascorbate is characterized by what is depicted in figure 204¹H NMR spectrum.

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

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

in some embodiments, form B ascorbate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 234.

In some embodiments, form B ascorbate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 235A in figure 235.

In some embodiments, form B ascorbate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 235B in figure 235.

In some embodiments of the complex form of compound 1, X is gallic acid. In some such embodiments, the complex form of compound 1 is a gallate salt. In some embodiments, the gallate salt of compound 1 is a crystalline gallate salt. In some embodiments, the complex form of compound 1 comprises 1 equivalent of gallic acid. In some embodiments, the gallic acid salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the gallate salt of compound 1 is a crystalline hydrate form of the gallate salt. In some embodiments, the crystalline hydrate form of the gallic acid salt of compound 1 is characterized by one or more peaks in its X-ray powder diffraction pattern selected from the group consisting of 3.8, 7.6, 11.5, 15.4, and 19.2 ± 0.2 degrees 2 Θ. In some such embodiments, the complex form of compound 1 is form a gallate.

In some embodiments, the form a gallate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, form a gallate is characterized by an FT-raman spectrum depicted in figure 205.

In some embodiments, form a gallate is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 206.

In some embodiments, the form a gallate is characterized by a thermogravimetric analysis (TGA) pattern depicted in trace 207A of figure 207.

In some embodiments, the form a gallate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 207B in figure 207.

In some embodiments, form a gallate is characterized as depicted in figure 208¹H NMR spectrum.

In some embodiments of the complex form of compound 1, X is salicylic acid. In some such embodiments, the complex form of compound 1 is a salicylate. In some embodiments, the salicylate salt of compound 1 is a crystalline salicylate salt. In some embodiments, the salicylate salt of compound 1 is a hydrate. In some embodiments, the hydrate form of the salicylate salt of compound 1 is a crystalline hydrate form of the salicylate salt. In some embodiments, the crystalline hydrate form of the 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 20. In some such embodiments, the complex form of compound 1 is form a salicylate.

In some embodiments, form a salicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, form a salicylate is characterized by an FT-raman spectrum depicted in figure 209.

In some embodiments, form a salicylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 210.

In some embodiments, form a salicylate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 211A in figure 211.

In some embodiments, form a salicylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 211B in figure 211.

In some embodiments, form a salicylate is characterized by what is depicted in figure 212¹H NMR spectrum.

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

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

In some embodiments, form B salicylate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 241.

In some embodiments, form B salicylate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 242A in figure 242.

In some embodiments, form B salicylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 242B in figure 242.

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

in some embodiments, form a orotate salt is characterized by an x-ray powder diffraction (XRPD) pattern as depicted in figure 213.

In some embodiments, form a orotate salt is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 214A in figure 214.

In some embodiments, form a orotate salt is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 214B in figure 214.

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

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

in some embodiments, form D orotate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 217.

In some embodiments, form D orotate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 218A in figure 218.

In some embodiments, form D orotate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 218B in figure 218.

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

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

in some embodiments, form F orotate is characterized by an FT-raman spectrum depicted in figure 222.

In some embodiments, form F orotate is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 223.

In some embodiments, form F orotate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 224A in figure 224.

In some embodiments, form F orotate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 224B in figure 224.

In some embodiments, form F orotate is characterized by what is depicted in figure 225¹H NMR spectrum.

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

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

In some embodiments, form H orotate is characterized by an FT-raman spectrum depicted in figure 226.

In some embodiments, the form H orotate salt is characterized by an x-ray powder diffraction (XRPD) pattern depicted in figure 227.

In some embodiments, form H orotate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 228A in figure 228.

In some embodiments, form H orotate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 228B in figure 228.

In some embodiments, form H orotate is characterized by what is depicted in figure 229¹H NMR spectrum.

In some embodiments of the complex form of compound 1, X is acetylsalicylic acid. In some such embodiments, the complex form of compound 1 is acetylsalicylate. In some embodiments, the acetylsalicylate of compound 1 is a crystalline acetylsalicylate. In some embodiments, the crystalline acetylsalicylate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form a acetylsalicylate.

In some embodiments, form a acetylsalicylate is characterized by the following peaks in its X-ray powder diffraction pattern:

in some embodiments, the crystalline acetylsalicylate 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 2 Θ. In some such embodiments, the complex form of compound 1 is form B acetylsalicylate.

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

in some embodiments, form B acetylsalicylate is characterized by the x-ray powder diffraction (XRPD) pattern depicted in figure 239.

In some embodiments, form B acetylsalicylate is characterized by a thermogravimetric analysis (TGA) pattern depicted by trace 240A in figure 240.

In some embodiments, form B acetylsalicylate is characterized by a Differential Scanning Calorimetry (DSC) pattern depicted in trace 240B of figure 240.

Use, formulation and application

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 the compositions of the present disclosure is effective to measurably inhibit JAK2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the compositions of the present disclosure are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions of the present disclosure are formulated for oral administration to a patient.

In accordance with the methods of the present invention, the compounds and compositions are administered in any amount and by any route of administration effective to treat or reduce the severity of the conditions provided herein (i.e., JAK 2-mediated diseases or conditions). 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 its crystalline form or complex is preferably formulated in a unit dosage form for ease of administration and uniformity of dosage.

The compositions of the present disclosure may be administered orally, parenterally, by aerosol inhalation, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously.

Sterile injectable forms of the compositions of the present disclosure may be aqueous or oleaginous suspensions. 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, water, Ringer's solution and isotonic sodium chloride solution may be used. 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 diglycerides. 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 the 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 commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween, Span and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for formulation purposes.

The 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 its crystalline forms or complexes, it is often desirable to slow the absorption of the compound injected subcutaneously or intramuscularly. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of compound 1 or its crystalline form or complex then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of compound 1 or a crystalline form or complex thereof for parenteral administration is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by embedding compound 1 or a crystalline form or complex thereof in liposomes or microemulsions which are compatible with body tissues.

In some embodiments, the provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

The pharmaceutically acceptable compositions of the present disclosure may be administered orally 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 which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. 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 admixed 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 starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, 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 promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite; and/or i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols. 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 may also have a composition such that they release only or preferentially one or more active ingredients in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose (lactose/milk sugar) and high molecular weight polyethylene glycols.

Compound 1 or its crystalline form or complex may also be in the form of microcapsules with one or more of the above excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release 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 mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as is conventional, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have a composition such that they release only or preferentially one or more active ingredients in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may 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 its crystalline forms or complexes, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (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. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Alternatively, the pharmaceutically acceptable compositions of the present disclosure may be administered in the form of suppositories for rectal administration. These may be prepared by mixing compound 1 or its crystalline forms or complexes with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore 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 its crystalline forms or complexes 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.

The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

For topical use, the provided pharmaceutically acceptable compositions can be formulated into a suitable ointment containing compound 1, or a crystalline form or complex thereof, suspended or dissolved in one or more carriers. Carriers for topical application of compound 1 or its crystalline forms or complexes include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated into suitable lotions or creams 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, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably, as solutions in isotonic, pH adjusted sterile saline with or without the use of preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated into an ointment such as petrolatum.

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

Dosage forms for topical or transdermal administration of compound 1 or its crystalline forms or complexes include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. If desired, compound 1 or a crystalline form or complex thereof is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the invention. In addition, the present disclosure encompasses the use of transdermal patches that have the added advantage of providing controlled delivery of compound 1 or its crystalline forms or complexes to the body. Such dosage forms may be prepared by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of compound 1 or its crystalline form or complex across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing compound 1 or its crystalline form or complex in a polymer matrix or gel.

In some embodiments, the compositions described herein comprise an amount of compound 1, or a crystalline form or complex thereof, that is a molar equivalent of the free base N-tert-butyl-3- [ (5-methyl-2- { [4- (2-pyrrolidin-1-ylethoxy) phenyl ] amino } pyrimidin-4-yl) amino ] benzenesulfonamide. For example, a 100mg formulation of compound 1 (i.e., the unsolvated free base parent N-tert-butyl-3- [ (5-methyl-2- { [4- (2-pyrrolidin-1-ylethoxy) phenyl ] amino } pyrimidin-4-yl) amino ] benzenesulfonamide, MW-524.26) contained 117.30mg of compound 1 in the form of the dihydrochloride monohydrate (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 binders and lubricants.

In some embodiments, the binder is 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:

In certain embodiments, the composition comprises:

use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for inhibiting the kinase activity of one or more enzymes. Examples of kinases that are inhibited by the compounds and compositions described herein and for which the methods described herein are useful include JAK2 or mutants thereof.

The activity of compound 1 or a crystalline form or complex thereof useful as an inhibitor of JAK2 kinase or a mutant thereof can be determined in vitro, in vivo, or in a cell line. In vitro assays include assays to determine phosphorylation activity and/or subsequent functional outcome or inhibition of ATPase activity of activated JAK2 kinase or mutants thereof.

According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity in a biological sample, said method 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 invention relates to a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with compound 1 or a crystalline form or complex thereof or a composition thereof.

According to another embodiment, the present invention relates to a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, 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 of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient compound 1 or a crystalline form or complex thereof, or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

Compound 1 or its crystalline forms or complexes can be used to treat a variety of conditions including, but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy, and other angiogenesis-related disorders, including solid tumors and other types of cancer, ocular diseases, inflammation, psoriasis, and viral infections. The types of cancer that can be treated include, but are not limited to, cancers of the digestive/gastrointestinal tract, colon, liver, skin, breast, ovary, prostate, lymphoma, leukemia (including acute and chronic myelogenous leukemias), kidney, lung, muscle, bone, bladder, or brain.

Some examples of diseases and conditions that may be treated also include ocular neovascularization, infantile hemangiomas; organ hypoxia, vascular proliferation, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 1 diabetes and diabetic complications, inflammatory diseases, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular diseases, liver diseases, other blood disorders, asthma, rhinitis, atopy, dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, cytokine-related disorders; and other autoimmune diseases, including glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft-versus-host disease; neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, stroke, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and ischemia/reperfusion injury with platelet aggregation.

Some other examples of diseases and conditions that can be treated also include cell-mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., Systemic Lupus Erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus), hepatitis b, hepatitis c, HIV, HTLVI, varicella-zoster Virus, human papilloma Virus), food allergies, skin inflammation, and immunosuppression induced by solid tumors.

In some embodiments, compound 1 or a crystalline form or complex thereof can be used to treat a myeloproliferative disorder. In some embodiments, the myeloproliferative disorder is selected from the group consisting of primary myelofibrosis, polycythemia vera, and primary 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 the group consisting of post-polycythemia vera myelofibrosis and post-primary thrombocythemia myelofibrosis.

In some embodiments, provided methods comprise administering compound 1 or a crystalline form or complex thereof to a patient previously treated with a JAK2 inhibitor. In some such embodiments, provided methods comprise administering to a patient previously administered ruxotinib (ruxo)litinib)The patient being treated is administered compound 1 or a crystalline form or complex thereof.

In some embodiments, provided methods comprise administering compound 1 or a crystalline form or complex thereof to a patient suffering from or diagnosed with a myeloproliferative disorder that is non-responsive to ruxotinib. In some embodiments, the patient has or has been diagnosed with a myeloproliferative disorder that is refractory or resistant to ruxotinib.

In some embodiments, the patient has relapsed during or after ruxotinib therapy.

In some embodiments, the patient is intolerant to ruxotinib. In some embodiments, intolerance of ruxotinib in patients is evidenced by hematologic toxicity (e.g., anemia, thrombocytopenia, etc.) or non-hematologic toxicity.

In some embodiments, the patient is inadequately or 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 ruxotinib: at any time during ruxotinib treatment, the response is absent, disease progression or response is lost. In some embodiments, disease progression is evidenced by an increase in spleen size during ruxotinib treatment.

In some embodiments, a patient previously treated with ruxotinib has a somatic mutation or clonal marker associated with or indicative of a myeloproliferative disorder. In some embodiments, the somatic mutation is selected from the JAK2 mutation, CALR mutation, or 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 the group consisting of 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 ruxotinib-refractory.

In some embodiments, the myeloproliferative disorder is selected from the group consisting of intermediate-risk myelofibrosis and high-risk myelofibrosis.

In some embodiments, the stroke risk myelofibrosis is selected from primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis, and post-primary thrombocythemia (post-ET) myelofibrosis. In some embodiments, myelofibrosis is at risk level 1 (also referred to as intermediate level 1 risk). In some embodiments, myelofibrosis is grade 2 medium risk (also referred to as intermediate grade 2 risk).

In some embodiments, the high risk myelofibrosis is selected from primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis, and post-primary 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 indicating that the pharmaceutical composition can be used to treat one or more of the disorders identified above.

Further 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 2 Θ.

Embodiment 4 the crystalline form of embodiment 2, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

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-methyl-tetrahydrofuran 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 2 Θ.

Embodiment 8 the crystalline form of embodiment 6, wherein said form is characterized by the following peaks in its X-ray powder diffraction pattern:

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 2 Θ.

Embodiment 12 the crystalline form of embodiment 10, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

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 2 Θ.

Embodiment 15 the crystalline form of embodiment 13, wherein the form is characterized by the following peaks in its X-ray powder diffraction pattern:

embodiment 16. a sample comprising the crystalline form of any one of embodiments 1 to 15, wherein the sample is substantially free of impurities.

Embodiment 17 the sample of embodiment 16, wherein said sample comprises at least about 90% by weight of compound 1.

Embodiment 18 the sample of embodiment 16, wherein said sample comprises at least about 95% by weight of compound 1.

Embodiment 19 the sample of embodiment 16, wherein said 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% total organic impurities.

Embodiment 21 the sample of embodiment 16, wherein the sample comprises no more than about 3.0% total organic impurities.

Embodiment 22 the sample of embodiment 16, wherein the sample comprises no more than about 1.5% total organic impurities.

Embodiment 23 the sample of embodiment 16, wherein the sample comprises no more than about 1.0% total organic impurities.

Embodiment 24 the sample of embodiment 16, wherein the sample comprises no more than about 0.5% total organic impurities.

Embodiment 25. a complex comprising compound 1:

and a co-former X;

wherein the complex is crystalline, and

Embodiment 26. a complex comprising compound 1:

and a co-former X;

wherein:

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 of embodiments 25-69, wherein the sample is substantially free of impurities.

Embodiment 71 the sample of embodiment 70, wherein said sample comprises at least about 90% by weight of said complex.

Embodiment 72 the sample of embodiment 70, wherein said sample comprises at least about 95% by weight of said complex.

Embodiment 73 the sample of embodiment 70, wherein said sample comprises at least about 99% by weight of said complex.

Embodiment 74 the sample of embodiment 70, wherein the sample comprises no more than about 5.0% total organic impurities.

Embodiment 75 the sample of embodiment 70, wherein the sample comprises no more than about 3.0% total organic impurities.

Embodiment 76 the sample of embodiment 70, wherein the sample comprises no more than about 1.5% total organic impurities.

Embodiment 77 the sample of embodiment 70, wherein the sample comprises no more than about 1.0% total organic impurities.

Embodiment 78 the sample of embodiment 70, wherein the sample comprises no more than about 0.5% total organic impurities.

Embodiment 79 a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with the crystalline form of any one of embodiments 1-15 or a composition thereof.

Embodiment 80 a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient the crystalline form of any one of embodiments 1-15 or a composition thereof.

Embodiment 81 a method of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method comprising the step of administering to the patient the crystalline form of any one of embodiments 1-15, or a pharmaceutically acceptable composition thereof.

Embodiment 82 a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a complex of any one of embodiments 25-69, or a composition thereof.

Embodiment 83 a method of inhibiting the activity of JAK2 kinase or a mutant thereof in a patient, the method comprising the step of administering to the patient a complex of any one of embodiments 25-69, or a composition thereof.

Embodiment 84. a method of treating a JAK 2-mediated disease or disorder in a patient in need thereof, the method 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 1 equivalent of hydrobromic acid.

Embodiment 86. the complex of embodiment 27, wherein the complex comprises 2 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 1 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 1 equivalent of phosphoric acid.

Embodiment 92 the complex of embodiment 33 wherein the complex comprises 1 equivalent of DL-tartaric acid.

Embodiment 93. the complex of embodiment 34 wherein the complex comprises 1 equivalent of succinic acid.

Embodiment 94 the complex of embodiment 35 wherein the complex comprises 1 equivalent of gentisic acid.

Embodiment 95 the complex of embodiment 36 wherein the complex comprises 1 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 1 equivalent of galactaric acid.

Embodiment 98 the complex of embodiment 63 wherein the complex comprises 1 equivalent of saccharin.

Embodiment 99 the complex of embodiment 64 wherein the complex comprises 1 equivalent of niacin.

Embodiment 100 the complex of embodiment 65 wherein the complex comprises 1 equivalent of ascorbic acid.

Embodiment 101 the complex of embodiment 66, wherein the complex comprises 1 equivalent of gallic acid.

Embodiment 102 the complex of embodiment 68 wherein the complex comprises 1 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.

Example

Instrument for measuring the position of a moving object

FT-raman spectroscopy using a spectrometer equipped with 1064nm Nd: YVO₄Excitation laser, InGaAs and liquid N₂Raman spectra were collected from a cooled Ge detector and a Nicolet NXR9650 or NXR 960 spectrometer (Thermo Electron) from MicroStage. At 4cm^-1Resolution, 64 scans, all spectra were obtained using the Happ-Genzel apodization function and 2-step zero fill.

Powder X-ray diffraction (PXRD or XRPD) Cu Ka (45kV/40mA) radiation and 0.02 ° 2 θ step size and X 'cell on a PANalytical X' Pert Pro diffractometer using Ni filtering^TMThe RTMS (real time strip) detector obtains a PXRD (or XRPD) diffraction pattern. Arrangement of incident beam side: fixed divergence slit (0.25 deg.), 0.04rad Soller slit, anti-divergence slit (0.25 deg.) and 10mm beam mask. Arrangement on diffracted beam side: fixed divergence slit (0.25 °) and 0.04rad Soller slit. The sample was laid down on a zero background Si wafer.

Differential Scanning Calorimetry (DSC). Using a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a cryocooling system, at 40mL/min N₂DSC was performed under purge. DSC thermograms were obtained at 15 ℃/min in crimped A1 pans.

Thermogravimetric analysis (TGA) using a TA Instruments Q500 thermogravimetric analyzer at 40mL/minN₂TGA thermograms were obtained in Pt or a1 trays at 15 ℃/min under a purge.

Thermogravimetric analysis and infrared exhaust gas detection (TGA-IR) use and provision of an external TGA-IR module andTGA-IR was performed with a TA Instruments Q5000 thermogravimetric analyzer interfaced with Nicolet 6700 FT-IR spectrometer (Thermo Electron) of a gas flow cell and DTGS detector. At 60mL/min N₂TGA was performed in Pt or A1 trays at flow rates and 15 deg.C/min heating rates. At 4cm^-1Resolution and 32 scans IR spectra were collected at each time point.

High Performance Liquid Chromatography (HPLC) analysis was performed using an HP1100 system equipped with a G1131 quadrupole pump, a G1367A autosampler, and a G1315B diode array detector. Column: luna C18(2) (50X2.0mm, 3 μm). Mobile phase: 100% water (0.05% TFA) to 95% ACN (0.05% TFA) and 2 min re-equilibration over 8 min. Flow rate: 1 mL/min. And (3) detection: 254 nm.

Proton nuclear magnetic resonance (¹H NMR) prepared by dissolving the solid in DMSO-d6 ¹Solution by H NMR. Spectra were collected using an Agilent DD 2500 MHz spectrometer with TMS reference.

Ion Chromatography (IC) ion chromatography was performed on Dionex ICS-3000. Column: dionex lonpac AS12A 4x200 mm; and (3) detection: inhibited conductivity, ASRS 300 with 22mA inhibited current; eluent (2.7mM Na)₂CO₃/0.3mM NaHCO₃)，1.5mL/min。

EXAMPLE 1 Compound 1 free base (form C)

Compound 1 dihydrochloride (44.5g) was dissolved in water (498 mL). Aqueous sodium hydroxide (2.0 equiv.; 5N; 28.9mL) was added slowly, followed by acetonitrile (80mL) and seed crystals of Compound 1 form C (400 mg). The suspension was stirred at room temperature for 2 hours. The crystalline solid was isolated by vacuum filtration, washed with water (2x100mL) and MTBE (2x50mL), and air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ while passing nitrogen for 24 hours. The yield of crystalline free base was 97.5% (37 g).

Compound 1 form C is a white crystalline powder and characterized by XRPD (fig. 5), TGA (fig. 6A), DSC (fig. 6B), and DVS (fig. 7). The thermal data shows that the free base is in the monohydrate form with a weight loss of 3.2% water. HPLC analysis indicated a purity of 99.5%. IC data detected no chloride present, confirming conversion to the free base.

The solubility of compound 1 free base (form C) was estimated by visual assessment of dissolution in various solvents at room temperature and 40 ℃. An aliquot of the solvent was added to 10mg of the free base at room temperature until complete dissolution or until a maximum volume of 1.8mL was added. The suspension which did not dissolve at room temperature was heated to 40 ℃ and checked for dissolution. After visual assessment of solubility, additional form C was added to the dissolved sample to produce a dilute suspension. The suspension was stirred at room temperature for 18 hours and the solid was isolated by vacuum filtration. Solids were analyzed by PXRD and compared to the parent group identified during concurrent salt screening.

Example 2 Primary salt screening for Feratinib (Fedratinib)

Phenanthroline has two basic sites (pK)_a9.3, 6.4) for salt formation. Fifty-three counter ion and stoichiometric combinations were selected. Table 1 provides the additives, pK_aSummary of values, method of administration and dose equivalents for each additive.

TABLE 1 additives utilized in the screening study

Various crystallization patterns were used for salt screening studies and are shown below:

1. the solution/suspension was aged for two days with temperature cycling between 40 ℃ and 5 ℃.

2. The solvent was rapidly evaporated under reduced pressure.

3. The solution was cooled at 5 ℃ for up to two days.

4. The solvent was slowly evaporated at room temperature for up to seven days.

At the end of each crystallization mode, all samples were checked for crystallinity by Polarized Light Microscopy (PLM). If the experiment yields a birefringent selection, the solid is isolated by vacuum filtration and air dried at room temperature for up to two hours while applying vacuum. The solids were analyzed by FT-raman spectroscopy and/or PXRD.

FT-raman spectra/PXRD patterns of samples prepared using the same additives were compared to determine if they were the same crystal form. Representative samples from each unique group were further characterized using PXRD, DSC, TGA, and TGA-IR analysis (as appropriate).

Table 2 summarizes the results of the salt screening study. Salt screening experiments crystalline salt hits were obtained from 36 out of 42 unique additives. All remaining experiments yielded non-crystalline product (gum/amorphous glassy material) and was not isolated.

TABLE 2 salt screening results for phenanthroitinib

Symbol table:

the letters represent the Raman/PXRD grouping for each counterion

Example 3 Secondary salt Screen of Feizinib

Of the 36 salt selections, the following 13 salts were scaled up to the 200mg scale: HBr (forms a and B), sulfate (form a), tosylate (form a), mesylate (form a), 2-naphthalenesulfonate (form a/B mixture), phosphate (form D), DL-tartrate (form a), succinate (form a), gentisate (form a), hippurate (form a), adipate (form a) and galactarate (form a).

Example 3.1 hydrobromide salt

Two crystalline forms of the hydrobromide salt were identified from the salt screening experiments and designated form a and form B. Form a was identified using 1 equivalent of HBr, while form B was identified using 2 equivalents of HBr. Both forms a and B have promising thermal properties and are selected for scale-up.

Preparation of form A THF (6.3mL) was combined with crystalline free base form C (315mg) and aqueous hydrobromic acid (1.0 eq; 3M aq; 200 uL). Seed crystals of form a hydrobromide (ca 1mg) were added. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 1 hour. The yield of crystalline form a was 89.9% (327 mg).

Form a was crystalline as determined by FT-raman (fig. 10) and PXRD (fig. 11), and this material was birefringent as determined by PLM, with tiny irregular particles. DSC analysis showed two large endotherms at 215 ℃ and 231 ℃ (fig. 12, trace 12B), while TGA analysis showed a weight loss of 0.4% up to 100 ℃ (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 may be due to traces of form B (dihydrobromide).

Preparation of form B2-propanol (6.0mL) was combined with crystalline free base form C (300mg) and aqueous hydrobromic acid (2.0 eq; 3M aq; 381. mu.L). Seed crystals of hydrobromic acid salt (ca 1mg) were added. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 1 hour. The yield of crystalline form B was 83.8% (329 mg).

Form B was determined to be crystalline by FT-raman (fig. 13) and PXRD (fig. 14), and this material was determined to be birefringent by PLM, with tiny needles. DSC analysis showed a small broad endotherm at 72 ℃ and a large sharp endotherm at 233 ℃ (fig. 15, trace 15B), while TGA-IR analysis showed a weight loss of 2.4% water with trace amounts of IPA up to 100 ℃ (fig. 15, trace 15A). DVS analysis showed a water uptake of 0.9% between 5-95% RH (fig. 16). The 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 sulfate were identified from salt screening experiments and were designated as 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 has the most promising thermal properties and is selected for scaling up. A new form, form D, was identified from scale-up experiments.

Preparation of form D acetone (7.4mL) was combined with crystalline free base form C (372mg) and aqueous sulfuric acid (0.5 eq; 2.5M; 142. mu.L). Seed crystals of sulfate (about 1mg) were added. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline sulfate salt was 77.4% (315 mg).

Form D was crystalline as determined by FT-raman (fig. 27) and PXRD (fig. 28), but did not match form a. DSC analysis showed multiple complex endotherms (figure 29, trace 29B), while TGA-IR analysis showed a weight loss of 1.0% water followed by 6.7% acetone up to 160 ℃ (figure 29, trace 29A). Thermal data indicates that form D is an acetone solvate. Form D was 0.5: 1.0 (counterion: parent) sulfate as determined by ion chromatography.

EXAMPLE 3.3 tosylate

Two crystalline forms were identified from salt screening experiments and designated form a and form B. Form a was identified using 1 equivalent of p-toluenesulfonic acid, while form B was identified using 2 equivalents of p-toluenesulfonic acid. 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 has the most promising thermal properties and is selected for scaling up. A new form, form C, was identified from scale-up experiments.

Preparation of form C acetone (5.3mL) was combined with crystalline free base form C (265mg) and aqueous toluene sulfonic acid (1.0 equiv; 3M; 168. mu.L). Seeds of tosylate (form a, about 1mg) were added. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline tosylate was 86.7% (305 mg).

The tosylate salt was crystalline as determined by FT-raman (fig. 34) and PXRD (fig. 35), but did not match form a. DSC analysis (figure 36, trace 36B) shows a sharp higher temperature endotherm at 241 ℃, while TGA analysis (figure 36, trace 36A) shows a weight loss of 0.1% up to 100 ℃. Thermal data indicates that form C is unsolvated and is a more stable form than form a. DVS analysis (fig. 37) showed a moisture uptake of 1.2% between 5-95% RH. The PXRD pattern of the post-DVS sample did not show any change in crystal form (fig. 38). By passing¹H NMR (FIG. 39) determined that form C was 1.0: 1.0 (counterion: parent) tosylate.

Example 3.4 methanesulfonic acid salt

Three crystalline forms were identified from the salt screening experiments and were designated as forms A, B and C. Forms a and B were identified using 1 equivalent of methanesulfonic acid, while form C was identified using 2 equivalents of methanesulfonic acid. 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 has the most promising thermal properties and is selected for scaling up.

Preparation of form A acetone (6.0mL) was combined with crystalline free base form C (298mg) and aqueous methanesulfonic acid (1.0 eq; 3M; 189. mu.L). Seed crystals of the mesylate salt (form a, about 1mg) were added to the solution, and the solution was concentrated to dryness in vacuo. Acetone (3.0mL) was added and the suspension was reseeded with form a. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of the crystalline mesylate was 91.3% (322 mg).

The mesylate salt was crystalline and was substantially consistent with form a as determined by FT-raman (figure 40) and PXRD (figure 41). DSC analysis (fig. 42, trace 42B) showed a sharp endotherm at 207 ℃, while TGA analysis (fig. 42, trace 42A) showed a weight loss of 0.3% up to 100 ℃. By passing ¹H NMR (FIG. 43) determined that form A was 1.2: 1.0 (counterion: parent) methanesulfonate.¹H NMR data indicate that trace amounts of additional peaks in PXRD of form a may be due to the bis-mesylate salt impurity and that control of stoichiometry may be difficult.

Example 3.5.2-Naphthalenesulfonic acid salt

A crystalline form of 2-naphthalenesulfonate (form a) was identified from salt screening experiments using 1 or 2 equivalents of 2-naphthalenesulfonic acid. Form a has promising thermal properties and is selected for scaling up.

Preparation of form A acetone (5.0mL) was combined with crystalline free base form C (252mg) and 2-naphthalenesulfonic acid (1.0 equiv; 3M in THF; 160. mu.L). Seed crystals of 2-naphthalenesulfonate (form A, about 1mg) were added. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline 2-naphthalenesulfonate was 86.8% (349 mg).

The 2-naphthalenesulfonate salt was determined to be crystalline by FT-Raman (FIG. 47) and PXRD (FIG. 48). Form a was found to be a mixture with group B (acetone solvate) (fig. 49). The thermal data is very complex and shows a gradual loss of 0.9% of water up to 75 ℃ followed by a loss of 2.6% of acetone during 75-175 ℃ (figure 50). By passing ¹H NMR (FIG. 51) determined that form A was 1.5: 1.0 (counterion: parent) 2-naphthalenesulfonate and had 0.5 equivalents of acetone. Thermal data and¹h NMR data indicates the presence of acetone solvate impurity (form B) and that control of stoichiometry may be difficult.

EXAMPLE 3.6 phosphate salt

Four crystalline forms of phosphate were identified from the salt screening experiments and were designated as 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 has the most promising thermal properties and is selected for scaling up. A new form, form E, was identified from scale-up experiments.

Preparation of form E methanol (7.0mL) was combined with crystalline free base form C (350mg) and aqueous phosphoric acid (1.0 eq; 3M; 222. mu.L). Seed crystals of phosphate (form D, about 1mg) were added to the solution, and the solution was concentrated to dryness in vacuo. Methanol (3.0mL) was added and the suspension was reseeded. The suspension was stirred at room temperature (about 25 ℃) for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 1 hour and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline phosphate was 81.4% (338 mg).

Phosphate was determined to be crystalline by FT-raman (fig. 57) and PXRD (fig. 58), but not to match the target form, form D. DSC analysis showed multiple complex endotherms (figure 59, trace 59B), while TGA-IR analysis showed a weight loss of 3.8% water and methanol up to 125 ℃ (figure 59, trace 59A). The thermal data indicate that form E is a methanol solvate. Form E was determined to be 1.0: 1.0 (counterion: parent) phosphate by ion chromatography.

Example 3.7 DL-tartrate

The crystalline DL-tartrate hit was isolated from all eight salt formation experiments. The eight hits were divided into two groups (designated form a and form B) based on FT-raman spectral matching. Form a was isolated from seven of eight experiments and scaled up on a 200mg 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 (4.0mL) was combined with crystalline free base form C (198.88mg) and DL-tartaric acid (1.0 equivalent, administered as a solid). Seed crystals of DL-tartrate (ca. 1mg) were added. The suspension was heated to 50 ℃, stirred at 50 ℃ for 15 minutes, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline DL-tartrate was 66.8% (171 mg).

Form a was crystalline as determined by FT-raman (fig. 60) and PXRD (fig. 61). The DSC data showed a small, wide endotherm beginning at 25.4 ℃ followed by a second sharp endotherm at 194.4 ℃ (fig. 62, trace 62B). The TGA data shows a loss of about 3 wt% between 30-85 ℃ (fig. 62, trace 62A). TGA-IR analysis of the evolved gas showed water loss, indicating that form a of the DL-tartrate salt is a hydrate. DVS analysis (fig. 63) showed moisture uptake of about 2.2% between 5-95% RH. The PXRD pattern of the post-DVS sample did not show any change in crystal form. By passing¹H NMR analysis (FIG. 64), the stoichiometry of the DL-tartrate salt showed 1.0: 1.0 (counterion: parent).

EXAMPLE 3.8 succinate salt

The crystalline succinate salt hit was isolated from four out of eight salt formation experiments. The FT-raman spectra of all four hits were consistent with each other, indicating a single crystal form (designated form a). Form a was characterized by PXRD (fig. 67), TGA (fig. 68, trace 68A), and DSC (fig. 68, trace 68B). Attempts to prepare succinate form a on a 200mg scale were unsuccessful and resulted in a new crystalline form (designated form B).

Form B preparation IPA (7.5mL) was combined with crystalline free base form C (213.26mg) and succinic acid (1.0 equivalent, dosed as a solid). Seed crystals of succinate (ca.1 mg) were added. The suspension was heated to 40 ℃, stirred at 40 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. MeOH (0.75mL) was added to the suspension. The suspension was heated to 50 ℃, stirred at 50 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline succinate salt was 76.2% (199.3 mg).

Form B was crystalline as determined by FT-raman (fig. 69) and PXRD (fig. 70). The DSC data (fig. 71, trace 71B) shows a single endotherm at 153.2 ℃. TGA data (fig. 71, trace 71A) shows a loss of about 0.8 wt% between 30-165 ℃, indicating that form B may be a non-solvated form. By passing¹H NMR analysis (FIG. 72), the stoichiometry of the succinate salt showed 1.0: 1.0 (counterion: parent).

Example 3.9 gentisate salt

The crystalline gentisate salt hit was isolated from six of the eight salt formation experiments. The remaining experiments yielded gums/oils. The FT-raman spectra of all six hits were consistent with each other, indicating a single crystal form (designated form a). Form a was scaled up on a 200mg scale.

Preparation of form a IPA (7.5mL) was combined with crystalline free base form C (230.82mg) and gentisic acid (1.0 eq, administered as a solid). Seed crystals of gentisate (ca. 1mg) were added. The suspension was heated to 40 ℃, stirred at 40 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline gentisate salt was 79.3% (237.2 mg).

Form a was crystalline as determined by FT-raman (fig. 73) and PXRD (fig. 74). The DSC data showed a single endotherm at 200.2 ℃ (figure 75, trace 75B). TGA data showed a loss of about 0.8 wt% between 30-196 ℃, indicating that form a gentisate salt is likely to be the non-solvated form (figure 75, trace 75A). By passing¹H NMR analysis (FIG. 76), the stoichiometry of gentisate salt showed 1.0: 1.0 (counterion: parent).

Example 3.10 hippurate

The crystalline hippurate hits were isolated from six of the eight salt formation experiments. The remaining experiments yielded gums/oils. The FT-raman spectra of all six hits were consistent with each other, indicating a single crystal form (designated form a). Hippurate form a was scaled up on a 200mg scale.

Preparation of form a acetone (7.5mL) was combined with crystalline free base form C (218.98mg) and hippuric acid (1.0 equivalent, administered as a solid). Seed crystals of hippurate (about 1mg) were added. The suspension was heated to 40 ℃, stirred at 40 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline hippurate was 73.7% (217 mg).

Form a was crystalline as determined by FT-raman (fig. 77) and PXRD (fig. 78). The DSC data showed a single endotherm at 170.1 ℃ (fig. 79, trace 79B). TGA data shows a loss of about 0.1 wt% between 30-157 ℃, indicating that hippurate form a is the unsolvated form (fig. 79, trace 79A). By passing¹H NMR analysis (FIG. 80), the stoichiometry of hippurate showed 1.0: 1.0 (counterion: parent).

Example 3.11 adipic acid salt

The crystalline adipate selection was isolated from six of the eight salt formation experiments. The FT-raman spectra of five of the six crystalline hits coincided with each other, indicating a single crystalline form (designated form a), whereas the FT-raman spectra of samples isolated from acetone indicated a mixture of forms. Form a was characterized by PXRD (fig. 81), TGA (fig. 82, trace 82A), and DSC (fig. 82, trace 82B). Attempts to prepare form a on a 200mg scale were unsuccessful and resulted in a new crystalline form (designated form C).

Preparation of group C EtOAc (7.5mL) was combined with crystalline free base form C (210.27mg) and adipic acid (1.0 equivalent, dosed as a solid). Seed crystals of adipate (ca. 1mg) were added. The suspension was heated to 40 ℃, stirred at 40 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The suspension was heated to 50 ℃, stirred at 50 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The yield of crystalline adipate was 76.2% (205.2 mg).

Form C was crystalline as determined by FT-raman (fig. 83) and PXRD (fig. 84). The DSC data showed a small endotherm beginning at 93.2 ℃ followed by two sharp endotherms at 132.6 ℃ and 171.2 ℃ (fig. 85, trace 85B). The TGA data shows a loss of about 0.9 wt% between 30-180 ℃ (fig. 85, trace 85A). By passing¹H NMR analysis (FIG. 86), the stoichiometry of adipate showed 0.9: 1.0 (counterion: parent).

Example 3.12 galactaric acid salt

The crystalline galactarate salt selection was isolated from five of the eight salt formation experiments. The remaining experiments yielded gums/oils, free base or counter ion. The FT-raman spectra of all five salt hits were consistent with each other, indicating a single crystal form (designated form a). Galactarate form a was scaled up on a 200mg scale.

Preparation of form a acetone (7.5mL) was combined with crystalline free base form C (194.89mg) and galactaric acid (1.0 eq, administered as a solid). Seed crystals of galactaric acid salt (about 1mg) were added. The suspension was heated to 40 ℃, stirred at 40 ℃ for 5 hours, slowly cooled (0.1 ℃/min) to 25 ℃, and stirred at 25 ℃ for 16 hours. The crystalline solid was isolated by vacuum filtration, air dried under vacuum for 2 hours and dried in a vacuum oven at 40 ℃ for 4 hours. The crystalline galactaric acid salt was obtained in a yield of 86.9(237.5 mg).

Form a was crystalline as determined by FT-raman (fig. 87) and PXRD (fig. 88). The DSC data showed a single endotherm at 184.4 ℃ (figure 89, trace 89B). TGA data showed a loss of about 0.7 wt% between 30-157 ℃, indicating that galactaric acid salt form a is the unsolvated form (fig. 89, trace 89A). By passing¹H NMR analysis (FIG. 90), the stoichiometry of the galactarate salt showed 1.0: 1.0 (counterion: parent).

Example 3.13 crystallization of the salt intermediate

In addition to the crystalline salts discussed in examples 3.1-3.12, salt screening studies also yielded salts from various additives. Characterization data for these salt candidates are provided in table 3.

TABLE 3 crystallization options from screening

Example 4 Primary Co-Crystal Screen of Feizotinib

A total of 24 co-crystal formers (CCFs) were selected based on hydrogen bonding propensity, molecular diversity and pharmaceutical acceptability. 1 equivalent of CCF was given in all screening experiments. Table 4 presents the set of CCFs utilized.

TABLE 4 eutectic formers utilized in the screen

A total of five pure solvents and two binary mixtures were utilized in the presented eutectic screening experiments: THF, EtOAc, DCM, MIBK, MeOH, THF/cyclohexane (2: 8v/v) and IPA: water (9: 1 v/v). The selection is based on the diversity of the molecular structure and the characteristics of the solvent (e.g., polarity, chemical diversity) as well as the solubility of the free base form C ("API") from visual assessment of solubility.

A total of about 240 eutectic screening trials were performed using 24 CCFs and the following combinations: i) solvent drop milling (SDG) -using four solvents, ii) Slurry Ripening (SR) in six solvents, and iii) evaporating the solution obtained in step ii.

Solvent drop milling (SDG) several preliminary experiments were performed to determine the appropriate milling parameters for the SDG experiments. Table 5 summarizes the results of these experiments (milling with a milling ball at 15Hz for 15 minutes). The data indicate that for 100mg of API with 2-15 μ L of solvent, milling with a milling ball at 15Hz for 15 minutes is appropriate. The specific (initial) solvent volumes selected for the four solvents were: THF-5 μ L; EtOAc, DCM and MIBK-15. mu.L.

TABLE 5 determination of appropriate solvent drop milling (SDG) parameters

For the SDG experiment, API (about 100mg), stoichiometric CCF (1 eq) and the solvent THF, EtOAc, DCM or MIBK were combined in a stainless steel grind pot (10 mL). Milling was carried out at room temperature (about 23 ℃) on a Retsch mill (model MM301) for 15 minutes at 15Hz with a milling ball (7 MM). In cases where these parameters (based on the characteristics of CCF) were observed or expected to result in low yields or cementation, the grinding time was reduced to 10 minutes or hand ground using a mortar and pestle.

Slurry maturation (SR) the product from the SDG experiment was utilized and combined with the same four pure solvents used in the SDG experiment to perform the SR study, except that THF was replaced with THF: cyclohexane (2: 8 v/v). For CCF that gave the latent co-crystal (or salt) from SDG, a saturated solution of CCF was prepared in the specific solvent that gave the latent co-crystal or salt and used for SR experiments.

For the other two solvents (MeOH and IPA: water (9: 1v/v)), a 1: 1 (API: CCF) equivalent mixture was prepared and combined with the two solvent systems.

A saturated solution of CCF was prepared by combining CCF (to obtain an estimate of the suspension) with 2mL of solvent, then mixing for 16 hours at 23 ℃. The suspension was filtered through a 0.20 μm PTFE filter to give a saturated solution.

SR experiments were performed in 2mL vials containing flip-chip stirred discs and up to 1.9mL of solvent [ THF: cyclohexane (2: 8v/v), EtOAc, DCM, MIBK, MeOH, or IPA: water (9: 1v/v) ]. The samples were mixed and temperature cycled between 40 ℃ and 5 ℃ for 7 days followed by mixing at 25 ℃ for 5 days. During this treatment time, additional solvent is added to obtain a miscible suspension with sufficient solids for separation and analysis. The suspended solids were isolated by filtration and air dried for 18 hours.

Evaporate (EV) the solution obtained in the slurry maturation experiment was slowly evaporated (by loosening the small cap) in a fume hood until dry. The product was first checked for birefringence by PLM and if birefringent, further analyzed by PXRD.

All solids outputs screened were analyzed by PXRD to assess co-crystal formation. Possible co-crystals were analyzed by additional techniques (FT-raman, DSC, TGA-IR, PLM, etc.) as the case may be and if the amount of sample allowed.

The experiments performed resulted in potential co-crystals of form C free base with isonicotinamide, pyrogallol, saccharin and xylitol (pure or mixed with the parent and/or CCF), 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 for salicylic acid form a and acetylsalicylic acid form a were observed to be identical. Proton NMR analysis confirmed that acetylsalicylate form a was identical to salicylate form a, since no acetyl groups were observed. This is probably due to the hydrolysis of acetylsalicylic acid to salicylic acid during the maturation of the slurry.

Eutectic formers which do not give potential eutectics include urea, caffeine, niacinamide, L-prolinamide, vanillin, methyl paraben, propyl paraben, butylated hydroxyanisole, chrysin, resveratrol, quercetin, aspartame, sucralose and D-mannitol. These eutectic formers result in amorphous materials, parent forms, CCFs, or combinations thereof. The products obtained in the SDG and SR/EV experiments are shown in tables 6 and 7, respectively.

TABLE 6 screening of products from cocrystals or salts obtained by the SDG Process

Symbol table:

note that: A. b-identified crystalline forms

TABLE 8 Properties of Co-crystals or salts scaled up

Example 5 scaling up of the co-crystal.

Among the potential eutectic (or salt) candidates, seven of the following exhibit desirable physicochemical properties and are scaled up on the 250mg scale: saccharin form a, niacin form a, ascorbic acid form a, gallic acid form a, salicylic acid form a, and orotic acid forms F and H. The results are described in detail below.

Example 5.1 saccharin cocrystals

The saccharin co-crystal hit was obtained from six SR experiments. PXRD analysis of the samples indicated one form, designated form a. Form a (unsolvated) was scaled up (250mg scale) and characterized in detail.

Preparation of form A (non-solvated) form C free base (244.5mg) was combined with saccharin (83.1 mg; 1 eq.) and solvent (DCM, 3.5mL) and mixed for 30 min at 40 ℃ to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 2 hours and dried in a vacuum oven at 40 ℃ for 18 hours. The product weight was 287mg of form a (87% yield relative to the co-crystal).

Form a was determined to be a crystalline powder by FT-raman (fig. 189) and PXRD (fig. 190). DSC analysis showed that the melting endotherm started to appear at 183.8 ℃ (Δ H ═ 104.2J/g) (fig. 191, trace 191B). TGA analysis showed a weight loss of 0.1% between 26-174 ℃, indicating an unsolvated form (fig. 191, trace 191A). Proton NMR analysis of form a indicated that form a contained 1 equivalent of saccharin (fig. 192).

EXAMPLE 5.2 nicotinate

The nicotinate chow was obtained from three SR and one EV experiments. PXRD analysis of the samples indicated three forms, designated form a, form B and form C. Form a (unsolvated) was scaled up (250mg scale) and characterized in detail. 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 (252.8mg) was combined with nicotinic acid (57.9 mg; 1 eq.) and solvent (THF/cyclohexane (2: 8), 3.0mL) and mixed for 30 min at 40 ℃ to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 2 hours and dried in a vacuum oven at 40 ℃ for 18 hours. The weight of the product was 247mg of nicotinate form a (79% yield relative to salt).

Form a was determined to be a crystalline powder by FT-raman (fig. 193) and PXRD (fig. 194). DSC analysis showed the onset of the melting endotherm at 179.9 ℃ (Δ H-120.4J/g) (fig. 195, trace 195B). TGA analysis showed a weight loss of 0.2% between 29-168 ℃, indicating an unsolvated form (figure 195, trace 195A). Proton NMR analysis of form a indicated that form a contained 1 equivalent of niacin (fig. 196).

Example 5.3. L-ascorbic acid salt

The ascorbate selection was obtained from six SR experiments. PXRD analysis of the samples indicated two forms, designated form a and form B. Form a (hydrate) was scaled up (250mg scale) and characterized in detail.

Preparation of form A (hydrate). form C free base (249.7mg) was combined with L-ascorbic acid (81.6 mg; 1 eq.) and solvent (IPA/water (9: 1) v/v, 6.0mL) and mixed for 30 minutes at 40 deg.C to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 4 hours and kept open in a fume hood for 18 hours. The weight of the product was 294mg ascorbate form a (83% yield relative to salt).

Form a was determined to be a crystalline powder by FT-raman (figure 201) and PXRD (figure 202). DSC analysis showed an onset of dehydration endotherm at 46.0 ℃ (Δ H-168.5J/g), followed by a small endotherm at 116.8 ℃ (Δ H-7.5J/g) and an onset of melting endotherm (possibly two mergers) at 157.0 ℃ (Δ H-71.4J/g) (fig. 203, trace 203B). TGA analysis showed 5.4 wt% (2.2 equivalents) water loss between 29-140 ℃, indicating a hydrated form (figure 203, trace 203A). Proton NMR analysis of form a indicated that form a contained 1 equivalent of L-ascorbic acid (fig. 204).

Example 5.4 Gallic acid salt

The gallate hits were obtained from four SR experiments. PXRD analysis of the samples indicated two forms, designated form a and form B. Form a is obtained in pure form, while form B is obtained only in admixture with form a. Gallate form a (hydrate) was scaled up (250mg scale) and characterized in detail.

Preparation of form a (hydrate) form C free base (245.0mg) was combined with gallic acid (77.0 mg; 1 eq.) and solvent (MeOH, 4.0mL) and mixed for 30 min at 40 ℃ to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 4 hours and kept open in a fume hood for 18 hours. The product weight was 256mg gallate form A (77% yield relative to salt).

Form a was determined to be a crystalline powder by FT-raman (fig. 205) and PXRD (fig. 206). DSC analysis showed an onset of dehydration endotherm at 48.5 ℃ (Δ H-79.8J/g), followed by an onset of melting endotherm at 193.5 ℃ (Δ H-176.1J/g) (fig. 207, trace 207B). TGA analysis showed 2.4 wt% (1.0 eq) water loss between 22-89 ℃, indicating a hydrated form (figure 207, trace 207A). Proton NMR analysis of form a indicated that form B contained 1 equivalent of gallic acid (figure 208).

EXAMPLE 5.5 salicylates

Obtaining a salicylate hit from one SDG experiment and six SR experiments; however, the hits from SDG were a mixture of latent salts, parent and CCF. PXRD analysis of the six SR hits indicated two forms, designated form a and form B. Most of the hits (5/6) are consistent with form A. Salicylate form a (hydrate) was scaled up (250mg scale) and characterized in detail.

Preparation of form A (hydrate). form C free base (253.8mg) was combined with salicylic acid (64.7 mg; 1 eq.) and solvent (IPA/water 9: 1, 4.5mL) and mixed for 30 minutes at 40 ℃ to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 18 hours. The weight of the product was 272mg of salicylate form a (83% yield relative to salt).

Form a was determined to be a crystalline powder by FT-raman (fig. 209) and PXRD (fig. 210). DSC analysis showed an onset of dehydration endotherm at 34.9 ℃ (Δ H71.0J/g), followed by an onset of melting endotherm at 159.8 ℃ (Δ H83.8J/g) (fig. 211, trace 211B). TGA analysis showed 2.5 wt% (1.0 eq) water loss between 26-96 ℃, indicating a hydrated form (fig. 211, trace 211A). Proton NMR analysis of form a indicated that form a contained 1 equivalent of salicylic acid (fig. 212).

EXAMPLE 5.6 orotate salt

The orotate selection was obtained from six SR experiments. PXRD analysis of the hits indicated six forms, designated form a, form B, form C, form D, form E and form F. Scale-up experiments (250mg) were performed for forms E and F (hydrates) and the other groups were de-prioritized either by solvation or because they were a mixture of the two groups, as shown in table 7. Scale-up experiments of form E were unsuccessful and resulted in two new groups: form G and form H. Form G is MeOH/water solvate that desolvates to form H hydrate under ambient conditions. Form a was characterized by PXRD (panel 213), TGA (panel 214, trace 214A), and DSC (panel 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 (graph 219), TGA (graph 220, trace 220A), and DSC (graph 220, trace 220B). Form G was characterized by PXRD (fig. 221). Form F and form H (hydrate) of the orotate salt were scaled up (250mg) and characterized in detail.

Preparation of form F (hydrate). form C free base (250.0mg) was combined with orotic acid (77.0 mg; 1 eq.) and solvent (IPA/water 9: 1, 10.0mL) and mixed for 30 minutes at 40 deg.C to give a suspension. Seed crystals (about 5mg) were added and the suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 60 hours to give a medium consistency slurry. The solid was isolated by vacuum filtration for 22 hours. The product weight was 297mg orotate form F (82% yield relative to co-crystal).

Form F was determined to be a crystalline powder by FT-raman (figure 222) and PXRD (figure 223). DSC analysis showed two dehydration endotherms beginning at 56.5 ℃ (Δ H-86.1J/g) and 104.7 ℃ (Δ H-15.4J/g), respectively, followed by a melting endotherm beginning at 135.2 ℃ (Δ H-12.3J/g) (fig. 224, trace 224B). TGA analysis showed 10.8 wt% (4.5 equivalents) water loss between 24 ° -129 ℃, indicating a hydrated form (fig. 224, trace 224A). Proton NMR analysis of form F indicated that form F contained 1 equivalent of orotic acid (figure 225).

PXRD analysis of the sample after heating indicated a significant loss of crystallinity, but no change in form.

Preparation of form H (hydrate) form C free base (251.7mg) was combined with orotic acid (72.7 mg; 1 eq.) and solvent (MeOH, 1.0mL) and mixed for 10 min at 40 deg.C to give a near clear solution. Seed crystals (group E, about 5mg) were added and the suspension became very thick, so additional solvent (MeOH, 1.5mL) was added. The suspension was mixed at 40 ℃ for 2 hours, slowly cooled to 20 ℃ and mixed at 20 ℃ for 18 hours to give a medium consistency slurry. PXRD indicates a new form and DSC/TGA-IR indicates MeOH/water solvate, designated form G. The batch solids were isolated by vacuum filtration for 18 hours. The weight of the product was 178 mg. PXRD in turn indicates a new form, and DSC/TGA-IR indicates the hydrate, designated form H (53% yield relative to 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 beginning at 34.3 ℃ (Δ H ═ 23.4J/g), followed by two small endotherms at 134.5 ℃ and 144.4 ℃, respectively, a large endotherm beginning at 165.8 ℃ (Δ H ═ 44.6J/g), and a broad endotherm beginning at 203.4 ℃ (Δ H ═ 11.1J/g) (fig. 228, trace 228B). TGA analysis showed 3.2 wt% (1.2 equivalents) water loss between 23-95 ℃, indicating a hydrated form (figure 228, trace 228A). Proton NMR analysis of form H indicated that form H contained 1 equivalent of orotic acid (fig. 229).

PXRD analysis of the sample after heating indicated a loss of crystallinity and loss of several major peaks.

Example 5.7 other Co-crystals or salt selections

Acetylsalicylate form a was scaled up, however, the PXRD pattern was observed to be the same as that of salicylate form a. Proton NMR analysis confirmed that acetylsalicylate form a was identical to salicylate form a, since no acetyl groups were observed. This is probably due to the hydrolysis of acetylsalicylic acid to salicylic acid during the maturation of the slurry.

In addition to scaled-up co-crystals (or salts), several other potential co-crystals were obtained from the screen. These options are not fully characterized and/or scaled up because:

-the amount of samples is limited,

the physicochemical characteristics are not ideal (poor crystallinity/poor thermal characteristics),

identified as a mixture with the parent and/or CCF.

Table 9 summarizes representative samples of these co-crystal (or salt) candidates.

TABLE 9 attributes of other cocrystal or salt options identified in the Screen

Example 6 Water solubility of certain complexes

The solid/salt form (about 20-30mg) was transferred to a clear glass vial (4 ml). Water (about 0.2-2ml) was added separately to each vial containing the solid form. The volume of water added and the weight of the solid/salt form were adjusted appropriately to give an excess of undissolved solid/salt form. The vial containing the solid/salt form/water mixture was transferred to a stand held in rotation and the sample was equilibrated at ambient temperature for 24 hours with stirring. At the end of the equilibration process, the suspension was visually observed, and a sample was removed and centrifuged (14,000rpm for 3 minutes) in a Costar SPIN-X polypropylene centrifuge tube (2.0ml) filter (0.22mm nylon filter) to separate any undissolved drug. The drug content of the clear filtrate was determined and the solubility of the active substance in the solution was determined after appropriate dilution in acetonitrile/water (50: 50) if necessary. A standard curve was prepared for concentrations ranging from 0.126mg/ml to 0.001mg/ml using the free base. Drug content of samples and standards were determined using HPLC. The results are listed in table 10:

TABLE 10 solubility of certain forms of Compound 1

Solid forms	Solubility (mg/mL)
		Free base form A	0.003
HBr form A	2.3
		HBr form B	14.6
Sulfate salt form D	2.9
		Tosylate salt form C	0.1
Mesylate salt form A	11.0
		2-naphthalenesulfonates A	0.1
Phosphate form E	5.0
		Gentisate salt form a	0.1
Hippurate form A	1.4
		Adipate salt form a	9.7
Succinate salt form B	10.6
		DL-tartrate form A	0.6
Galactarate salt form a	15.3
		Niacin form A	4.0
Saccharin form A	0.1
		Ascorbic acid form A	5.4
Food without eatingDaughter acid form A	0.2
		Orotic acid form F	0.9
Orotic acid form H	0.6
		Salicylic acid form A	0.05

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