EA044284B1 - SOLID FORMS CONTAINING (S)-4-(4-(4-(((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YL)OXY)METHYL)BENZYL)PIPERAZINE-1 -IL)-3-FLUOROBENZONITRILE AND ITS SALTS, AND COMPOSITIONS CONTAINING THEM AND METHODS OF THEIR APPLICATION - Google Patents

Description

The invention claims benefit from U.S. Provisional Application No. 62/790342, filed January 9, 2019, which is incorporated herein by reference in its entirety.

1. Field of technology

Provided herein are salts and solid forms containing the free base or salts of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)oxy )methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. Also provided herein are pharmaceutical compositions containing such salts and solid forms, and methods of using such salts and solid forms for the treatment, prevention and control of various disorders.

2. Prerequisites for creating the invention

Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Plasma cells typically produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections and other complications. Multiple myeloma is the second most common hematologic malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M protein and other immunoglobulins (antibodies), albumin, and beta-2 microglobulin, except in some patients (estimated at 1 to 5%) , whose myeloma cells do not secrete these proteins (so-called nonsecretory myeloma). M protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma, except patients with nonsecretory myeloma or whose myeloma cells produce immunoglobulin light chains with a heavy chain.

Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells secrete osteoclast-stimulating factors (including IL-1, IL-6, and TNF), which cause calcium to be leached from bone, causing lytic lesions; hypercalcemia is another symptom. Osteoclast stimulating factors, also called cytokines, can prevent apoptosis or death of myeloma cells. Fifty percent of patients have radiologically detectable skeletal lesions associated with myeloma at the time of diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections and kidney failure.

Current therapy for multiple myeloma may involve one or more of surgery, stem cell transplant, chemotherapy, immunotherapy, and/or radiation therapy to destroy a patient's multiple myeloma cells. All modern therapeutic approaches create significant disadvantages for the patient.

In the last decade, new therapeutic agents, particularly immunomodulatory drugs such as lenalidomide and pomalidomide, have significantly improved response rates and prolonged progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma. However, persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, protein immunofixation electrophoresis, and light chain quantitation exist in many patients with multiple myeloma even after these patients achieve a complete response (CR), and over time will cause a relapse of the disease. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is being considered as a surrogate trial endpoint to improve identification of effective treatments, especially for exploratory studies that currently require 5 to 10 years of follow-up to identify differences in survival. Thus, minimal residual disease (MRD) monitoring in patients with multiple myeloma provides prognostic value for predicting PFS and OS and making treatment decisions. To detect minimal residual disease (MRD) in myeloma, a threshold of 0.01% (10 ^-4 ) after treatment can be used, i.e. having 10 ^-4 cells or less of multiple myeloma cells as a percentage of total bone marrow mononuclear cells is considered MRD-negative and having 10 ^-4 cells or more is MRD-positive. The 10 ^-4 MRD threshold was originally based on technical feasibility, but it is now possible to quantify MRD at 10 ^-5 using flow cytometry and 10 ^-6 using high-throughput sequencing. (Rawstron et al., Blood 2015;125(12):1932-1935). Methods for measuring MRD include DNA VDJ sequencing, polymerase chain reaction (PCR) (including allele-specific PCR, ASO-PCR), and multiparameter flow cytometry (MPF). MRD assays, for example, based on clonotype profile measurements, are also described in US Pat. No. 8,628,927 to Faham et al., which is incorporated herein by reference.

There is a significant need for safe and effective compounds and methods for the treatment, prevention and treatment of multiple myeloma, including for patients who are newly diagnosed with multiple myeloma or who are refractory to standard treatment, while reducing or preventing toxicity and/or side effects associated with conventional treatments.

Alternative solid forms of pharmaceutical compounds have emerged as a possible approach to modulate or enhance the physical and chemical properties of drugs. Identification and selection of the solid form of a pharmaceutical compound is complex, given that changing the solid form can affect various physical and chemical properties, which may provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, handling (eg, shipping), among other important pharmaceutical characteristics. Suitable pharmaceutical solid forms include crystalline solids and amorphous solids, depending on the product and route of administration. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired grade of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected based on, for example, improved dissolution profile, while crystalline solids may be desirable for properties such as, for example, physical or chemical stability (see, for example, S. R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

Notably, it is impossible to predict a priori whether crystalline forms of a compound exist at all, let alone how to successfully obtain them (see, for example, Braga and Grepioni, 2005, Making crystals from crystals: a green route to crystal engineering and polymorphism , Chem. Commun.: 3635-3645 (with respect to crystal engineering, if the instructions are not very precise and/or if other external factors influence the process, the result may be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement, MRS Bulletin 31:875-879 (at present, it is generally impossible to computationally predict the number of observed polymorphs of even the simplest molecules); Price, 2004, The computational prediction of pharmaceutical crystal structures and polymorphism, Advanced Drug Delivery Reviews 56:301-319 (Price); and Bernstein, 2004, Crystal Structure Prediction and Polymorphism, ACA Transactions 39:14-23 (much remains to be studied and done before predictive ability can be claimed with any degree of confidence crystal structure, not to mention polymorphic forms)).

The type of salt form of a particular active pharmaceutical ingredient may influence certain properties of the active pharmaceutical ingredient. These properties include solubility, stability and bioavailability.

The variety of possible solid forms, including both free base and salt forms, creates a potential diversity of physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms is of great importance for the development of an effective, stable and marketable pharmaceutical product.

3. Summary of the invention

Provided herein are solid forms (e.g., crystalline forms, amorphous forms, polymorphs, or mixtures thereof) containing Compound 1:

having the chemical name (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4yl)oxy)methyl)benzyl)piperazin-1-yl) -3-fluorobenzonitrile. Methods for the preparation, isolation and characterization of solid forms are also presented herein.

In one embodiment, the solid form comprises the free base of Compound 1. In one embodiment, the solid form is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form K', Form L, Form M, Form N, Form O, Form P, Form Q, Form R or Form S of the free base of Compound 1, as provided herein.

In one embodiment of the invention, the solid form includes a salt of Compound 1.

In one embodiment, the solid form comprises the hydrochloride salt of Compound 1. In one embodiment, the solid form is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, K shape, L shape, M shape, N shape, O shape, P shape, Q shape, R shape, S shape, T shape, U shape, V shape, W shape, X shape, Y shape, Z shape, Form AA, Form AB or Form AC of the hydrochloride salt of Compound 1 as provided herein.

In one embodiment, the solid form comprises the mesylate salt of Compound 1. In one embodiment, the solid form is Form A or

- 2 044284 form B of the mesylate salt of compound 1, as provided herein.

In one embodiment, the solid form includes the hydrobromide salt of Compound 1. In one embodiment, the solid form is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J hydrobromide salt of Compound 1 as provided herein.

In one embodiment of the invention, the solid form comprises the besylate salt of Compound 1. In one embodiment of the invention, the solid form is Form A or Form B of the besylate salt of Compound 1, as provided herein.

In one embodiment, the solid form comprises a glycolate salt of Compound 1. In one embodiment, the solid form is Form A of a glycolate salt of Compound 1, as provided herein.

In one embodiment, the solid form comprises the L-malate salt of Compound 1. In one embodiment, the solid form is the L-malate salt of Compound 1, Form A, as provided herein.

Also provided herein are salts of Compound 1. In one embodiment, the salt is a hydrochloride salt, mesylate salt, hydrobromide salt, besylate salt, glycolate salt, L-malate salt, napadisylate salt, sulfate salt, tosylate salt, oxalate salt, isethionate salt salt, maleate salt, phosphate salt, malonate salt, gentisate salt, L-tartrate salt, fumarate salt, citrate salt, R-almond salt, L-ascorbate salt, succinate salt, nitrate salt, salicylate salt, edisylate salt, cyclamate salt, esylate salt , D-glucuronate salt, 4-aminosalicylate salt, caproate salt, cinnamon salt, caprylate salt, camphor salt, D-aspartate salt or D-glutamate salt.

The solid forms provided herein can be used as active pharmaceutical ingredients for the preparation of formulations for use in animals or humans. Thus, embodiments of the invention herein cover the use of these solid forms as a final drug product. Some embodiments of the invention provide solid forms useful for the manufacture of final dosage forms with improved properties, such as powder flow properties, compaction properties, tabletting properties, stability properties, and excipient compatibility properties, among others, that are needed for manufacturing, processing, formulation and/or storage of finished medicinal products. Certain embodiments of the invention herein provide pharmaceutical compositions containing a single-component crystalline form, a multi-component crystalline form, a single-component amorphous form and/or a multi-component amorphous form containing Compound 1 and a pharmaceutically acceptable diluent, excipient or carrier.

Also provided are pharmaceutical compositions formulated for administration by a suitable route and means, containing effective concentrations of a solid form containing Compound 1 provided herein, and optionally containing at least one pharmaceutical carrier.

In one embodiment of the invention, the pharmaceutical compositions deliver amounts effective to treat multiple myeloma. In one embodiment of the invention, the pharmaceutical compositions deliver amounts effective to prevent multiple myeloma. In one embodiment of the invention, the pharmaceutical compositions deliver amounts effective to improve multiple myeloma.

In one embodiment of the invention, methods of treating multiple myeloma are provided herein, including administration of solid forms, salts or pharmaceutical compositions provided herein. Also provided herein are combination therapies using the solid forms, salts or pharmaceutical compositions provided herein in combination with therapy, for example, with another pharmaceutical agent having activity against multiple myeloma or its symptoms. Examples of therapies within the methods include, but are not limited to, surgery, chemotherapy, radiation therapy, biological therapy, stem cell transplantation, cell therapy, and combinations thereof.

Also provided is a pharmaceutical package or kit including one or more containers filled with one or more ingredients of the pharmaceutical compositions. Such container(s) may not necessarily be accompanied by a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting the agency's approval of the manufacture, use, and sale for administration to humans. The package or kit may include information regarding the route of administration, the sequence of administration of the drug (eg, separately, sequentially or simultaneously), or the like.

These and other aspects of the subject matter described herein will become apparent upon reference to the following detailed description.

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4. Brief description of the drawings

In fig. 1 shows a representative X-ray powder diffraction (XRPD) pattern of Compound 1 free base Form A.

In fig. Figure 2 shows a representative thermal gravimetric analysis (TGA) thermogram of Compound 1 free base Form A.

In fig. 3 shows a representative differential scanning calorimetry (DSC) thermogram of Compound 1 free base Form A.

In fig. Figure 4 shows a representative dynamic vapor sorption (DVS) isotherm curve of Compound 1 free base Form A.

In fig. Figure 5 shows a representative XRPD diffraction pattern of Form B of the free base of compound 1.

In fig. Figure 6 shows a representative TGA thermogram of Form B of the free base of compound 1.

In fig. Figure 7 shows a representative DSC thermogram of Form B of the free base of Compound 1.

In fig. Figure 8 shows a representative DVS isotherm curve of the free base of compound 1.

In fig. Figure 9 shows a representative XRPD diffraction pattern of Form C of the free base of compound 1.

In fig. 10 is a representative TGA thermogram of Form C of the free base of Compound 1.

In fig. 11 shows a representative DSC thermogram of Form C of the free base of Compound 1.

In fig. 12 is a representative DVS isotherm curve of Form C free base of Compound 1.

In fig. Figure 13 shows a representative XRPD diffraction pattern of Form D of the free base of compound 1.

In fig. 14 is a representative TGA thermogram of Form D of the free base of Compound 1.

In fig. 15 is a representative DSC thermogram of Form D of the free base of Compound 1.

In fig. 16 is a representative DVS isotherm curve of Form D free base of Compound 1.

In fig. Figure 17 is a representative XRPD diffraction pattern of Form E of the free base of compound 1.

In fig. Figure 18 shows a representative TGA thermogram of Form E of the free base of compound 1.

In fig. 19 is a representative DSC thermogram of Form E of the free base of Compound 1.

In fig. 20 is a representative DVS isotherm curve of Form E of the free base of Compound 1.

In fig. Figure 21 shows a representative XRPD diffraction pattern of Form F of the free base of compound 1.

In fig. Figure 22 shows a representative TGA thermogram of Form F of the free base of Compound 1.

In fig. 23 is a representative DSC thermogram of Form F of the free base of Compound 1.

In fig. Figure 24 shows a representative XRPD diffraction pattern of Form G of the free base of compound 1.

In fig. Figure 25 shows a representative TGA thermogram of Form G of the free base of compound 1.

In fig. 26 is a representative DSC thermogram of Form G of the free base of Compound 1.

In fig. Figure 27 shows a representative XRPD diffraction pattern of Form H of the free base of compound 1.

In fig. 28 is a representative TGA thermogram of Form H of the free base of Compound 1.

In fig. 29 is a representative DSC thermogram of Form H of the free base of Compound 1.

In fig. 30 is a representative XRPD diffraction pattern of Compound 1 free base Form I.

In fig. Figure 31 shows a representative TGA thermogram of Form I of the free base of compound 1.

In fig. Figure 32 shows a representative XRPD diffraction pattern of Form J of the free base of compound 1.

In fig. Figure 33 shows a representative TGA thermogram of Form J of the free base of compound 1.

In fig. 34 is a representative DSC thermogram of Form J of the free base of Compound 1.

In fig. Figure 35 is a representative XRPD diffraction pattern of Form K of the free base of compound 1.

In fig. Figure 36 is a representative XRPD diffraction pattern of Form K' of the free base of compound 1.

In fig. Figure 37 shows a representative TGA thermogram of Form K of the free base of compound 1.

In fig. 38 is a representative DSC thermogram of Form K of the free base of Compound 1.

In fig. Figure 39 shows a representative DVS isotherm curve of Form K of the free base of compound 1.

In fig. 40 is a representative XRPD diffraction pattern of Form L of the free base of compound 1.

In fig. 41 shows a representative XRPD diffraction pattern of the free base form M of compound 1.

In fig. 42 shows a representative TGA thermogram of Form M of the free base of Compound 1.

In fig. 43 is a representative DSC thermogram of Form M of the free base of Compound 1.

In fig. 44 is a representative XRPD diffraction pattern of Form N of the free base of compound 1.

In fig. Figure 45 shows a representative XRPD diffraction pattern of Form O of the free base of compound 1.

In fig. 46 shows representative TG/DTA thermograms of Form O of the free base of compound 1.

In fig. 47 is a representative XRPD diagram of the free base form P of compound 1.

In fig. 48 shows representative TG/DTA thermograms of Form P of the free base of Compound 1.

In fig. Figure 49 shows a representative XRPD diffraction pattern of Form Q of the free base of compound 1.

In fig. 50 shows representative TG/DTA thermograms of Form Q of the free base of compound 1.

In fig. 51 shows a representative XRPD diffraction pattern of Form R of the free base of compound 1.

In fig. 52 shows representative TG/DTA thermograms of Form R of the free base of compound 1.

In fig. Figure 53 shows a representative XRPD diffraction pattern of Form S of the free base of compound 1.

In fig. 54 shows representative TG/DTA thermograms of Form S of the free base of compound 1.

In fig. 55 shows a representative XRPD thermogram of Form A of the hydrochloride salt of Compound 1.

In fig. 56 shows a representative TGA thermogram of Compound 1 hydrochloride salt Form A.

In fig. 57 shows a representative DSC thermogram of Form A of the hydrochloride salt of Compound 1.

In fig. 58 is a representative DVS isotherm curve of Form A hydrochloride salt of Compound 1.

In fig. 59 shows a representative XRPD diffraction pattern of Form B of the hydrochloride salt of compound 1.

In fig. 60 is a representative TGA thermogram of Compound 1 hydrochloride salt Form B.

In fig. 61 shows a representative DSC thermogram of Form B of the hydrochloride salt of Compound 1.

In fig. 62 shows a representative DVS isotherm curve of Form B hydrochloride salt.

- 5 044284 connections 1.

In fig. 63 shows a representative XRPD diffraction pattern of Form C of the hydrochloride salt of Compound 1.

In fig. 64 shows a representative XRPD diffraction pattern of Form D of the hydrochloride salt of compound 1.

In fig. 65 is a representative XRPD diffraction pattern of Form E of the hydrochloride salt of Compound 1.

In fig. Figure 66 shows a representative XRPD diffraction pattern of Form F of the hydrochloride salt of Compound 1.

In fig. 67 shows a representative XRPD diffraction pattern of Form G of the hydrochloride salt of compound 1.

In fig. Figure 68 shows a representative XRPD diffraction pattern of Form H of the hydrochloride salt of Compound 1.

In fig. 69 shows a representative XRPD diffraction pattern of Form I of the hydrochloride salt of compound 1.

In fig. 70 is a representative XRPD diffraction pattern of Compound 1 mesylate salt Form A.

In fig. 71 shows a representative TGA thermogram of Compound 1 mesylate salt Form A.

In fig. 72 is a representative DSC thermogram of Compound 1 mesylate salt Form A.

In fig. 73 shows a representative DVS isotherm curve of Form A of the mesylate salt of Compound 1.

In fig. 74 shows a representative XRPD diffraction pattern of Form B of the hydrobromide salt of Compound 1.

In fig. 75 shows representative TG/DTA thermograms of Form B of the hydrobromide salt of Compound 1.

In fig. 76 shows a representative XRPD diffraction pattern of Compound 1 hydrobromide salt Form A.

In fig. 77 shows representative TG/DSC thermograms of Form A of the hydrobromide salt of Compound 1.

In fig. 78 shows a representative DVS isotherm curve of Form A of the hydrobromide salt of Compound 1.

In fig. 79 shows a representative XRPD diffraction pattern of Form C of the hydrobromide salt of Compound 1.

In fig. 80 shows representative TG/DTA thermograms of Form C of the hydrobromide salt of Compound 1.

In fig. 81 shows a representative XRPD diffraction pattern of Form D of the hydrobromide salt of Compound 1.

In fig. 82 shows representative TG/DTA thermograms of Form D of the hydrobromide salt of Compound 1.

In fig. 83 shows a representative XRPD diffraction pattern of Form A of the besylate salt of Compound 1.

In fig. 84 shows representative TG/DTA thermograms of Form A of the besylate salt of Compound 1.

In fig. 85 shows a representative XRPD diffraction pattern of Form B of the besylate salt of Compound 1.

In fig. 86A is a representative DSC thermogram of Compound 1 besylate salt Form B.

In fig. 86B is a representative TGA thermogram of Compound 1 besylate salt Form B.

In fig. 87 shows a representative DVS isotherm curve of Form B of the besylate salt of Compound 1.

In fig. 88 shows a representative XRPD diffraction pattern of Form A of the glycolate salt of Compound 1.

In fig. 89 shows representative TG/DTA thermograms of Form A of the glycolate salt of Compound 1.

In fig. 90 is a representative XRPD diffraction pattern of Form A of the L-malate salt of Compound 1.

In fig. 91 shows representative TG/DTA thermograms of Form A of the L-malate salt of Compound 1.

In fig. 92 shows a representative XRPD diffraction pattern of form A of the napadisylate salt.

- 6 044284 connections 1.

In fig. 93 shows a representative XRPD diffraction pattern of Form A of the tosylate salt of Compound 1.

In fig. 94 shows a representative XRPD diffraction pattern of Form A of the oxalate salt of Compound 1.

In fig. 95 is a representative XRPD diffraction pattern of Form A of the isethionate salt of Compound 1.

In fig. 96 shows a representative XRPD diffraction pattern of Form B of the isethionate salt of Compound 1.

In fig. 97 shows a representative XRPD diffraction pattern of Form A of the maleate salt of Compound 1.

In fig. 98 shows a representative XRPD diffraction pattern of Form B of the maleate salt of Compound 1.

In fig. 99 shows a representative XRPD diffraction pattern of Form A of the phosphate salt of compound 1.

In fig. 100 shows a representative XRPD diffraction pattern of Compound 1 malonate salt Form A.

In fig. 101 shows a representative XRPD diffraction pattern of Form A of the gentisate salt of Compound 1.

In fig. 102 shows a representative XRPD diffraction pattern of Form B of the gentisate salt of Compound 1.

In fig. 103 shows a representative XRPD diffraction pattern of Form C of the gentisate salt of Compound 1.

In fig. 104 shows a representative XRPD diffraction pattern of Form A of the L-tartrate salt of Compound 1.

In fig. 105 shows a representative XRPD diffraction pattern of Form A of the fumarate salt of Compound 1.

In fig. 106 shows a representative XRPD diffraction pattern of Form A of the R-mandelate salt of Compound 1.

In fig. 107 shows a representative XRPD diffraction pattern of Form A of the L-ascorbate salt of Compound 1.

In fig. 108 shows a representative XRPD diffraction pattern of Compound 1 succinate salt Form A.

In fig. 109 shows a representative XRPD diffraction pattern of Form A of the nitrate salt of compound 1.

In fig. 110 is a representative XRPD diffraction pattern of Form A of the salicylate salt of Compound 1.

In fig. 111 shows a representative XRPD diffraction pattern of Form B of the salicylate salt of Compound 1.

In fig. 112 shows a representative XRPD diffraction pattern of Form C of the salicylate salt of Compound 1.

In fig. 113 shows a representative XRPD diffraction pattern of Form A of the edisylate salt of Compound 1.

In fig. 114 shows a representative XRPD diffraction pattern of Form B of the edisylate salt of compound 1.

In fig. 115 shows a representative XRPD diffraction pattern of Form A of the cyclamate salt of Compound 1.

In fig. 116 shows a representative XRPD diffraction pattern of Form B of the cyclamate salt of Compound 1.

In fig. 117 shows a representative XRPD diffraction pattern of Form C of the cyclamate salt of compound 1.

In fig. 118 shows a representative XRPD diffraction pattern of Form D of the cyclamate salt of compound 1.

In fig. 119 shows a representative XRPD diffraction pattern of Form E of the cyclamate salt of compound 1.

In fig. 120 is a representative XRPD diffraction pattern of Compound 1 esylate salt Form A.

In fig. 121 shows a representative XRPD diffraction pattern of Form B of the esylate salt of compound 1.

In fig. 122 shows a representative XRPD diffraction pattern of Form A of the D-glucuronate salt of Compound 1.

In fig. 123 shows a representative XRPD diffraction pattern of Form A of 4-aminosalicylate

- 7 044284 salts of compound 1.

In fig. 124 shows a representative XRPD diffraction pattern of Form A of the caproate salt of Compound 1.

In fig. 125 shows a representative XRPD diffraction pattern of Form A of the cinnamate salt of compound 1.

In fig. 126 shows a representative XRPD diffraction pattern of Form B of the cinnamate salt of compound 1.

In fig. 127 shows a representative XRPD diffractogram of form A of the caprylate salt of compound 1.

In fig. 128 shows a representative XRPD diffraction pattern of Form A of the camphorate salt of Compound 1.

In fig. 129 shows a representative XRPD diffraction pattern of Form A of the D-aspartate salt of compound 1.

In fig. 130 is a representative XRPD diffraction pattern of Form B of the D-aspartate salt of Compound 1.

In fig. 131 shows a representative XRPD diffraction pattern of D-glutamate salt form A of compound 1.

In fig. 132 shows an overlay of XRPD diffraction patterns of Form K of the free base of compound 1 at various RH at ambient temperature for 2 days.

In fig. 133 shows an overlay of XRPD diffraction patterns of Form K' of the free base of compound 1 at various RH at ambient temperature for 2 days.

In fig. 134 shows a representative XRPD diffraction pattern of Form B of the mesylate salt of Compound 1.

In fig. 135 shows representative TG/DTA thermograms of Form B of the mesylate salt of Compound 1.

In fig. 136 shows a representative XRPD diffraction pattern of Form J of the hydrochloride salt of Compound 1.

In fig. 137 shows a representative XRPD diffraction pattern of Form K of the hydrochloride salt of compound 1.

In fig. 138 shows a representative XRPD diffraction pattern of Form L of the hydrochloride salt of Compound 1.

In fig. 139 shows a representative TGA thermogram of Form L of the hydrochloride salt of Compound 1.

In fig. 140 shows a representative DSC thermogram of Compound 1 hydrochloride salt Form L.

In fig. 141 shows a representative DVS isotherm curve of Form L of the hydrochloride salt of Compound 1.

In fig. 142 shows a representative XRPD diffraction pattern of Form M hydrochloride salt of compound 1.

In fig. 143 shows a representative DSC thermogram of Form M of the hydrochloride salt of Compound 1.

In fig. 144 shows a representative XRPD diffraction pattern of the N form of the hydrochloride salt of compound 1.

In fig. 145 shows a representative TG-MS thermogram of Form N of the hydrochloride salt of Compound 1.

In fig. 146 shows a representative DSC thermogram of Form N of the hydrochloride salt of Compound 1.

In fig. 147 shows a representative XRPD diffraction pattern of the O form of the hydrochloride salt of compound 1.

In fig. 148 shows a representative XRPD diffraction pattern of Form P of the hydrochloride salt of Compound 1.

In fig. 149 shows a representative XRPD diffraction pattern of Form Q of the hydrochloride salt of compound 1.

In fig. 150 is a representative XRPD diffraction pattern of Form R of the hydrochloride salt of Compound 1.

In fig. 151 shows a representative XRPD diffraction pattern of Form S of the hydrochloride salt of compound 1.

In fig. 152 shows a representative XRPD diffraction pattern of Form T of the hydrochloride salt of Compound 1.

In fig. 153 shows a representative XRPD diffraction pattern of Form U of the hydrochloride salt of compound 1.

In fig. 154 shows a representative XRPD diffraction pattern of Form V hydrochloride salt

- 8 044284 connections 1.

In fig. 155 shows a representative XRPD diffraction pattern of Form W of the hydrochloride salt of Compound 1.

In fig. 156 shows a representative XRPD diffraction pattern of Form X of the hydrochloride salt of Compound 1.

In fig. 157 shows a representative XRPD diffraction pattern of Form Y of the hydrochloride salt of Compound 1.

In fig. 158 shows a representative XRPD diffraction pattern of Form Z of the hydrochloride salt of Compound 1.

In fig. 159 shows a representative XRPD diffraction pattern of the AA form of the hydrochloride salt of compound 1.

In fig. 160 shows a representative XRPD diffraction pattern of the AB form of the hydrochloride salt of compound 1.

In fig. 161 shows a representative XRPD diffractogram of the AC form of the hydrochloride salt of compound 1.

In fig. 162 shows a representative XRPD diffraction pattern of Form E of the hydrobromide salt of Compound 1.

In fig. 163 shows a representative XRPD diffraction pattern of Form F of the hydrobromide salt of compound 1.

In fig. 164 shows a representative XRPD diffraction pattern of Form G of the hydrobromide salt of compound 1.

In fig. 165 shows a representative XRPD diffraction pattern of Form H of the hydrobromide salt of Compound 1.

In fig. 166 shows a representative TGA sample of Compound 1 hydrobromide salt Form H.

In fig. 167 shows a representative DSC sample of Form H of the hydrobromide salt of Compound 1.

In fig. 168 shows a representative XRPD diffraction pattern of Form I of the hydrobromide salt of Compound 1.

In fig. 169 shows a representative XRPD diffraction pattern of Form J of the hydrobromide salt of Compound 1.

In fig. 170 shows a form conversion diagram for Form L, Form M, and Form N of the hydrochloride salt of Compound 1.

5. Detailed Description

5.1 Definitions.

As used herein and in the specification and appended claims, the singular forms of the singular include the plural as well as single references unless the context clearly indicates otherwise.

As used herein, the terms containing and including may be used interchangeably. The terms containing and including should be interpreted as indicating the presence of the specified features or components, but do not exclude the presence or addition of one or more features or components, or groups thereof. Additionally, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that the object contains at least 90, 95, 97, 98 or 99% of the declared features or components of which it is composed. In another embodiment of the invention, the term consisting of excludes from the scope of any subsequent listing any other features or components other than those that are not essential to the technical effect to be achieved.

As used herein, the term or should be interpreted to include or mean any or every combination. Therefore, A, B or C means any of the following: A; IN; WITH; A and B; A and C; B and C; A, B, and C. An exception to this definition will occur only when the combination of elements, functions, steps, or actions is in some way inherently mutually exclusive.

As used herein, and unless otherwise indicated, the terms about and approximately, when used in connection with doses, amounts, or weight percentages of the ingredients of a composition or dosage form, mean the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide pharmacological an effect equivalent to the effect obtained from a specified dose, amount or mass percentage. In some embodiments, the terms about and about when used in this context mean a dose, amount, or weight percentage within 30, within 20, within 15, within 10, or within

- 9 044284 within 5% of the specified dose, amount or mass percentage.

As used herein and unless otherwise specified, the terms about and approximately when used in connection with a numerical value or range of values that is provided to characterize a particular solid form, such as a specific temperature or range of temperatures, such as, for example, describing a melting point, dehydration, desolvation or glass transition; a change in mass, such as, for example, a change in mass depending on temperature or humidity; solvent or water content, for example, by weight or percentage; or peak position, such as in IR or Raman spectroscopy or XRPD analysis; indicate that the value or range of values may deviate to an extent considered reasonable by one skilled in the art while still describing a particular solid form. For example, in specific embodiments, the terms about and about when used in this context indicate that the numerical value or range of values may vary within the range of 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 , 1.5, 1, 0.5 or 0.25% of the specified value or range of values. For example, in some embodiments of the invention, the XRPD peak position value may vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak. In this context, a tilde (i.e. ~) before a numeric value or range of values indicates about or approximately.

Unless otherwise indicated, the terms X-ray powder diffractometry, X-ray powder diffraction, PXRD and XRPD are used interchangeably in this invention.

As used herein and unless otherwise noted, the terms solid form and related terms refer to a physical form that is not primarily in a liquid or gaseous state. As used herein, the terms solid form and solid forms cover semi-solids. Solid forms may be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms.

The solid forms provided herein may have varying degrees of crystallinity or lattice order. The solid forms provided herein are not limited to any particular degree of crystallinity or lattice order and may be 0-100% crystalline. Methods for determining the degree of crystallinity are known to those skilled in the art, for example, as described in Suryanarayanan, R., X-Ray Power Diffractometry, Physical Characterization of Pharmaceutical Salts, HG Brittain, Editor, Mercel Dekkter, Murray Hill, NJ, 1995, cc. 187-199, which is incorporated herein by reference in its entirety. In some embodiments, the solid forms provided herein are about 0.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 crystalline. , 95 or 100%.

As used herein and unless otherwise indicated, the term crystalline and related terms used herein, when used to describe a substance, component, product or form, mean that the substance, component, product or form is substantially crystalline, e.g. as determined by x-ray diffraction. See, for example, Remington: The Science and Practice of Pharmacy, 21 ^st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, ^23rd edition, 1843-1844 (1995).

As used herein and unless otherwise indicated, the terms crystalline form, crystalline forms and related terms herein refer to solid forms that are crystalline. Crystal forms include single-component crystal forms and multi-component crystal forms and include, but are not limited to, polymorphs, solvates, hydrates and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, related substances, crystals of salts, other molecular complexes of salts and polymorphs thereof . In some embodiments, the crystalline form of the substance may be substantially free of amorphous forms and/or other crystalline forms. In some embodiments, the crystalline form of the substance may contain less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50% of one or more amorphous form(s) and/or other crystalline form(s) on a weight basis. In some embodiments, the crystalline form of the substance may be physically and/or chemically pure. In some embodiments, the crystalline form of the substance may be physically and/or chemically pure to about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92% pure, 91% pure, or 90% pure.

The one-component solid form containing the compound essentially consists of the compound. A multicomponent solid form containing a compound includes a significant amount of one or more additional particles, such as ions and/or molecules, in solid form. For example, in some embodiments of the invention, the crystalline multicomponent solid form containing the compound further includes one or more components non-covalently bonded at regular positions in the crystal lattice. In another example, in certain embodiments of the invention, the amorphous multicomponent solid form containing the compound further contains one or more polymers, and the compound is dispersed in a solid matrix that includes the polymer(s).

- 10 044284

Crystalline forms of a substance can be obtained in several ways. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, confined space recrystallization such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives, such as, for example, cocrystalline antimolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent droplet grinding.

Unless otherwise specified, the terms polymorph, polymorphic form, polymorphs, polymorphic forms and related terms as used herein refer to two or more crystalline forms that are substantially composed of the same molecule, molecules or ions. Like different crystal forms, different polymorphs may have different physical properties, such as, for example, melting points, heats of fusion, solubility, dissolution rates, and/or vibrational spectra as a result of different arrangements or conformations of molecules or ions in the crystal lattice. Differences in the physical properties of polymorphs can affect pharmaceutical parameters such as shelf stability, compressibility and density (important in formulation and product manufacturing) and dissolution rate (an important factor in bioavailability). Differences in stability may result from changes in chemical reactivity (for example, differential oxidation, so that the dosage form discolors faster when it is composed of one polymorph than when it is composed of another polymorph) or mechanical changes (for example, tablets crumble during storage because kinetically the preferred polymorph is converted to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to degradation under high humidity). As a result of differences in solubility/dissolution, at the extreme, some polymorphic transitions can lead to loss of activity or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing (for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash away impurities, and the shape and particle size distribution may differ between polymorphs).

As used herein, and unless otherwise indicated, the terms amorphous, amorphous form and related terms as used herein mean that the substance, component or product in question is not substantially crystalline as determined by x-ray diffraction. In particular, the term amorphous form describes a disordered solid form, that is, a solid form lacking long-range crystalline order. In some embodiments, the amorphous form of the substance may be substantially free of other amorphous forms and/or crystalline forms. In other embodiments, the amorphous form of the substance may contain less than about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% of one or more other amorphous forms and/or crystalline forms based on weight. In some embodiments, the amorphous form of the substance may be physically and/or chemically pure. In some embodiments, the amorphous form of the substance may be physically and/or chemically pure to about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92% pure, 91% pure, or 90% pure. In some embodiments, the amorphous form of the substance may contain additional components or ingredients (eg, an additive, polymer, or filler that may serve to further stabilize the amorphous form). In some embodiments, the amorphous form may be a solid solution.

Amorphous forms of a substance can be obtained in several ways. Such methods include, but are not limited to, heating, melt cooling, melt rapid cooling, solvent evaporation, solvent flash evaporation, desolvation, sublimation, grinding, ball milling, cryoprelling, spray drying and freeze drying.

Unless otherwise specified, the terms solvate and solvated as used herein mean the solid form of a substance that contains a solvent. The terms hydrate and hydrated mean a solvate in which the solvent includes water. The term solvate polymorphs means the existence of more than one solid form for a particular solvate composition. Similarly, the term hydrate polymorphs refers to the existence of more than one solid form for a particular hydrate composition. As used herein, the term desolvated solvate means a solid form of a substance that can be obtained by removing the solvent from the solvate. The terms solvate and solvated as used herein can also mean a solvate of a salt, co-crystal or molecular complex. The terms hydrate and hydrated as used herein can also refer to the hydrate of a salt, cocrystal, or molecular complex.

Methods for determining crystalline forms and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid-state and nuclear magnetic resonance (NMR) spectroscopy of solution, optical microscopy, optical

- 11 044284 hot stage microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more techniques such as, but not limited to, x-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Techniques useful for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample containing more than one solid phase. Other techniques useful for analyzing powder diffraction data include unit cell indexing, which allows one skilled in the art to determine unit cell parameters from a sample containing crystalline powder.

In some embodiments, the solid forms, such as crystalline or amorphous forms, provided herein are substantially pure, that is, substantially free from other solid forms and/or other chemical compounds containing less than about 25, 20, 15, 10. 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.25 or 0.1% by weight of one or more other solids of the form and/or other chemical compounds.

As used herein, unless otherwise indicated, a chemical compound, solid form, or composition that is substantially free of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments of the invention, less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.4, 0.3, 0, 2, 0.1, 0.05 or 0.01% by weight of another compound, solid form or composition.

As used herein, unless otherwise indicated, a solid form that is substantially physically pure is substantially free of other solid forms. In some embodiments, the crystalline form that is substantially physically pure contains less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3. 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01% of one or more other solids by weight.

Detection of other solid forms may be accomplished by any method apparent to one skilled in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis, and/or spectroscopic analysis.

As used herein, unless otherwise indicated, a solid form that is substantially chemically pure is substantially free of other chemical compounds (ie, chemical impurities). In some embodiments, the solid form, which is substantially chemically pure, contains less than about 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3. 2, 1, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05 or 0.01% of one or more other chemical compounds by weight. Detection of other chemical compounds may be accomplished by any method apparent to one skilled in the art, including, but not limited to, chemical analysis techniques such as, for example, mass spectrometric analysis, spectroscopic analysis, thermal analysis, etc. elemental combustion analysis and/or chromatographic analysis.

Solid forms may exhibit a variety of physical characteristics that are unique to a particular solid form, such as the crystalline forms presented herein. This characterization data can be obtained by various methods known to those skilled in the art, including, for example, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis and nuclear magnetic resonance spectroscopy. Data obtained from these methods can be used to identify a specific solid form. One skilled in the art can determine whether a solid form is one of the forms presented herein by performing one of these characterization methods and determining whether the data obtained corresponds to the reference data provided herein, which are determined to be characteristic of a particular solid form. Those skilled in the art understand that characteristic data that is the same as that of a reference solid form corresponds to the same solid form as the reference solid form. In assessing whether the data are consistent, one skilled in the art will recognize that specific data points characteristics may vary to a reasonable extent while still describing a given solid form, due to, for example, experimental error and standard assay variations from sample to sample. sample.

As used herein, unless otherwise noted, the term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable, relatively non-toxic acids, including inorganic acids and organic acids. In some embodiments, suitable acids include, but are not limited to, acetic, adipic, 4-aminosalicylic, ascorbic, aspartic, benzenesulfonic, benzoic, camphoric, camphorsulfonic, capric, caproic, caprylic, cinnamic, carbonic, citric, cyclamic, dihydrogenphos

- 12 044284 foric, 2,5-dihydroxybenzoic (gentisic), 1,2-ethanedisulfonic, ethanesulfonic, fumaric, galacturonic, gluconic, glucuronic, glutamic, glutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic, isobutyric, isethionic, lactic , Maleine, apple, mild, almond, methane sulfone, monohydarbon, monohydrophosphorus, monohydroseric, mucosa, 1.5-naftindindiulfone, nicotine, nitrogen, sorrel, pamine, pantothenic, phosphorus, fluttered, propion, pyroglutamin, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, salicylic, salicylic, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, salicylic, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, salicylic, salicylics, salicylic, salicylic, salicylic, solicyl. new, amber, sulfuric, tartaric acid, toluenesulfonic acid and the like (see, for example, S. M. Berge et al., J. Pharm. Sci., 66:1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). In some embodiments, suitable acids are strong acids (e.g., with a pKa less than about 1), including, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, methanesulfonic, benzenesulfonic, toluenesulfonic, naphthalene sulfonic, naphthalene disulfonic, pyridine sulfonic, or others substituted sulfonic acids. Also included are salts of other relatively non-toxic compounds that have acidic properties, including amino acids such as aspartic acid and the like, and other compounds such as aspirin, ibuprofen, saccharin and the like. Acid addition salts can be prepared by contacting the neutral form of the compound with a sufficient amount of the desired acid, either pure or in a suitable solvent. As solids, salts can exist in crystalline or amorphous forms or mixtures thereof. Salts can also exist in polymorphic forms.

As used herein, the term multiple myeloma refers to hematologic conditions characterized by malignant plasma cells and includes the following disorders: monoclonal gammopathy of undetermined significance (MGUS); low, intermediate and high risk multiple myeloma; newly diagnosed multiple myeloma (including newly diagnosed low-, intermediate- and high-risk multiple myeloma); Transplant eligible and transplant ineligible multiple myeloma; smoldering (sluggish) multiple myeloma (including smoldering multiple myeloma of low, intermediate and high risk); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; multiple myeloma of the central nervous system; light chain myeloma; nonsecretory myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma; and multiple myeloma, characterized by genetic abnormalities such as cyclin D translocations (eg, t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32) ); or t(6;20);); MMSET translocations (e.g. t(4;14)(p16;q32)); MAF translocations (e.g. t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (eg, deletion of 17p13 or chromosome 13; del(17/17p), non-hyperdiploidy and mutation(1q)).

As used herein and unless otherwise noted, the terms treat, treating and treatment refer to alleviating or reducing the severity of a symptom associated with the disease or condition being treated, such as multiple myeloma.

The term prevention includes suppression of a symptom of a specific disease or disorder, such as multiple myeloma. In some embodiments, patients with a family history of multiple myeloma are candidates for prophylactic treatment regimens. Typically, the term prevention refers to administering a drug before symptoms appear, especially in patients at risk for multiple myeloma.

As used herein, unless otherwise specified, the term management includes preventing the recurrence of a particular disease or disorder, such as multiple myeloma, in a patient who has suffered from it, prolonging the patient's time suffering from the disease, or the disorder remaining in remission, reducing the mortality rate patients and/or supporting reduction in severity or avoidance of a symptom associated with the disease or condition being treated.

As used herein, subject or patient means an animal, typically a mammal, including a human, such as a human patient.

The term relapse refers to a situation where patients who have had multiple myeloma in remission after therapy experience a return of myeloma cells and/or a decrease in normal cells in the bone marrow.

The term refractory or resistant refers to circumstances where patients, even after intensive treatment, have residual myeloma cells and/or reduced normal cells in the bone marrow.

As used herein, the term induction therapy refers to the first treatment of a disease or the first treatment to induce complete remission of a disease, such as cancer. Induction therapy itself is considered the best treatment available. If residual cancer is found, patients are treated with another therapy called re-induction. If the patient is in complete remission after induction therapy, additional consolidation and/or maintenance therapy is given to prolong remission or potentially cure the patient.

As used herein, the term consolidation therapy refers to the treatment of a disease after

- 13 044284 of how remission was first achieved. For example, consolidation therapy for cancer is treatment given after the cancer has disappeared after initial therapy. Consolidation therapy may include radiation therapy, a stem cell transplant, or treatment with cancer drugs. Consolidation therapy is also called intensification therapy and post-remission therapy.

As used herein, the term maintenance therapy refers to the treatment of a disease after remission or best response has been achieved to prevent or delay relapse. Maintenance therapy may include chemotherapy, hormonal therapy, or targeted therapy.

Remission as used herein means a reduction or disappearance of the signs and symptoms of a cancer, such as multiple myeloma. During partial remission, some, but not all, signs and symptoms of cancer disappear. In complete remission, all signs and symptoms of cancer have disappeared, although cancer may still remain in the body.

As used herein, the term transplant refers to high-dose therapy to salvage stem cells. Hematopoietic (blood) or bone marrow stem cells are used not for treatment, but to save the patient after high-dose therapy, such as chemotherapy and/or high-dose radiation. The transplant includes an autologous stem cell transplant (ASCT), which refers to the use of the patient's own stem cells, which are collected and used as replacement cells. In some embodiments, the graft also includes a tandem graft or multiple grafts.

As used herein, unless otherwise indicated, the terms a therapeutically effective amount and an effective amount of a compound refer to an amount sufficient to provide a therapeutic effect in the treatment, prevention and/or management of a disease, such as multiple myelomas, or to delay or minimize one or more symptoms. associated with a disease or disorder that needs to be treated. The terms therapeutically effective amount and effective amount can encompass an amount that improves overall therapy, reduces or eliminates symptoms or causes of a disease or disorder, or increases the therapeutic effectiveness of another therapeutic agent.

The terms co-administration and in combination with include the administration of one or more therapeutic agents (eg, a compound provided herein and another anti-multiple myeloma agent, anti-cancer agent or supportive care agent) either simultaneously or sequentially without any specific timing. In one embodiment, the agents are present in the patient's cell or body at the same time or exert their biological or therapeutic effects at the same time. In one embodiment of the invention, the therapeutic agents are in the same composition or unit dosage form. In another embodiment of the invention, the therapeutic agents are in separate compositions or unit dosage forms.

The term maintenance agent refers to any substance that treats, prevents, or controls the adverse effect of treatment with Compound 1, or an enantiomer, or a mixture of enantiomers, tautomers, isotopologues, or a pharmaceutically acceptable salt thereof.

The term biological therapy refers to the administration of biological therapeutics such as umbilical cord blood, stem cells, growth factors and the like.

In the context of a cancer such as multiple myeloma, inhibition can be assessed by inhibiting disease progression, inhibiting tumor growth, shrinking the primary tumor, alleviating tumor-associated symptoms, inhibiting factors secreted by the tumor, delaying the appearance of primary or secondary tumors, delaying the development of primary or secondary tumors. tumors, reducing the incidence of primary or secondary tumors, slowing or reducing the severity of secondary effects of the disease, delaying tumor growth and regression, increasing time to progression (TTP), increasing progression-free survival (PFS), increasing overall survival (OS), among others. As used herein, OS refers to the time from the start of treatment to death from any cause. As used herein, the term TTP refers to the time from initiation of treatment to tumor progression; The TTP does not include deaths. In one embodiment of the invention, PFS means the time from the start of treatment until tumor progression or death. In one embodiment of the invention, PFS means the time from the first dose of a compound until the first occurrence of disease progression or death from any cause. In one embodiment of the invention, PFS scores will be calculated using Kaplan-Meier estimates. Event-free survival (EFS) refers to the time from the start of treatment to any treatment failure, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment of the invention, the overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment of the invention, ORR means the sum of the percentage of patients who achieve a complete response and a partial response. In one embodiment, ORR means the percentage of patients who have best response > partial response (PR), according to the IMWG Unified Response criteria. In one embodiment, the Duration of Response (DoR) is before

- 14 044284 is the time from achieving response to relapse or disease progression. In one embodiment, DoR is the time from achieving response > partial response (PR) to disease relapse or progression. In one embodiment, the DoR is the time from the first documentation of a response to the first documentation of progressive disease or death. In one embodiment, DoR is the time from first documentation of response > partial response (PR) to first documentation of progressive disease or death. In one embodiment, time to response (TTR) means the time from the first dose of a compound to the first confirmation of a response. In one embodiment, TTR means the time from the first dose of a compound to the first confirmation of response > partial response (PR). In extreme cases, complete inhibition is referred to here as prophylaxis or chemoprevention. In this context, the term prevention includes either completely preventing the occurrence of clinically obvious cancer or preventing the occurrence of preclinically obvious cancer. This definition is also intended to include preventing transformation into malignant cells or stopping or reversing the development of precancerous cells into malignant cells. This includes preventive treatment for individuals at risk of developing cancer.

In some embodiments, treatment for multiple myeloma can be assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International Uniform Response Criteria for Multiple Myeloma. Leukemia, 2006. ;(10)10:1-7), using the response and endpoint definitions shown below:

Response subcategory Criteria answer ^a CR as defined below plus sCR Normal FLC coefficient and Absence of clonal cells in the bone marrow ^according to immunohistochemistry and immunofluorescence ⁰ Negative immunofixation for serum and urine and CR Disappearance of any soft tissue plasmacytomas and <5% plasma cells in the bone marrow ^b M protein in serum and urine is detected by VGPR immunofixation, but not by electrophoresis, or a 90% or greater decrease in serum M-protein plus urinary M-protein <100 mg in 24 hours Reduction in serum M-protein levels by >50% and reduction in 24-hour urine M-protein levels by >90% or <200 mg in 24 hours PR hours If serum and urine M-protein are not measurable, a >50% reduction in the difference between levels ^is required.

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SD (non-involved and non-involved FLC instead of M-protein criteria If serum and urine M-protein is not measurable and the serum-free light assay is also not measurable, a >50% reduction in plasma cells is required instead of M-protein, provided that the initial percentage bone marrow plasma cells were >30%.

In addition to the above criteria, if present at baseline, a >50% reduction in the size of soft tissue plasmacytomas is also required.

recommended for use as a response indicator; disease stability is better

Failure to meet criteria for CR, VGPR, PR or progressive disease (all described, indicating time to assess progression)

Abbreviations: CR: complete response; FLC: free light chain; PR: partial response; SD: stable disease; sCR: strict complete response; VGPR: very good partial answer.

^a All response categories require two consecutive assessments made at any time before the start of any new therapy; All categories also do not require known evidence of progressive or new bone disease if radiographic studies were performed. Radiographic examinations are not required to satisfy these response requirements.

confirmation by repeat bone marrow biopsy is not required.

The presence/absence of clonal cells is based on the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. The abnormal ratio, reflecting the presence of an abnormal clone, is κ/λ>4:1 or <1:2.

measurable disease defined by at least one of the following: bone marrow plasma cells >30%; serum M-protein >1 g/dL (>10 mg/L) [10 g/L]; M-protein in urine >200 mg/24 h; serum FLC analysis: level of involved FLC >10 mg/dL (>100 mg/L); provided that the serum FLC ratio is abnormal.

In this context, ECOG status refers to Eastern Cooperative Oncology Group (ECOG) performance status (Oken M, et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655) as below:_______________________

Check Description 0 Fully active, able to perform all pre-disease activities without restrictions. 1 Limited in physically strenuous activities, but ambulatory and can perform light or sedentary work, such as light housework, office work. 2 Ambulatory and capable of self-care, but unable to perform any work. Wakeful and about 50% of the time awake. 3 Capable of only limited self-care and confined to bed or chair more than 50% of waking hours. 4 Completely disabled. Cannot perform self-care. Completely confined to a bed or chair 5 Dead

Unless otherwise indicated, to the extent there is a discrepancy between the depicted chemical structure of a compound presented herein and the chemical name of the compound presented herein, the chemical structure shall control.

5.2. Salts and solid forms containing compound 1.

In certain embodiments of the invention, a solid form containing Compound 1 is provided herein:

1.

Compound 1 has the chemical name (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1- yl)-3-fluorobenzonitrile. Methods for preparing Compound 1 are described in US Application No. 16/030,695, which is incorporated herein by reference in its entirety.

In one embodiment, the solid form includes the free base of Compound 1. In one embodiment, the solid form includes a salt of Compound 1. In one embodiment, the solid form includes the hydrochloride salt of Compound 1. In one embodiment, the solid form includes the mesylate salt of Compound 1. In one embodiment, the solid form includes the hydrobromide salt of Compound 1. In one embodiment, the solid form includes the besylate salt of Compound 1. In one embodiment, the solid form includes the glycolate salt of Compound 1. In one embodiment, the solid form includes the L-malate salt of Compound 1.

In one embodiment of the invention, the solid form is crystalline. In one embodiment of the invention, the solid form is a hydrate. In one embodiment of the invention, the solid form is anhydrous. In one embodiment of the invention, the solid form is a solvate. In one embodiment of the invention, the solid form is not solvated.

The provided solid forms can be characterized using a variety of techniques known to one skilled in the art, including, but not limited to, single crystal x-ray diffraction, powder x-ray diffraction (PXRD), microscopy (e.g., optical microscopy, scanning electron microscopy ( SEM), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy), dynamic vapor sorption (DVS), spectroscopy (e.g., infrared, Raman, and nuclear magnetic resonance), high performance liquid chromatography (HPLC). The particle size and particle size distribution of the solid form presented herein can be determined by conventional methods such as laser light scattering.

Also provided herein are salts of Compound 1. In one embodiment, the salt is a hydrochloride salt of Compound 1. In one embodiment, the salt is a mesylate salt of Compound 1. In one embodiment, the salt is a hydrobromide salt of Compound 1. In one of In embodiments, the salt is a besylate salt of Compound 1. In one embodiment, the salt is a glycolate salt of Compound 1. In one embodiment, the salt is an L-malate salt of Compound 1.

Without being limited to any particular theory, the acids are bonded to one or more basic nitrogen atoms of Compound 1. Without being limited to any particular theory, the acids are bonded to the nitrogen atom on the piperazine ring of Compound 1.

The purity of the solid forms and salts presented here can be determined by standard analytical methods such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrometry.

Without being limited to any particular theory, certain solid forms and salts are characterized by physical properties, such as stability, solubility and dissolution rate, suitable for pharmaceutical and therapeutic dosage forms. Moreover, without being limited to any particular theory, certain solid forms and salts are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water absorption, electrical properties, thermal behavior, hardness - state of reactivity, physical stability and chemical stability) affecting specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make certain solid forms and salts suitable for solid dosage form manufacture . Such properties can be determined using specific analytical chemical methods, including solid-state analytical methods (e.g. X-ray diffraction, micro

- 17 044284 scopy, spectroscopy and thermal analysis), as described here and known in the art. Without being limited to any particular theory, certain solid forms and salts provided herein exhibit suitable pharmaceutical properties, such as pharmaceutical kinetics, pharmaceutical dynamics, half-life, C _max and bioavailability. Such properties can be determined using assays known to one skilled in the art.

Free connection base 1.

In some embodiments, the free base of Compound 1 is provided herein. It is contemplated that the free base of Compound 1 may exist in a variety of solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline free base of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form containing the free base of Compound 1. In one embodiment, the solid form is a solvate of the free base of Compound 1. In one embodiment, the solid form is a hydrate of the free base of Compound 1. In one embodiment, the solid form is is the unsolvated free base form of Compound 1. In one embodiment, the solid form is the desolvated free base form of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the free base of Compound 1. In one embodiment, the solid form is the dehydrated form free base form of compound 1.

Form A of the free base of compound 1.

In some embodiments, Compound 1 free base Form A is provided herein.

In one embodiment of the invention, Form A is crystalline. In one embodiment of the invention, Form A is substantially crystalline. In one embodiment of the invention, Form A is moderately crystalline. In one embodiment of the invention, Form A is partially crystalline.

In one embodiment, Form A is the anhydrous free base form of Compound 1. In one embodiment, Form A is the desolvated free base form of Compound 1.

Shown is a representative XRPD diffraction pattern of Form A in FIG. 1.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 6.5, 7.0, 11.3, 13.1, 14.1, 16.8, 17.2, 17.4, 17.7, 18.0, 18.8, 19.7, 21.2, 21.4, 21.7, 22.2, 23.5, 23.9, 24.9, 25, 8, 26.3, 27.2 and 27.5° 2θ. In one embodiment of the invention, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 11.3, 14.1 and 17.4° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 6.5, 19.7 and 25.8° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 13.1 and 17.2° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 6.5, 11.3, 13.1, 14.1, 17.2, 17.4, 17.7, 18.8, 19.7, 22.2 and 25.8° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 1.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form A is shown in FIG. 2. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 0.3% when heated from about 25 to about 160°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of trace amounts of residual solvent or water. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 2.

- 18 044284

A representative differential scanning calorimetry (DSC) thermogram of Form A is shown in FIG. 3. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 138°C, a second thermal event with an initial temperature of about 183°C, and third thermal event with an initial temperature of about 217°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 146°C, the second thermal event also has a peak temperature of about 195°C, and the third thermal event also has a peak temperature of about 225°C. In one embodiment of the invention, without being limited to any particular theory, the first thermal event corresponds to the melting of Form A. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, characterized by a DSC thermogram that corresponds to the DSC thermogram represented by in fig. 3.

A representative dynamic vapor sorption (DVS) isotherm plot of Form A is shown in FIG. 4. In one embodiment of the invention, a solid form is provided herein containing the free base of Compound 1, which exhibits a weight increase of about 2.4% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 having a DVS isotherm curve that corresponds to the DVS isotherm curve presented in FIG. 4. In one embodiment of the invention, Form A is slightly hygroscopic.

In one embodiment of the invention, Form A remains as Form A after grinding (eg, with a mortar and pestle) for about two minutes.

In one embodiment, Compound 1 Free Base Form A is prepared by drying Compound 1 Free Base Form E (eg, about 40° C., vacuum, about 18 hours).

In one embodiment, provided herein is a solid form containing the free base Form A of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form A of Compound 1 and one or more other crystalline compounds forms the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form A of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Free base form B of compound 1.

In some embodiments, Compound 1 free base Form B is provided herein.

In one embodiment of the invention, Form B is crystalline. In one embodiment of the invention, Form B is substantially crystalline. In one embodiment of the invention, Form B is moderately crystalline. In one embodiment of the invention, Form B is partially crystalline.

In one embodiment, Form B is a channel solvate of the free base of Compound 1. In one embodiment, Form B is a channel hydrate of the free base of Compound 1.

Shown is a representative XRPD diffraction pattern of Form B in FIG. 5.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23 or all peaks located approximately in the following positions: 5.5, 6.6, 9.8, 11.0, 12.8, 13.3, 14, 2, 14.6, 15.9, 16.3, 17.1, 18.3, 18.6, 19.1, 19.5, 19.9, 20.6, 22.2, 23.6, 26.3, 26.9, 27.1, 28.1 and 28.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 6.6, 16.3 and 17.1° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 11.0 and 19.9° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 9.8 and 12.8° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 6.6, 9.8, 11.0, 12.8, 16.3, 17.1, 19.1, 19.9 and 26.9° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 5.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form B is shown in FIG. 6. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 1.7% when heated from about 25 to about 175°C. In one embodiment of the invention, without being limited to any particular theory, weight loss corresponds to water loss. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 6.

A representative differential scanning calorimetry (DSC) thermogram of Form B is shown in FIG. 7. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 which exhibits, as characterized by DSC, a first (broad) thermal event of about 20 to about 100° C., a second thermal event with an initial temperature of about 127 °C, a third thermal event with an initial temperature of about 180°C, and a fourth thermal event with an initial temperature of about 224°C. In one embodiment of the invention, the second thermal event also has a peak temperature of about 138°C, the third thermal event also has a peak temperature of about 189°C, and the fourth thermal event also has a peak temperature of about 227°C. In one embodiment of the invention, without being limited to any particular theory, the first (broad) heat event corresponds to dehydration and the second heat event corresponds to melting of dehydrated Form B. In alternative embodiments of the invention, Form B has a melting point in the range of about 122-129°C ( peak temperature), according to DSC. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 7.

A representative dynamic vapor sorption (DVS) isotherm plot of Form B is shown in FIG. 8. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight increase of about 3.1% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by a DVS isotherm curve that corresponds to the DVS isotherm curve presented in FIG. 8. In one embodiment of the invention, Form B is slightly hygroscopic.

In one embodiment of the invention, Form B remains as Form B after grinding (eg, with a mortar and pestle) for about two minutes.

In one embodiment, Compound 1 free base Form B is prepared by desolvation of a solvate of Compound 1 free base form. In one embodiment, Compound 1 free base Form B is prepared by desolvation of Compound 1 free base Form E. In one embodiment, desolvation of Form E occurs spontaneously under environmental conditions. In one embodiment of the invention, Compound 1 Free Base Form B is prepared by drying Compound 1 Free Base Form E (eg, about 40° C., vacuum, about 19 to about 24 hours). In one embodiment of the invention, Compound 1 Freebase Form B is prepared by drying Compound 1 Freebase Form F. In one embodiment, Compound 1 Freebase Form B is prepared by drying Compound 1 Freebase Form G (e.g., about 40° C., vacuum, about 31 hours). In one embodiment, Compound 1 Free Base Form B is prepared by drying a mixture of Compound 1 Free Base Form E and Form C (eg, about 40° C., vacuum, about 25 hours).

In one embodiment of the invention, Compound 1 Free Base Form B is prepared by crystallizing Compound 1 Free Base from MeOAc followed by drying (eg, at about 80° C.).

In one embodiment, provided herein is a solid form containing Free Base Form B of Compound 1 and an amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Free Base Form B of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form B of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form C of free base connection 1.

In some embodiments of the invention, Form C is provided herein

- 20 044284 free base of connection 1.

In one embodiment of the invention, Form C is crystalline. In one embodiment of the invention, Form C is substantially crystalline. In one embodiment of the invention, Form C is moderately crystalline. In one embodiment of the invention, Form C is partially crystalline.

In one embodiment, Form C is the desolvated free base form of Compound 1. In one embodiment, Form C is the anhydrous free base form of Compound 1.

Shown is a representative XRPD diffraction pattern of Form C in FIG. 9.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17 or all peaks located approximately at the following positions: 2.5, 9.9, 14.2, 14.6, 15.7, 15.9, 16.5, 17.2, 18.8, 19, 7, 20.6, 21.5, 21.8, 22.4, 23.5, 24.5, 25.7, and 26.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 14.2, 15.9 and 21.5° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 2.5, 20.6 and 23.5° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 15.7 and 21.8° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 2.5, 14.2, 15.7, 15.9, 16.5, 17.2, 20.6, 21.5, 21.8 and 23.5 °2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 9.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form C is shown in FIG. 10. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 0.6% when heated from about 25 to about 210°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of trace amounts of residual solvent or water. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 10.

A representative differential scanning calorimetry (DSC) thermogram of Form C is shown in FIG. 11. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 160°C and a second thermal event with an initial temperature of about 224°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 172°C, and the second thermal event also has a peak temperature of about 226°C. In one embodiment of the invention, without being limited to any particular theory, the first thermal event corresponds to the melting of Form C. In alternative embodiments of the invention, the melting peak of Form C is shifted to a lower temperature (for example, with an initial temperature of about 113°C and a peak temperature of about 125°C). Without being limited to any particular theory, the melting peak shift is caused by the plasticizing effect of the residual solvent, and the complete desolvation process in a Form C sample may take about two months. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. eleven.

A representative graph of the Dynamic Vapor Sorption (DVS) Form C isotherm is shown in FIG. 12. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight increase of about 8.3% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by a DVS isotherm curve that corresponds to the DVS isotherm curve presented in FIG. 12. In one embodiment of the invention, Form C is hygroscopic at high relative humidity.

- 21 044284

In one embodiment of the invention, Compound 1 Free Base Form C is prepared by crystallizing Compound 1 Free Base from a mixture of solvents containing water. In one embodiment, the solvent is a mixture of 2-PrOH and water (eg, 95:5 v/v or 90:10 v/v). In one embodiment, the solvent is a mixture of DMSO and water (eg, 1:3 v/v). In one embodiment of the invention, the formulation comprises suspending Compound 1 in a solvent at about 50°C for a specified period of time. In one embodiment of the invention, the preparation comprises cooling the solvent containing Compound 1 from about 60°C.

In one embodiment of the invention, Compound 1 Free Base Form C is prepared by evaporating a solution of Compound 1 Free Base in a solvent mixture of acetone and 2-PrOH under ambient conditions.

In one embodiment, provided herein is a solid form containing the free base Form C of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form C of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form C of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form D of the free base of connection 1.

In some embodiments, Compound 1 free base Form D is provided herein.

In one embodiment of the invention, Form D is crystalline. In one embodiment of the invention, Form D is substantially crystalline. In one embodiment of the invention, Form D is moderately crystalline. In one embodiment of the invention, Form D is partially crystalline.

In one embodiment of the invention, Form D is the free base hydration channel of Compound 1.

Shown is a representative XRPD diffraction pattern of Form D in FIG. 13.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 6.1, 9.6, 11.1, 11.6, 14.2, 14.4, 15.9, 16.4, 16.9, 17.5, 17.7, 17.9, 18.5, 19.4, 20.4, 23.3, 24.7, 24.8, 26.0, 27, 2, 27.4 and 29.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diffractogram containing peaks at approximately 6.1, 11.1 and 18.5° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 11.6 and 17.7° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 15.9 and 23.3° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 6.1, 11.1, 11.6, 14.2, 14.4, 15.9, 17.7, 17.9, 18.5, 19.4 , 23.3 and 26.0° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 13.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form D is shown in FIG. 14. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 2.0% when heated from about 25 to about 150°C. In one embodiment of the invention, without being limited to any particular theory, weight loss corresponds to water loss. Without being limited to any particular theory, water molecules are loosely bound (or residual), given that the mass is released below the boiling point of water. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 14.

A representative differential scanning calorimetry (DSC) thermogram of Form D is shown in FIG. 15. In one embodiment of the invention herein,

- 22 044284 provides a solid form containing the free base of compound 1, which exhibits, as characterized by DSC, a first (broad) thermal event from about 30 to about 120°C, a second thermal event with an initial temperature of about 129°C, a third thermal event from an initial temperature of about 171°C and a fourth thermal event with an initial temperature of about 222°C. In one embodiment of the invention, the second thermal event also has a peak temperature of about 136°C, the third thermal event also has a peak temperature of about 184°C, and the fourth thermal event also has a peak temperature of about 226°C. In one embodiment of the invention, without being limited to any particular theory, the first (broad) heat event corresponds to dehydration and the second heat event corresponds to melting of dehydrated Form D. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 , characterized by a DSC thermogram, which corresponds to the DSC thermogram presented in FIG. 15.

A representative dynamic vapor sorption (DVS) isotherm plot of Form D is shown in FIG. 16. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein that exhibits a weight increase of about 3.0% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by a DVS isotherm curve that corresponds to the DVS isotherm curve presented in FIG. 16. In one embodiment of the invention, Form D is slightly hygroscopic. In one embodiment of the invention, Form D is converted to a mixture of Form B and Form E after a DVS humidity cycle.

In one embodiment of the invention, Compound 1 Free Base Form D is prepared by crystallizing Compound 1 Free Base from ethanol. In one embodiment of the invention, the formulation comprises suspending Compound 1 in ethanol at a temperature of about 25 to about 35°C for a period of time. In one embodiment of the invention, the formulation comprises suspending Compound 1 in ethanol at room temperature for a specified period of time.

In one embodiment of the invention, Compound 1 free base Form D is prepared by suspending Compound 1 in diglyme at about 40° C. for a period of time (eg, about 14 days). In one embodiment of the invention, Compound 1 free base Form D is prepared by suspending Compound 1 in carbitol at about 40° C. for a period of time (eg, about 14 days).

In one embodiment, provided herein is a solid form containing the free base Form D of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form D of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form D of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form E of free base connection 1.

In some embodiments, Compound 1 free base Form E is provided herein.

In one embodiment of the invention, Form E is crystalline. In one embodiment of the invention, Form E is substantially crystalline. In one embodiment of the invention, Form E is moderately crystalline. In one embodiment of the invention, Form E is partially crystalline.

In one embodiment, Form E is a solvate of the free base of Compound 1. In one embodiment, Form E is an isomorphic solvate of the free base of Compound 1. In one embodiment, Form E is a hydrate of the free base of Compound 1. In one embodiment of the invention, Form E is the MEK solvate of the free base of Compound 1. In one embodiment of the invention, Form E is the solvate of the free base of Compound 1, ethyl formate.

Shown is a representative XRPD diffraction pattern of Form E in FIG. 17.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 6.2, 9.8, 11.3, 11.7, 12.5, 13.6, 14.2, 14.3, 16.5, 16.9, 17.2, 17.7, 17.8, 18.0, 18.8, 19.6, 20.5, 21.4, 23.6, 24, 0, 25.7, 26.4 and 26.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form is characterized by 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 6.2, 14.3 and 18.8° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 11.3 and 11.7° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 16.5, 17.2 and 26.4° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 6.2, 11.3, 11.7, 14.3, 16.5, 17.2, 17.8, 18.0, 18.8, 20.5 and 26.4° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 17.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form E is shown in FIG. 18. In one embodiment, provided herein is a solid form containing the free base of Compound 1 which exhibits a weight loss of about 9.7% when heated from about 25 to about 180°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of MEK. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 18.

A representative differential scanning calorimetry (DSC) thermogram of Form E is shown in FIG. 19. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 118°C, a second thermal event with an initial temperature of about 147°C, and third thermal event with an initial temperature of about 224°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 132°C, the second thermal event also has a peak temperature of about 170°C, and the third thermal event also has a peak temperature of about 226°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to melting (after partial dehydration/desolvation). In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 19.

A representative dynamic vapor sorption (DVS) isotherm plot of Form E is shown in FIG. 20. In one embodiment, Form E loses mass both during the initial equilibration period at 50% relative humidity (RH) and during the subsequent humidity cycle, even as humidity increases. Without being limited to any particular theory, this corresponds to the replacement of many of the heavier MEK molecules with lighter H ₂ O molecules. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by a DVS isotherm curve that corresponds to the isotherm curve DVS shown in FIG. 20. In one embodiment of the invention, Form E is converted to a predominantly amorphous material after a DVS humidity cycle.

In one embodiment of the invention, Form E of the free base of Compound 1 is prepared by crystallizing the free base of Compound 1 from a solvent. In one embodiment, the solvent is ethyl formate, toluene, MEK, a mixture of iPrOAc and DMA, a mixture of IPE and DMF, and a mixture of IPE and NMP. In one embodiment of the invention, the solvent is MEK. In one embodiment of the invention, the preparation comprises cooling a solution of Compound 1 in MEK. In one embodiment of the invention, the solvent is ethyl formate. In one embodiment of the invention, the formulation comprises suspending Compound 1 in ethyl formate at a temperature of about 25 to about 35°C for a period of time.

In one embodiment, provided herein is a solid form containing the free base Form E of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form E of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form E of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

- 24 044284

Form F of the free base of connection 1.

In some embodiments, Compound 1 free base Form F is provided herein.

In one embodiment of the invention, Form F is crystalline. In one embodiment of the invention, Form F is substantially crystalline. In one embodiment of the invention, Form F is moderately crystalline. In one embodiment of the invention, Form F is partially crystalline.

In one embodiment, Form F is a solvate of the free base of Compound 1. In one embodiment, Form F is an isomorphic solvate of the free base of Compound 1. In one embodiment, Form F is an anisole solvate of the free base of Compound 1. In one embodiment, Form F is a toluene solvate of the free base of Compound 1. In one embodiment, Form F is an ethyl formate solvate of the free base of Compound 1. In one embodiment, Form F is a methyl acetate solvate of the free base of Compound 1. In one embodiment, Form F is an ethyl acetate solvate the free base of Compound 1. In one embodiment, Form F is an isopropyl acetate solvate of the free base of Compound 1. In one embodiment, Form F is an acetone solvate of the free base of Compound 1. In one embodiment, Form F is a dioxane solvate of the free base of Compound 1. In one embodiment, Form F is the cumene solvate of the free base of Compound 1. In one embodiment, Form F is the trifluorotoluene solvate of the free base of Compound 1. In one embodiment, Form F is the n-xylene solvate of the free base of Compound 1.

Shown is a representative XRPD diffraction pattern of Form F in FIG. 21.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 5.0, 5.5, 7.8, 10.1, 13.1, 14.1, 14.3, 15.6, 16.5, 16.9, 17.3, 18.0, 18.6, 21.3, 21.7, 21.8, 22.2, 23.9, 25.8, 26, 3, 26.4, 27.0 and 28.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffraction pattern containing peaks at approximately 5.0, 14.3 and 26.3° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 18.0 and 26.4° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 7.8 and 18.6° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 5.0, 7.8, 14.1, 14.3, 18.0, 18.6, 21.7, 21.8, 26.3 and 26.4 °2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 21.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form F is shown in FIG. 22. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 21.5% when heated from about 25 to about 200°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of anisole and some water. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 22.

A representative differential scanning calorimetry (DSC) thermogram of Form F is shown in FIG. 23. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 113°C and a second thermal event with an initial temperature of about 223°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 121°C, and the second thermal event also has a peak temperature of about 225°C. In one embodiment of the invention, without being limited to any particular theory, an irregular baseline on a DSC thermogram is likely due to

- 25 044284 some release of the solvent at a temperature below 100°C, and the first thermal event corresponds to the melting of the solvate itself, while the release of the solvent continues. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 23.

In one embodiment of the invention, Form F of the free base of Compound 1 is prepared by crystallizing the free base of Compound 1 from a solvent. In one embodiment of the invention, the solvent is anisole, toluene, a mixture of acetone and water, ethyl formate, EtOAc, a mixture of iPrOAc and THF, MeOAc, a mixture of 2-propanol and water, and a mixture of dioxane and toluene. In one embodiment of the invention, the solvent is anisole. In one embodiment, the formulation includes cooling an anisole solution of Compound 1. In one embodiment, the formulation includes suspending Compound 1 in anisole at room temperature for a specified period of time. In one embodiment of the invention, a formulation comprising suspending Compound 1 in anisole at a temperature of about 25 to about 35°C for a period of time. In one embodiment of the invention, the solvent is toluene. In one embodiment of the invention, the formulation comprises suspending Compound 1 in toluene at a temperature of about 25 to about 35°C for a period of time.

In one embodiment, provided herein is a solid form containing the free base Form F of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form F of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form F of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form G of the free base of connection 1.

In some embodiments, Compound 1 free base Form G is provided herein.

In one embodiment of the invention, Form G is crystalline. In one embodiment of the invention, Form G is substantially crystalline. In one embodiment of the invention, Form G is moderately crystalline. In one embodiment of the invention, Form G is partially crystalline.

In one embodiment of the invention, Form G is the free base solvate of Compound 1. In one embodiment of the invention, Form G is the free base solvate of Compound 1.

Shown is a representative XRPD diffraction pattern of Form G in FIG. 24.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21 or all peaks located approximately in the following positions: 5.6, 6.4, 6.9, 9.8, 10.9, 11.2, 12.1, 13, 9, 14.4, 16.0, 16.4, 16.7, 18.0, 18.7, 19.1, 19.6, 23.6, 24.3, 26.0, 26.3, 26.9 and 28.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 6.4, 19.1 and 19.6° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 12.1 and 13.9° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 14.4, 16.7 and 26.0° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 5.6, 6.4, 11.2, 12.1, 13.9, 14.4, 16.7, 19.1, 19.6 and 26.0 °2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 24.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form G is shown in FIG. 25. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of approximately 6.1% at

- 26 044284 heating from about 25 to about 170°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of acetonitrile. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 25.

A representative differential scanning calorimetry (DSC) thermogram of Form G is shown in FIG. 26. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 132°C and a second thermal event with an initial temperature of about 225°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 140°C, and the second thermal event also has a peak temperature of about 226°C. In one embodiment of the invention, without being limited to any particular theory, the first thermal event corresponds to melting (after desolvation). In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 26.

In one embodiment of the invention, Form G of the free base of Compound 1 is prepared by crystallizing the free base of Compound 1 from a solvent containing acetonitrile. In one embodiment of the invention, the solvent is acetonitrile. In one embodiment of the invention, the solvent is a mixture of acetonitrile and water (eg, 95:5 v/v). In one embodiment of the invention, the formulation comprises suspending Compound 1 in acetonitrile at room temperature for a specified period of time. In one embodiment of the invention, the formulation comprises suspending Compound 1 in acetonitrile at a temperature of about 25 to about 35°C for a period of time.

In one embodiment, provided herein is a solid form containing the free base Form G of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form G of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form G of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form H of the free base of compound 1.

In some embodiments, Compound 1 free base Form H is provided herein.

In one embodiment of the invention, Form H is crystalline. In one embodiment of the invention, Form H is substantially crystalline. In one embodiment of the invention, Form H is moderately crystalline. In one embodiment of the invention, Form H is partially crystalline.

In one embodiment, Form H is a solvate of the free base of Compound 1. In one embodiment, Form H is an isomorphic solvate of the free base of Compound 1. In one embodiment, Form H is a THF solvate of the free base of Compound 1. In one embodiment In carrying out the invention, Form H is the TBME solvate of the free base of compound 1.

Shown is a representative XRPD diffraction pattern of Form H in FIG. 27.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19 or all peaks located approximately in the following positions: 5.4, 5.7, 7.5, 10.7, 13.3, 14.2, 14.5, 15.1, 15, 4, 16.7, 17.2, 17.6, 18.4, 19.2, 19.6, 20.6, 26.1, 26.6, 26.8 and 27.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 5.4, 7.5 and 10.7° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 14.2 and 14.5° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 17.2, 17.6 and 26.1° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 5.4, 7.5, 10.7, 14.2, 14.5, 17.2, 17.6, 26.1, 26.6 and 26.8 °2θ.

- 27 044284

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 27.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form H is shown in FIG. 28. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 11.8% when heated from about 25 to about 220°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of TBME. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 28.

A representative differential scanning calorimetry (DSC) thermogram of Form H is shown in FIG. 29. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits, as characterized by DSC, a first (broad) thermal event with a peak temperature of about 140° C., a second thermal event with an initial temperature of about 177° C, and a third thermal event with an initial temperature of about 221°C. In one embodiment of the invention, the second thermal event also has a peak temperature of about 193°C, and the third thermal event also has a peak temperature of about 224°C. In one embodiment of the invention, without being limited to any particular theory, the first (broad) thermal event corresponds to concomitant desolvation and melting. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 29.

In one embodiment of the invention, Compound 1 free base Form H is prepared by evaporating a solution of Compound 1 in THF at room temperature. In one embodiment of the invention, Compound 1 free base Form H is prepared by suspending Compound 1 in TBME at a temperature of about 25 to about 35° C. for a period of time. In one embodiment of the invention, Compound 1 free base Form H is prepared by suspending Compound 1 in TBME at about 50° C. for a period of time.

In one embodiment, provided herein is a solid form containing Form H of the free base of Compound 1 and an amorphous free base of Compound 1. In one embodiment of the invention, provided herein is a solid form containing Form H of the free base of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form H of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form I of the free base of compound 1.

In some embodiments, Compound 1 free base Form I is provided herein.

In one embodiment of the invention, Form I is crystalline. In one embodiment of the invention, Form I is substantially crystalline. In one embodiment of the invention, Form I is moderately crystalline. In one embodiment of the invention, Form I is partially crystalline.

In one embodiment of the invention, Form I is the free base solvate of Compound 1. In one embodiment of the invention, Form I is the DMSO solvate of the free base of Compound 1.

Shown is a representative XRPD diffraction pattern of Form I in FIG. thirty.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21 or all peaks located approximately in the following positions: 5.7, 6.2, 9.9, 11.3, 11.5, 14.9, 15.1, 15, 6, 16.3, 16.6, 16.7, 17.0, 18.0, 18.4, 19.6, 21.1, 21.3, 21.6, 23.2, 26.1, 26.4 and 26.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 14.9, 15.6 and 21.3° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 6.2, 16.7 and 18.0° 2θ. In one embodiment of the invention, the XRPD diffraction pattern additionally contains peaks at approximately 9.9 and

16.3° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 6.2, 9.9, 14.9, 15.6, 16.3, 16.7, 17.0, 18.0, 19.6, 21.1 ,21.3 and 26.1° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. thirty.

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form I is shown in FIG. 31. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 42.2% when heated from about 25 to about 300°C. In one embodiment of the invention, without being limited to any particular theory, the weight loss corresponds to the loss of DMSO (and some water). In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 31.

In one embodiment of the invention, Compound 1 free base Form I is prepared by suspending Compound 1 in a mixture of DMSO and 2-PrOH (eg, 1:3 v/v) at about 50° C. for a period of time. In one embodiment of the invention, Compound 1 free base Form I is prepared by suspending Compound 1 in a mixture of DMSO and water (eg, 95:5 v/v) at room temperature for a specified period of time.

In one embodiment, provided herein is a solid form containing Form I of the free base of Compound 1 and an amorphous free base of Compound 1. In one embodiment of the invention, provided herein is a solid form containing Form I of the free base of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form I of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form J of joint free base 1.

In some embodiments, Compound 1 free base Form J is provided herein.

In one embodiment of the invention, Form J is crystalline. In one embodiment of the invention, Form J is substantially crystalline. In one embodiment of the invention, Form J is moderately crystalline. In one embodiment of the invention, Form J is partially crystalline.

In one embodiment of the invention, Form J is the free base solvate of Compound 1. In one embodiment of the invention, Form J is the acetic acid solvate of the free base of Compound 1.

Shown is a representative XRPD diffraction pattern of Form J in FIG. 32.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22 or all peaks located approximately in the following positions: 5.9, 11.1, 11.8, 12.3, 13.5, 13.8, 14.1, 15.2, 17.0, 17.9, 20.3, 20.5, 22.0, 22.3, 23.3, 23.7, 24.3, 24.7, 25.7, 26, 2, 26.4, 26.7 and 28.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment of the invention, the solid form is characterized by all peaks.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram containing peaks at approximately 13.8, 15.2 and 22.0° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 23.3 and 23.7° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 5.9 and 25.7° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 5.9, 11.8, 13.8, 14.1, 15.2, 20.3, 22.0, 23.3, 23.7, 24.3 , 25.7 and 26.7° 2θ.

In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by an XRPD diffractogram that corresponds to the XRPD diffractogram presented in FIG. 32.

- 29 044284

In one embodiment of the invention, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form J is shown in FIG. 33. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 3.9% when heated from about 25 to about 110° C. and a weight loss of about 15.3% when heated from about 110°C to about 250°C. In one embodiment of the invention, without being limited to any particular theory, the first weight loss corresponds to the loss of acetic acid (and trace amounts of water) and the second weight loss corresponds to the loss of acetic acid. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 33.

A representative differential scanning calorimetry (DSC) thermogram of Form J is shown in FIG. 34. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1, which exhibits, as characterized by DSC, a first thermal event with a maximum temperature of about 70°C, a second thermal event with an initial temperature of about 138°C, and third thermal event with an initial temperature of about 219°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 80°C, the second thermal event also has a peak temperature of about 155°C, and the third thermal event also has a peak temperature of about 225°C. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 34.

In one embodiment of the invention, Compound 1 free base Form J is prepared by suspending Compound 1 in a mixture of acetic acid and isopropyl ether (eg, 1:9 v/v) at a temperature of about 25 to about 35° C. for a period of time.

In one embodiment, provided herein is a solid form containing the free base Form J of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing the free base Form J of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form J of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Forms K and K' of the free base of compound 1.

In certain embodiments of the invention, provided herein is Compound 1 free base Form K, Compound 1 free base Form K', a form intermediate between Form K and Form K', or a mixture thereof.

In one embodiment of the invention, Form K is crystalline. In one embodiment, Form K is substantially crystalline. In one embodiment of the invention, Form K is moderately crystalline. In one embodiment of the invention, Form K is partially crystalline. In one embodiment of the invention, form K' is crystalline. In one embodiment of the invention, form K' is substantially crystalline. In one embodiment of the invention, Form K' is moderately crystalline. In one embodiment of the invention, Form K' is partially crystalline.

In one embodiment of the invention, Form K is the hydrate channel of the free base of Compound 1. In one embodiment of the invention, Form K is the monohydrate of the free base of Compound 1. In one embodiment, Form K' is the dehydrated hydrate of Form K. In one embodiment of the invention Without being limited to any particular theory, the K' form converts to the K form as humidity increases, and the K form converts to the K' form as humidity decreases. Accordingly, intermediate forms between form K and form K' exist depending on the degree of moisture. Examples of conversion between form K and form K', including possible intermediate forms, are presented in FIG. 132 and 133. In one embodiment of the invention, form K is converted to form K' when the water activity does not exceed about 0.11. In one embodiment, Form K' is converted to Form K when the water activity is at least about 0.17.

In one embodiment of the invention, provided herein is Form K, Form K', or an intermediate form between Form K and Form K', or a mixture thereof, of the free base of Compound 1, characterized by an XRPD diffractogram containing peaks at approximately 14.6, 18.2 and 18.3° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 22.3 and 23.1° 2θ. In one embodiment of the invention, the diffraction pattern

- 30 044284

XRPD additionally contains peaks at approximately 20.5 and 20.9° 2θ. In one embodiment of the invention, the XRPD diffraction pattern contains peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, and 23.1 °2θ. In one embodiment of the invention, provided herein is Form K of the free base of Compound 1, characterized by an XRPD diffraction pattern further comprising at least a peak at about 14.2, 18.6, or 20.3° 2θ. In one embodiment of the invention, the free base form K' of compound 1 is provided herein, characterized by an XRPD diffractogram further containing at least a peak at about 18.0 or 18.8° 2θ.

Shown is a representative XRPD diffraction pattern of Form K in FIG. 35.

In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24 or all peaks located approximately at the following positions: 8.6, 10.8, 14.2, 14.3, 14.6, 16.6, 17.3, 17.5, 18.2, 18.3, 18.6, 20.3, 20.5, 20.9, 21.8, 22.3, 22.5, 23.1, 24, 5, 25.1, 25.7, 26.0, 27.4, 27.9 and 31.4° 2θ. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24 or all peaks located approximately at the following positions: 8.59, 10.78, 14.21, 14.32, 14.60, 16.55, 17.26, 17.45, 18.21, 18.34, 18.62, 20.25, 20.47, 20.87, 21.79, 22.28, 22.45, 23.05, 24, 54, 25.05, 25.67, 26.01, 27.43, 27.89 and 31.44° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 14.2, 14.6, 18.2 and 18.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.8° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.2, 14.6, 18.2 and 18.3° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.04° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.21, 14.60, 18.21 and 18.34° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.04° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.2, 14.6, 18.2 and 18.3° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.02° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.21, 14.60, 18.21 and 18.34° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart is additionally

- 31 044284 contains peaks at 20.47 and 20.87° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.02° 2θ.

In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.2, 14.6, 18.2 and 18.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.2, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD diagram containing peaks at 14.21, 14.60, 18.21 and 18.34° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.21, 14.32, 14.60, 16.55, 18.21, 18.34, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at approximately 14.6, 18.2, 18.3 and 18.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.8° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.6, 18.2, 18.3 and 18.6° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.04° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 18.62° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.04° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.6, 18.2, 18.3 and 18.6° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.02° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 18.62° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.02° 2θ.

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In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.6, 18.2, 18.3 and 18.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 18.6, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.60, 18.21, 18.34 and 18.62° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 18.62, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 14.6, 18.2, 18.3 and 20.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23.1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.8° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.6, 18.2, 18.3 and 20.3° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.04° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 20.25° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.04° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.6, 18.2, 18.3 and 20.3° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ ±0.02° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.60, 18.21, 18.34 and 20.25° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD diagram containing peaks at

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14.6, 18.2, 18.3 and 20.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.3, 23.1 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.5 and 20.9° 2θ. In one embodiment, the XRPD chart contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.3, 20.5, 20.9, 22.3, 23 ,1, 24.5 and 26.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.0° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD diagram containing peaks at 14.60, 18.21, 18.34 and 20.25° 2θ. In one embodiment, the XRPD diagram further contains peaks at 22.28, 23.05 and 24.54° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.47 and 20.87° 2θ. In one embodiment, the XRPD chart contains peaks at 8.59, 14.32, 14.60, 16.55, 18.21, 18.34, 20.25, 20.47, 20.87, 22.28, 23 .05, 24.54 and 26.01° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.75° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 35.

A typical K' shape XRPD diagram is shown in FIG. 36.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or all peaks located approximately at the following positions: 8.7, 10.8, 14.4, 14.6, 16.6, 17, 4, 17.5, 18.0, 18.3, 18.4, 18.8, 20.5, 20.9, 21.8, 22.4, 22.6, 23.2, 24.7, 25.2, 25.8, 26.2, 26.4, 27.5, 28.1, 31.7 and 38.4° 2θ. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all peaks located approximately at the following positions: 8.65, 10.79, 14.36, 14.63, 16.55, 17.35 , 17.53, 18.02, 18.25, 18.40, 18.75, 20.52, 20.92, 21.81, 22.36, 22.64, 23.19, 24.68, 25 ,20, 25.82, 26.17, 26.39, 27.54, 28.08, 31.69 and 38.41° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 14.6, 18.0, 18.3 and 18.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.9, 22.4 and 23.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.6 and 20.5° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23.2 and 24.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 14.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.6° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 20.3° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.6, 18.0, 18.3 and 18.4° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23 ,2 and 24.7° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ ±0.04° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.63, 18.02, 18.25 and 18.40° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23 .19 and 24.68° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ ±0.04° 2θ.

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In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.6, 18.0, 18.3 and 18.4° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23 ,2 and 24.7° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ ±0.02° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.63, 18.02, 18.25 and 18.40° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23 .19 and 24.68° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.6, 18.0, 18.3 and 18.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.0, 18.3, 18.4, 20.5, 20.9, 22.4, 23 .2 and 24.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at 14.63, 18.02, 18.25 and 18.40° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ. In one embodiment, the XRPD chart contains peaks at 8.65, 14.36, 14.63, 16.55, 18.02, 18.25, 18.40, 20.52, 20.92, 22.36, 23 .19 and 24.68° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at approximately 14.6, 18.3, 18.4 and 18.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.9, 22.4 and 23.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.6 and 20.5° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23.2 and 24.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 14.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.6° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 20.3° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.6, 18.3, 18.4 and 18.8° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23 ,2 and 24.7° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ ±0.04° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.63, 18.25, 18.40 and 18.75° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at

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8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23.19 and 24.68° 2θ ± 0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ ±0.04° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.6, 18.3, 18.4 and 18.8° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23 ,2 and 24.7° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ ±0.02° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern including peaks at 14.63, 18.25, 18.40 and 18.75° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23 .19 and 24.68° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.6, 18.3, 18.4 and 18.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.9, 22.4 and 23.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.6 and 20.5° 2θ. In one embodiment, the XRPD chart contains peaks at 8.7, 14.4, 14.6, 16.6, 18.3, 18.4, 18.8, 20.5, 20.9, 22.4, 23 .2 and 24.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.6° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ. In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD diagram containing peaks at 14.63, 18.25, 18.40 and 18.75° 2θ. In one embodiment, the XRPD diagram further contains peaks at 20.92, 22.36 and 23.19° 2θ. In one embodiment, the XRPD diagram further contains peaks at 16.55 and 20.52° 2θ. In one embodiment, the XRPD chart contains peaks at 8.65, 14.36, 14.63, 16.55, 18.25, 18.40, 18.75, 20.52, 20.92, 22.36, 23 .19 and 24.68° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.21° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.62° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.25° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 36.

In one embodiment, without being limited to any particular theory, compared to Form K, the XRPD peaks in Form K' shift slightly toward higher 2θ values, suggesting that Form K' has a slightly compressed lattice.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Form K is shown in FIG. 37. In one embodiment, provided herein is a solid form containing the free base of Compound 1 which exhibits a first weight loss of about 1.7% when heated from about 25 to about 75°C and a second weight loss of about 0.6% when heating from about 120 to about 160°C. In one embodiment, without being limited to any particular theory, the first mass loss corresponds to the loss of water in the channel, and the second mass loss corresponds to the loss of bound recrystallization solvent, which is considered part of the crystal structure and is released only when the enantiomer melts. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 37.

A typical Form K thermogram obtained by differential scanning calorimetry (DSC) is shown in FIG. 38. In one embodiment, provided herein is a solid form containing the free base of compound 1, which exhibits, as characterized by DSC, a first (broad) thermal event with a peak temperature of about 60° C., a second thermal event with an onset temperature around 148°C, a third (wide) thermal event with an initial temperature of around 190°C, and a fourth thermal event with an initial temperature around 224°C. In one embodiment of the invention, the second thermal event also has a peak temperature of about 153°C, the third thermal event also has a peak temperature of about 197°C, and the fourth thermal event also has a peak temperature of about 227°C. In one embodiment, without being limited to any particular theory, the first (broad) thermal event corresponds to the loss of water in the channel, the second thermal event corresponds to the melting of the dehydrated form K (i.e., form K'), the third thermal event corresponds to simultaneous racemization and crystallization of the compound, and the fourth thermal event corresponds to the melting of the racemate compound. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 38.

A typical Form K dynamic vapor sorption (DVS) isotherm plot is shown in FIG. 39. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein that exhibits a weight increase of about 3.2% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment of the invention, a solid form containing the free base of Compound 1 is provided herein, characterized by a DVS isotherm curve that corresponds to the DVS isotherm curve presented in FIG. 39. In one embodiment, Form K is slightly hygroscopic.

In one embodiment, Compound 1 free base Form K is prepared by crystallizing Compound 1 free base from a solvent mixture containing water. In one embodiment, the solvent is a mixture of 2-PrOH and water. In one embodiment, the ratio of 2-PrOH to water is from about 85:15 to about 95:5 (v/v). In one embodiment, the solvent is a mixture of 2-PrOH and water in a ratio of about 85/15 (v/v). In one embodiment, the solvent is a mixture of 2-PrOH and water in a ratio of about 90/10 (v/v). In one embodiment, the solvent is a mixture of 2-PrOH and water in a ratio of about 95/5 (v/v). In one embodiment, the solvent is a mixture of acetone and water (eg, 95:5, 90:10, 80:20 v/v). In one embodiment, the formulation includes suspending Compound 1 in a solvent at about 60° C. for a period of time (eg, 1 to 14 days, eg, 5 days). In one embodiment, the formulation includes suspending Compound 1 in a solvent at room temperature for a period of time (eg, 1 to 14 days, eg, 1 day or 4 days). In one embodiment, production occurs at high water activity (H ₂ O). In one embodiment, the water activity is at least 0.2. In one embodiment, the water activity is at least 0.3. In one embodiment, the water activity is at least 0.5. In one embodiment, the water activity is at least 0.7. In one embodiment, the water activity is about 0.7. In one embodiment, without being limited to any particular theory, crystallization of the free base of Compound 1 from a solvent mixture containing water first leads to Form B or Form C, which is converted to Form K.

In one embodiment, Form K' of the free base of Compound 1 is prepared by dehydration of Form K. In one embodiment, Form K is converted to Form K' when the water activity does not exceed about 0.11. In one embodiment, Form K' is converted to Form K when the water activity is at least about 0.17.

In one embodiment, provided herein is a solid form containing Form K of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form K of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form K of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

In one embodiment, provided herein is a solid form comprising Form K' of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form K' of the free base of Compound 1 and one or more other crystalline forms of the free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base form K' of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

- 37 044284

Form L of free base connection 1.

In some embodiments, Compound 1 free base Form L is provided herein.

In one embodiment, Form L is crystalline. In one embodiment, Form L is substantially crystalline. In one embodiment, Form L is moderately crystalline. In one embodiment, Form L is partially crystalline.

In one embodiment, Form L is a solvate of the free base of Compound 1. In one embodiment, Form L is a solvate of the free base of Compound 1 with tetrahydrofurfuryl alcohol.

A typical L-shape XRPD pattern is shown in FIG. 40.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all peaks located approximately at the following positions: 6.5, 11.8, 14.3, 14.7, 15.9, 16.1, 17.2, 17.9, 18, 4, 19.3, 19.8, 20.0, 20.3, 21.7, 24.9, 25.7, 26.2, 26.3, 26.7, and 27.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD pattern containing peaks at approximately 15.9, 17.9 and 26.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 19.8 and 20.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.3, 14.7 and 25.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 6.5, 14.3, 14.7, 15.9, 17.9, 18.4, 19.8, 20.3, 25.7, 26.2, and 26.3° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 40.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 free base Form L is prepared by suspending Compound 1 in tetrahydrofurfuryl alcohol at about 40° C. for a period of time (eg, about 14 days).

In one embodiment, provided herein is a solid form containing Form L of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form L of the free base

Compound 1 and one or more other free base crystalline forms of Compound 1 provided herein. In one embodiment, provided herein is a solid form containing the free base Form L of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form M of the free base of compound 1.

In some embodiments, Compound 1 free base Form M is provided herein.

In one embodiment, Form M is crystalline. In one embodiment, Form M is substantially crystalline. In one embodiment, Form M is moderately crystalline. In one embodiment, Form M is partially crystalline.

In one embodiment, Form M is the free base solvate of Compound 1. In one embodiment, Form M is the 2-pentyl acetate free base solvate of Compound 1. In one embodiment, Form M is the 2-pentyl acetate free base solvate of Compound 1.

A typical XRPD form M sample is shown in FIG. 41.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all peaks located approximately at the following positions: 5.1, 5.4, 5.8, 12.0, 13.3, 14.1, 15.3, 15.6, 16, 4, 17.0, 18.4, 18.9, 19.3, 22.6, 24.2, 25.6, 26.1, 26.2, 26.6, and 27.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 14.1, 17.0 and 18.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.8 and 15.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.4 and 24.2° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.1, 5.4, 5.8, 12.0, 14.1, 15.3, 16.4, 17.0, 18.4, 18.9, 24.2 and 26.2° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 41.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Form M is shown in FIG. 42. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 10.9% when heated from about 25 to about 200°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of 2-pentyl acetate (and trace amounts of water). In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 42.

A typical Form M thermogram obtained by differential scanning calorimetry (DSC) is shown in FIG. 43. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a thermal phenomenon as characterized by DSC with an onset temperature of about 141°C. In one embodiment, the thermal event also has a peak temperature of about 155°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to melting. In one embodiment of the invention, provided herein is a solid form containing the free base of Compound 1 characterized by a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 43.

In one embodiment, Compound 1 free base Form M is prepared by suspending Compound 1 in 2-pentyl acetate at about 40° C. for a period of time (eg, about 14 days). In one embodiment, Compound 1 free base Form M is prepared by suspending Compound 1 in 2-pentyl acetate at about 60° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing Form M of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form M of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base form M of compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of compound 1 provided herein.

Form N of the free base of compound 1.

In some embodiments, Compound 1 free base Form N is provided herein.

In one embodiment, form N is crystalline. In one embodiment, Form N is substantially crystalline. In one embodiment, Form N is moderately crystalline. In one embodiment, Form N is partially crystalline.

In one embodiment, Form N is the free base solvate of Compound 1. In one embodiment, Form N is the hexamethylphosphoramide solvate of Compound 1 free base.

A typical XRPD Form N sample is shown in FIG. 44.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located approximately at the following positions: 3.7, 5.5, 10.5, 12.6, 12.8, 13.0, 13.7, 13.9 , 14.1, 14.5, 14.7, 15.0, 15.3, 15.5, 16.4, 16.6, 16.8, 17.3, 18.8, 25.0, 25 .7 and 26.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at approximately 13.0, 25.0 and 25.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 13.9, 15.0 and 26.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 3.7 and 10.5° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 3.7, 10.5, 13.0, 13.9, 14.5, 15.0, 18.8, 25.0, 25.7, and 26.1° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 44.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form N of the free base of Compound 1 is prepared by suspending Compound 1 in hexamethylphosphoramide at about 40° C. for a period of time (eg, about 14 days) followed by evaporation of the solvent.

In one embodiment, provided herein is a solid form containing Form N of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form N of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form N of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form O of the free base of compound 1.

In some embodiments, Form O of the free base of Compound 1 is provided herein.

In one embodiment, Form O is crystalline. In one embodiment, Form O is substantially crystalline. In one embodiment, Form O is moderately crystalline. In one embodiment, Form O is partially crystalline.

A typical O-shape XRPD pattern is shown in FIG. 45.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located approximately at the following positions: 6.5, 7.2, 10.7, 13.5, 14.0, 14.3, 16.5, 17.7, 18 ,1, 18.8, 19.0, 19.9, 20.3, 20.6, 21.5, 21.7, 22.9, 23.3, 25.8, 28.7 and 29.2 °2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 6.5, 16.5 and 20.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.0 and 17.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.3, 19.9 and 21.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 6.5, 7.2, 10.7, 14.0, 14.3, 16.5, 17.7, 19.9, 20.6, 21.7, 22.9 and 25.8° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 45.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical Form O TG/DTA thermograms are shown in FIG. 46. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 1.5% when heated from about 25 to about 75° C. and a weight loss of about 3.0% when heated from about 75 to approximately 150°C. In one embodiment, without being limited to any particular theory, the first mass loss corresponds to the loss of unbound solvent, and the second mass loss corresponds to dehydration (about 1 equivalent of water). In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that

- 40 044284 corresponds to the TGA thermogram shown in FIG. 46.

In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 113°C. In one embodiment, the thermal event also has a peak temperature of about 117°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to dehydration. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 46.

In one embodiment, Form O of the free base of Compound 1 is prepared by subjecting a suspension containing Compound 1 and L-malic acid in IPA to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing Form O of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form O of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form O of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form P of the free base of compound 1.

In some embodiments, the free base form P of Compound 1 is provided herein.

In one embodiment, form P is crystalline. In one embodiment, Form P is substantially crystalline. In one embodiment, Form P is moderately crystalline. In one embodiment, Form P is partially crystalline.

A typical P-shape XRPD pattern is shown in FIG. 47.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located approximately at the following positions: 7.1, 10.5, 11.6, 12.8, 13.7, 14.3, 15.5, 16.3, 16 .6, 17.0, 17.8, 19.9, 21.0, 21.5, 21.7, 23.2, 27.4, 28.6, 28.9, 29.5 and 32.0 °2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 14.3, 16.3 and 21.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.6, 17.0 and 17.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.1 and 13.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.1, 13.7, 14.3, 16.3, 16.6, 17.0, 17.8, 19.9, 21.0, 23.2, and 28.9° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 47.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical TG/DTA form P thermograms are shown in FIG. 48. In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a weight loss of about 2.6% when heated from about 25°C to about 60°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of unbound solvent. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 48.

In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 132°C. In one embodiment, the thermal event also has a peak temperature of about 141°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to melting/decomposition. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 48.

In one embodiment, Form P of the free base of Compound 1 is prepared by subjecting a suspension containing Compound 1 and D-gluconic acid in ethanol to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing Form P of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form P of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form P of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form Q of the free base of compound 1.

In some embodiments, Compound 1 free base Form Q is provided herein.

In one embodiment, Form Q is crystalline. In one embodiment, Form Q is substantially crystalline. In one embodiment, Form Q is moderately crystalline. In one embodiment, Form Q is partially crystalline.

A typical Q-shape XRPD pattern is shown in FIG. 49.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all peaks located approximately at the following positions: 5.7, 12.5, 13.1, 15.2, 15.5, 15.7, 16.0, 16.8, 17.1, 17.3, 18 ,1, 18.4, 20.7, 22.1, 25.3, 27.0 and 31.0° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1, characterized by an XRPD diagram containing peaks at approximately 5.7, 15.5 and 20.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 13.1 and 16.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 12.5 and 18.1° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.7, 12.5, 13.1, 15.5, 16.0, 17.1, 18.1, 20.7, 22.1, 25.3, and 27.0° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 49.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical Form Q TG/DTA thermograms are shown in FIG. 50. In one embodiment, provided herein is a solid form containing the free base of Compound 1 that exhibits a weight loss of about 0.4% when heated from about 25 to about 125° C. and exhibits a weight loss of about 10.6% when heated from about 125 to about 200°C. In one embodiment, without being limited to any particular theory, the second weight loss corresponds to water loss. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 50.

In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 126°C. In one embodiment, the thermal event also has a peak temperature of about 132°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to dehydration. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 50.

In one embodiment, Compound 1 free base Form Q is prepared by subjecting a suspension containing Compound 1 and L-glutamic acid in THF/water (50:50 v/v) to

- 42 044284 temperature cycle (for example, at room temperature for about 4 hours, and then at about 40°C for about 4 hours) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing Form Q of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form Q of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing the free base Form Q of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form R of the free base of compound 1.

In some embodiments, Compound 1 free base Form R is provided herein.

In one embodiment, Form R is crystalline. In one embodiment, Form R is substantially crystalline. In one embodiment, Form R is moderately crystalline. In one embodiment, Form R is partially crystalline.

A typical Form R XRPD diagram is shown in FIG. 51.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by 1, 2, 3, 4, 5 or all peaks located at approximately the following positions: 3.7, 8.0, 13.9, 14 .9, 25.4 and 26.7° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of Compound 1, characterized by an XRPD pattern including peaks at approximately 14.9, 25.4 and 26.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 3.7 and 13.9° 2θ. In one embodiment, the XRPD diagram further contains a peak at approximately 8.0° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 3.7, 8.0, 13.9, 14.9, 25.4 and 26.7° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 51.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical TG/DTA Form R thermograms are shown in FIG. 52. In one embodiment, provided herein is a solid form containing the free base of Compound 1 that exhibits a weight loss of about 2.1% when heated from about 25°C to about 60°C, a weight loss of about 1.6% when heated from about 60 to about 110°C and a weight loss of about 18.9% when heated from about 110°C to about 200°C. In one embodiment, without being limited to any particular theory, the first two weight losses correspond to the loss of unbound solvent, and the third weight loss corresponds to the loss of water. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 52.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 that exhibits, as characterized by DTA, a first thermal event with an initial temperature of about 100°C and a second thermal event with an initial temperature of about 140°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 106°C, and the second thermal event also has a peak temperature of about 142°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to the loss of unbound solvent and the second thermal event corresponds to the loss of water. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 52.

In one embodiment, Form R of the free base of Compound 1 is prepared by subjecting a suspension containing Compound 1 and malonic acid in DCM to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40°C for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing Form R of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing

- 43 044284 Form R of the free base of Compound 1 and one or more other crystalline forms of the free base of Compound 1 provided herein. In one embodiment, provided herein is a solid form containing the free base Form R of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Form S of the free base of connection 1.

In some embodiments, Compound 1 free base Form S is provided herein.

In one embodiment, Form S is crystalline. In one embodiment, Form S is substantially crystalline. In one embodiment, Form S is moderately crystalline. In one embodiment, Form S is partially crystalline.

A representative Shape S XRPD diagram is shown in FIG. 53.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all peaks located approximately at the following positions: 6.6, 7.1, 9.8, 10.9, 13.5, 14.0, 14.3, 16.5, 17.7, 20.2 , 20.8, 21.7, 23.3, 26.1, 28.2, 29.0, 29.3, and 31.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the free base of compound 1 characterized by an XRPD pattern containing peaks at approximately 6.6, 16.5 and 20.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.0 and 17.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.3, 21.7 and 23.3° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 6.6, 7.1, 10.9, 14.0, 14.3, 16.5, 17.7, 20.8, 21.7, and 23.3° 2θ.

In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 53.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical Form S TG/DTA thermograms are shown in FIG. 54. In one embodiment, provided herein is a solid form containing the free base of Compound 1 that exhibits a weight loss of about 1.5% when heated from about 25 to about 60° C. (followed by sustained weight loss). In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of unbound solvent. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 54.

In one embodiment, provided herein is a solid form containing the free base of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 128°C. In one embodiment, the thermal event also has a peak temperature of about 136°C. In one embodiment, provided herein is a solid form containing the free base of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 54.

In one embodiment, Compound 1 free base Form S is prepared by subjecting a suspension containing Compound 1 and R-mandelic acid in ethanol to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing Form S of the free base of Compound 1 and the amorphous free base of Compound 1. In one embodiment, provided herein is a solid form containing Form S of the free base of Compound 1 and one or more other crystalline forms free base of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form S of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 provided herein.

Hydrochloride salt of compound 1.

In some embodiments, provided herein is a hydrochloride

- 44 044284 salt of compound 1. It is believed that the hydrochloride salt of compound 1 may exist in various solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline hydrochloride salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1. In one embodiment, the solid form is a solvate of the hydrochloride salt of Compound 1. In one embodiment, the solid form is a hydrate of the hydrochloride salt of Compound 1. In one embodiment, the solid form is is the unsolvated form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is the desolvated form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the hydrochloride salt of Compound 1. In one embodiment, the solid form is the dehydrated form of the hydrochloride salt salts of compound 1.

In some embodiments, the molar ratio of Compound 1 to hydrochloric acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-hydrochloride salt). In another embodiment, the molar ratio is about 1:1 (ie, monohydrochloride salt).

Form A of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

In one embodiment, the molar ratio of Compound 1 to hydrochloric acid in Form A is approximately 1:1. In one embodiment, Form A is the monohydrochloride salt of Compound 1.

In one embodiment, Form A is the hydrochloride salt solvate of Compound 1. In one embodiment, Form A is an isomorphic solvate of the hydrochloride salt of Compound 1. In one embodiment, Form A is the TBME hydrochloride salt solvate of Compound 1. In one embodiment, Form A is is the hydrochloride salt solvate of Compound 1. In one embodiment, Form A is the anisole solvate of the hydrochloride salt of Compound 1. In one embodiment, Form A is the ethyl formate hydrochloride salt solvate of Compound 1. In one embodiment, Form A is the isopropyl acetate solvate of the hydrochloride salt Compound 1. In one embodiment, Form A is the MEK hydrochloride salt solvate of Compound 1. In one embodiment, Form A is the toluene solvate of the hydrochloride salt of Compound 1. In one embodiment, Form A is the hydrochloride salt solvate of Compound 1 in DMF. In one embodiment, Form A is the DMA solvate of the hydrochloride salt of Compound 1.

A typical XRPD pattern of Form A of the hydrochloride salt of Compound 1 is shown in FIG. 55.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located approximately at the following positions: 5.6, 7.4, 7.7, 9.5, 14.1, 15.0, 15.5, 15.7 , 16.6, 17.3, 17.5, 17.9, 19.2, 19.4, 19.8, 20.9, 23.8, 24.0, 26.0, 26.6, 27 .7 and 28.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 14.1, 16.6 and 26.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.6, 7.4 and 15.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.7 and 17.9° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.6, 7.4, 7.7, 14.1, 15.5, 16.6, 17.9, 26.0, 26.6, and 27.7° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 55.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

- 45 044284

A typical thermogravimetric analysis (TGA) thermogram of Compound 1 hydrochloride salt Form A is shown in FIG. 56. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits a weight loss of about 2.9% when heated from about 25 to about 110° C. and a weight loss of about 8.0% when heated from about 110 to approximately 230°C. In one embodiment, without being limited to any particular theory, the first weight loss corresponds to the loss of water (and some TBME) and the weight loss corresponds to the loss of TBME. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 56.

A typical differential scanning calorimetry (DSC) thermogram of Compound 1 hydrochloride salt Form A is shown in FIG. 57. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits, as characterized by DSC, a first (broad) thermal event with a peak temperature of about 83°C and a second thermal event with an initial temperature of about 189°C . In one embodiment, the second thermal event also has a peak temperature of about 202°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to the loss of water (and some TBME) and the second thermal event corresponds to desolvation of TBME, possibly combined with simultaneous melting. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 57.

A typical dynamic vapor sorption (DVS) isotherm plot of Compound 1 hydrochloride salt Form A is shown in FIG. 58. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 that exhibits a weight increase of about 11.7% as relative humidity (RH) increases from about 5% to about 95%. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 58. In one embodiment, Form A is hygroscopic. In one embodiment, Form A remains as Form A after the DVS cycle.

In one embodiment, Compound 1 hydrochloride salt Form A is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., between about 25° C. and about 35° C.) for a period time (eg, from about 1 day to about 14 days, such as about 7 days). In one embodiment, the solvent is acetone, anisole, ethyl formate, iPrOAc, MEK, TBME, toluene, a mixture of DMA and iPrOAc (for example, 1:9 v/v), or a mixture of DMF and toluene (for example, 1:9 v/v). /about.). In one embodiment, the solvent is TBME.

In one embodiment, Compound 1 hydrochloride salt Form A is prepared by cooling a solution or suspension of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of toluene and DMF (e.g., about 9:1 v/v) from about 60°C to room temperature (eg overnight).

In one embodiment, the resulting product is optionally dried (eg, under vacuum at 40° C.) for a specified period of time (eg, about 4 hours).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing hydrochloride salt Form A of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing hydrochloride salt Form A of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form A of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form B of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form B is provided herein.

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is moderately crystalline. In one embodiment, Form B is partially crystalline.

In one embodiment, Form B is a hydrochloride salt solvate of Compound 1. In one embodiment, Form B is an isomorphic hydrochloride salt solvate of Compound 1. In one embodiment, Form B is an ethanol solvate of the hydrochloride salt of Compound 1. In one embodiment, Form B is an ethanol solvate of the hydrochloride salt of Compound 1. In one embodiment, In an embodiment, Form B is the 2-propanol solvate of the hydrochloride salt of Compound 1. In one embodiment, Form B is the ethyl acetate solvate of the hydrochloride salt of Compound 1. In one embodiment, Form B is the hydrate of the hydrochloride salt of Compound 1.

A typical XRPD diagram of Form B of the hydrochloride salt of Compound 1 is shown in FIG. 59.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 6.1, 7.7, 10.9, 12.2, 13.4, 13.6, 15.6, 16.3, 16.6 , 19.7, 22.1, 23.3, 23.4, 24.6, 24.8, 25.2, 25.7, 26.0, 27.4 and 27.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 6.1, 13.4 and 24.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 12.2 and 16.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 10.9 and 25.2° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 6.1, 10.9, 12.2, 13.4, 13.6, 15.6, 16.6, 24.6, 25.2, 25.7, and 27.6° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 59.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Compound 1 hydrochloride salt Form B is shown in FIG. 60. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits a weight loss of about 3.8% when heated from about 25° C. to about 120° C. and a weight loss of about 2.8% when heated from about 120 to approximately 220°C. In one embodiment, without being limited to any particular theory, the first weight loss corresponds to the loss of water (and some ethanol), and the second weight loss corresponds to the loss of ethanol and water. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 60.

A typical differential scanning calorimetry (DSC) thermogram of Form B hydrochloride salt of Compound 1 is shown in FIG. 61. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits, as characterized by DSC, a first (broad) thermal event with a peak temperature of about 80°C and a second thermal event with an initial temperature of about 200°C . In one embodiment, the second thermal event also has a peak temperature of about 210°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to the loss of water and the second thermal event corresponds to the melting of desolvated Form B. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1, characterized by a DSC thermogram , which corresponds to the DSC thermogram presented in Fig. 61.

A typical dynamic vapor sorption (DVS) isotherm plot of Form B of the hydrochloride salt of Compound 1 is shown in FIG. 62. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 that exhibits a weight increase of about 15.7% as relative humidity (RH) increases from about 5% to about 95%. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 62. In one embodiment, Form B is hygroscopic.

In one embodiment, Compound 1 hydrochloride salt Form B is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 7 days). In one embodiment, the solvent is a protic solvent. In one embodiment, the solvent is ethanol, a mixture of 2-PrOH and water (eg, 95:5 v/v), or water. In one embodiment, the solvent is ethanol.

In one embodiment, Compound 1 hydrochloride salt Form B is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in ethyl acetate to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 7 days). Although ethyl acetate is not a protic solvent, hydrolysis of ethyl acetate to ethanol and acetic acid can be expected under acidic conditions.

In one embodiment, provided herein is a solid form comprising the hydrochloride salt Form B of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form B of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form B of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form B of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form C of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form C is provided herein.

In one embodiment, Form C is crystalline. In one embodiment, Form C is substantially crystalline. In one embodiment, Form C is moderately crystalline. In one embodiment, Form C is partially crystalline.

In one embodiment, Form C is the hydrochloride salt solvate of Compound 1. In one embodiment, Form C is the acetone solvate of the hydrochloride salt of Compound 1. In one embodiment, Form C is the monoacetone solvate of the hydrochloride salt of Compound 1.

A typical XRPD diagram of Form C of the hydrochloride salt of Compound 1 is shown in FIG. 63.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or all peaks located approximately in the following positions: 2.8, 5.4, 5.7, 6.3, 7.2, 8.2, 11.4 , 13.7, 14.1, 14.3, 15.0, 15.3, 15.7, 17.0, 17.2, 18.0, 20.8, 21.6, 22.0, 25 ,4, 25.6, 26.1, 26.2 and 26.7° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.2, 8.2 and 15.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 2.8, 17.2 and 26.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 21.6 and 26.2° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 2.8, 7.2, 8.2, 14.1, 15.0, 17.2, 18.0, 21.6, 25.6, 26.2, and 26.7° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 63.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form C of the hydrochloride salt of Compound 1 is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of acetone and heptane (for example, about 1:1 v/v) to a temperature cycle ( for example, from about 25 to about 35°C) for a period of time (for example, from about 1 day to about 14 days, for example, about 3 days). In another embodiment, Form C is prepared from a mixture of acetone and water (eg, about 95:5 v/v).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form C of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising Form C of the hydrochloride salt of Compound 1 and the amorphous hydrochloride salt of Compound 1. In one embodiment, in an infusion

- 48 044284 This document provides a solid form containing Form C of the hydrochloride salt of Compound 1 and one or more of the other crystalline forms of the hydrochloride salt of Compound 1 provided herein. In one embodiment, provided herein is a solid form comprising Form C of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form D of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form D is provided herein.

In one embodiment, Form D is crystalline. In one embodiment, Form D is substantially crystalline. In one embodiment, Form D is moderately crystalline. In one embodiment, Form D is partially crystalline.

In one embodiment, Form D is the hydrochloride salt hydrate of Compound 1.

A typical XRPD diagram of Compound 1 hydrochloride salt Form D is shown in FIG. 64.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located approximately at the following positions: 3.4, 5.1, 6.8, 7.8, 8.2, 12.7, 13.2, 13.7, 14 .6, 15.3, 15.7, 16.4, 17.9, 20.0, 21.7, 22.8, 24.1, 25.1, 25.6, 26.4 and 27.5 °2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 14.6, 25.1 and 25.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 6.8, 13.7 and 26.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 8.2 and 12.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 3.4, 6.8, 7.8, 8.2, 12.7, 13.7, 14.6, 16.4, 25.1, 25.6, and 26.4° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 64.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form D is prepared by evaporating a solution of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of DCM and water (e.g., about 55:45 v/v) under conditions environment at room temperature.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form D of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising Form D of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form D of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form D of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form E of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form E is provided herein.

In one embodiment, Form E is crystalline. In one embodiment, Form E is substantially crystalline. In one embodiment, Form E is moderately crystalline. In one embodiment, Form E is partially crystalline.

In one embodiment, Form E is the hydrochloride salt solvate of Compound 1. In one embodiment, Form E is the isomorphic solvate of the hydrochloride salt of Compound 1. In one embodiment, Form E is the 2-49 044284 propanol solvate of the hydrochloride salt of Compound 1. In one embodiment of embodiments, Form E is the acetonitrile solvate of the hydrochloride salt of Compound 1.

A typical XRPD pattern of Form E of the hydrochloride salt of Compound 1 is shown in FIG.

65.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all peaks located approximately at the following positions: 4.8, 5.5, 9.1, 9.7, 13.3, 14.0, 14.6, 17.0, 17 .6, 19.4, 22.5, 23.3, 24.1, 25.7, 26.3, 26.8, 27.5, 28.1, 28.5, 29.0 and 29.7 °2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 5.5, 19.4 and 25.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 4.8 and 9.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.0 and 26.3° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 4.8, 5.5, 9.7, 14.0, 17.0, 17.6, 19.4, 22.5, 25.7, 26.3, and 27.5° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 65.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form E is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:10 molar ratio) in 2-PrOH to a temperature cycle (e.g., between about 25 and about 35° C.) for a period time (eg, from about 1 day to about 14 days, such as about 5 days).

In one embodiment, Compound 1 hydrochloride salt Form E is prepared by suspending Compound 1 hydrochloride salt Form C in acetonitrile.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form E of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising a hydrochloride salt Form E of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing a hydrochloride salt Form E of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form E of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form F of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form F is provided herein.

In one embodiment, Form F is crystalline. In one embodiment, Form F is substantially crystalline. In one embodiment, Form F is moderately crystalline. In one embodiment, Form F is partially crystalline.

In one embodiment, Form F is the hydrochloride salt solvate of Compound 1. In one embodiment, Form F is the hydrochloride salt solvate of Compound 1 with acetonitrile.

A typical XRPD diagram of Compound 1 hydrochloride salt Form F is shown in FIG. 66.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 5.0, 5.4, 5.7, 7.4, 9.6, 10.0, 10.4, 10 ,6, 11.4, 11.9, 14.4, 14.8, 15.0, 17.1, 21.8, 22.9, 24.0, 24.9, 25.5, 26.0 , 26.2, 28.4 and 30.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

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In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.4, 9.6 and 24.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.0 and 10.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.7, 11.4 and 11.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.0, 5.7, 7.4, 9.6, 10.0, 11.4, 11.9, 14.4, 24.0, 24.9, and 26.0° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 66.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form F of the hydrochloride salt of Compound 1 is prepared by subjecting a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of acetonitrile and water (e.g., 95:5 v/v) to a temperature cycle (e.g. , from about 25 to about 35°C) for a period of time (for example, from about 1 day to about 14 days, for example, about 7 days).

In one embodiment, Form F of the hydrochloride salt of Compound 1 is prepared by cooling a solution or suspension of Compound 1 and hydrochloric acid (eg, at a molar ratio of about 1:1) in a mixture of acetonitrile and water (eg, 95:5 v/v) from approximately 60°C to room temperature (e.g. overnight).

In one embodiment, provided herein is a solid form comprising the hydrochloride salt Form F of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrochloride salt Form F of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the hydrochloride salt Form F of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form F of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form G of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form G is provided herein.

In one embodiment, Form G is crystalline. In one embodiment, Form G is substantially crystalline. In one embodiment, Form G is moderately crystalline. In one embodiment, Form G is partially crystalline.

In one embodiment, Form G is the hydrochloride salt solvate of Compound 1. In one embodiment, Form G is the NMP hydrochloride salt solvate of Compound 1.

A typical XRPD pattern of Form G of the hydrochloride salt of Compound 1 is shown in FIG. 67.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 7.3, 9.5, 11.0, 12.7, 13.1, 13.9, 14.3, 14.5, 14.8 , 16.6, 16.7, 18.4, 18.7, 19.8, 21.5, 24.0, 25.1, 25.5, 25.8 and 26.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 9.5, 13.9 and 25.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.3 and 25.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 12.7 and 13.1° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.3, 9.5, 12.7, 13.1, 13.9, 16.6, 16.7, 21.5, 25.1, 25.5, and 25.8° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 67.

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In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form G is prepared by suspending a mixture of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of IPE and NMP (e.g., 9:1 v/v) at room temperature over a period of time (eg, from about 1 day to about 14 days, such as about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form G of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising a hydrochloride salt Form G of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing a hydrochloride salt Form G of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form G of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form H of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form H is provided herein.

In one embodiment, Form H is crystalline. In one embodiment, Form H is substantially crystalline. In one embodiment, Form H is moderately crystalline. In one embodiment, Form H is partially crystalline.

In one embodiment, Form H is the hydrochloride salt solvate of Compound 1. In one embodiment, Form H is the NMP hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form H of the hydrochloride salt of Compound 1 is shown in FIG. 68.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located approximately at the following positions: 4.8, 6.2, 7.3, 11.4, 13.7, 14.3, 14.8, 15.9 , 16.0, 16.3, 17.3, 18.0, 19.1, 19.6, 20.8, 22.1, 22.3, 23.3, 25.9, 26.7, 27 .0 and 27.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.3, 16.3 and 26.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.8, 19.1 and 25.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.3 and 16.0° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.3, 14.3, 14.8, 16.0, 16.3, 17.3, 19.1, 22.3, 25.9, 26.7, and 27.8° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 68.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form H is prepared by evaporating a solution of Compound 1 and hydrochloric acid (e.g., about 1:1 molar ratio) in a mixture of cyclohexane and NMP (e.g., about 1:1 v/v) in a stream N2.

In one embodiment, provided herein is a solid form containing the hydrochloride salt form H of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form H of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form H of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form H of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

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Form I of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form I is provided herein.

In one embodiment, Form I is crystalline. In one embodiment, Form I is substantially crystalline. In one embodiment, Form I is moderately crystalline. In one embodiment, Form I is partially crystalline.

In one embodiment, Form I is a hydrochloride salt solvate of Compound 1. In one embodiment, Form I is a hydrochloride salt solvate of Compound 1 in DMSO.

A typical XRPD pattern of Form I hydrochloride salt of Compound 1 is shown in FIG. 69.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 4.9, 6.3, 8.0, 9.8, 13.4, 14.4, 15.1, 16.1, 18.4 , 18.7, 19.6, 19.8, 20.5, 21.5, 21.8, 23.5, 25.6, 26.5, 26.8 and 27.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 4.9, 16.1 and 21.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.4 and 25.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 19.8, 21.8 and 26.5° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 4.9, 6.3, 14.4, 16.1, 19.8, 21.5, 21.8, 25.6, 26.5 and 27.5° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 69.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form I of the hydrochloride salt of Compound 1 is prepared by evaporating a solution of Compound 1 and hydrochloric acid (eg, about 1:1 molar ratio) in a mixture of IPE and DMSO (eg, about 89:11 v/v) in a stream N2.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form I of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising Form I of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form I of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form I of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form J of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form J is provided herein. A typical XRPD diagram of Compound 1 hydrochloride salt Form J is shown in FIG. 136. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 136.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form J of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising the hydrochloride salt Form J of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrochloride salt Form J of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form J of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

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Form K of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form K is provided herein. A typical XRPD diagram of Compound 1 hydrochloride salt Form K is shown in FIG. 137. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 137.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form K of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrochloride salt Form K of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the hydrochloride salt Form K of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form K of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form L of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form L is provided herein.

In one embodiment, Form L is crystalline. In one embodiment, Form L is substantially crystalline. In one embodiment, Form L is moderately crystalline. In one embodiment, Form L is partially crystalline.

In one embodiment, Form L is the anhydrous hydrochloride salt form of Compound 1.

A typical XRPD diagram of Compound 1 hydrochloride salt Form L is shown in FIG. 138.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all peaks located approximately at the following positions: 8.4, 10.1, 12.2, 12.7, 13.1, 15.7, 16.1, 17.2 , 17.9, 19.1, 19.4, 20.5, 22.6, 23.3, 23.6, 24.6, 25.7, 26.5, 26.9, 28.2, 28 .6 and 29.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 10.1, 19.1 and 24.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 8.4, 15.7 and 16.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 19.4 and 26.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.4, 10.1, 12.2, 13.1, 15.7, 16.1, 17.2, 19.1, 19.4, 20.5, 24.6 and 26.9° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 4.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 14.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 15.1° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 16.9° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 18.8° 2θ. In one embodiment, the XRPD diagram does not contain a peak at approximately 20.3° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at 10.1, 19.1 and 24.6 ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 8.4, 15.7 and 16.1 ±0.04° 2θ. In one embodiment, the XRPD diagram further contains peaks at 19.4 and 26.9 ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 8.4, 10.1, 12.2, 13.1, 15.7, 16.1, 17.2, 19.1, 19.4, 20.5, 24 .6 and 26.9 ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 4.2 ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.7 ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 15.1 ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 16.9 ±0.04° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8 ±0.04° 2θ. In one embodiment, the XRPD plot does not contain a peak at 20.3 ±0.04°

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2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at 10.1, 19.1 and 24.6 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 8.4, 15.7 and 16.1 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 19.4 and 26.9 ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 8.4, 10.1, 12.2, 13.1, 15.7, 16.1, 17.2, 19.1, 19.4, 20.5, 24 .6 and 26.9 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 4.2 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.7 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 15.1 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 16.9 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8 ±0.02° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3 ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at 10.1, 19.1 and 24.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at 8.4, 15.7 and 16.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at 19.4 and 26.9° 2θ. In one embodiment, the XRPD chart contains peaks at 8.4, 10.1, 12.2, 13.1, 15.7, 16.1, 17.2, 19.1, 19.4, 20.5, 24 .6 and 26.9° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 4.2° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 14.7° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 15.1° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 16.9° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 18.8° 2θ. In one embodiment, the XRPD diagram does not contain a peak at 20.3° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 138.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Compound 1 hydrochloride salt Form L is shown in FIG. 139. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that loses almost no weight when heated from about 30 to about 200°C. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 139.

A typical differential scanning calorimetry (DSC) thermogram of Compound 1 hydrochloride salt Form L is shown in FIG. 140. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 124°C and a second thermal event with an initial temperature of about 262°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 132°C, and the second thermal event also has a peak temperature of about 269°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to a solid-solid phase transition and the second thermal event corresponds to melting. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 140.

A typical dynamic vapor sorption (DVS) isotherm plot of Compound 1 hydrochloride salt Form L is shown in FIG. 141. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 that exhibits a weight increase of about 0.6% as relative humidity (RH) increases from about 0% to about 95%. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 141. In one embodiment, Form L is slightly hygroscopic. In one embodiment, Form L remains as Form L after the DVS cycle.

In one embodiment, Compound 1 hydrochloride salt Form L is prepared by a reaction crystallization process. In one embodiment, Compound 1 hydrochloride salt Form L is prepared by a process comprising adding a source of hydrochloric acid to a mixture (eg, suspension or solution) of Compound 1 free base in a solvent. In one embodiment, the free base of compound 1 is the free base form K of compound

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1. In one embodiment, the source of hydrochloric acid is hydrochloric acid in an organic solvent. In one embodiment, the source of hydrochloric acid is an aqueous solution of hydrochloric acid. In one embodiment, the solvent is acetonitrile. In one embodiment, the solvent is a mixture of CPME and water. In one embodiment, the solvent is a mixture of acetone and water. In one embodiment, the solvent is a mixture of DMSO and water. In one embodiment, the solvent is isopropyl acetate. In one embodiment, the solvent is ethyl acetate. In one embodiment, the solvent is a mixture of NMP and water. In one embodiment, the solvent is a mixture of DMF and water. In one embodiment, the solvent is a mixture of DMAc and water. In one embodiment, the solvent is n-propanol. In one embodiment, the solvent is n-butanol. In one embodiment, the amount of hydrochloric acid (relative to the amount of free base of Compound 1) is from about 1 to about 5 molar equivalents. In one embodiment, the amount of hydrochloric acid is from about 1.1 to about 4 molar equivalents. In one embodiment, the amount of hydrochloric acid is about 1.1 molar equivalents. In one embodiment, the amount of hydrochloric acid is about 1.2 molar equivalents. In one embodiment, the amount of hydrochloric acid is approximately 2 molar equivalents. In one embodiment, the amount of hydrochloric acid is about 2.5 molar equivalents. In one embodiment, the amount of hydrochloric acid is approximately 4 molar equivalents. In one embodiment, hydrochloric acid is added at a temperature of from about 0 to about 80°C. In one embodiment, the temperature is about 0°C. In one embodiment, the temperature is approximately room temperature. In one embodiment, the temperature is about 40°C. In one embodiment, the temperature is about 80°C. In one embodiment, the method further includes subjecting the mixture (after adding hydrochloric acid) to one or more temperature cycles (eg, from room temperature to about 40°C).

In one embodiment, Form L hydrochloride salt of Compound 1 is prepared by a process comprising adding an aqueous solution of hydrochloric acid (e.g., 1N HCl; e.g., about 4 molar equivalents) to a suspension of Form K of Compound 1 free base in a mixture of acetone and water (e.g. , 20% acetone/water v/v). In one embodiment, the method further includes subjecting the mixture (after adding hydrochloric acid) to one or more temperature cycles (eg, from room temperature to about 40°C).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form L of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrochloride salt Form L of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrochloride salt Form L of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form L of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form M of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form M is provided herein.

In one embodiment, Form M is crystalline. In one embodiment, Form M is substantially crystalline. In one embodiment, Form M is moderately crystalline. In one embodiment, Form M is partially crystalline.

In one embodiment, Form M is the anhydrous hydrochloride salt form of Compound 1.

A typical XRPD diagram of Form M hydrochloride salt of Compound 1 is shown in FIG. 142.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all peaks located approximately in the following positions: 4.2, 8.5, 10.3, 12.3, 12.7, 13.1 , 14.7, 15.1, 15.9, 16.1, 16.9, 17.4, 17.8, 18.8, 19.3, 19.8, 20.3, 20.6, 21 ,2, 22.7, 23.2, 23.9, 24.6, 25.5, 26.1 and 26.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 characterized by an XRPD diagram containing peaks at approximately 10.3, 19.3 and 24.6° 2θ. In one embodiment, the XRPD pattern further contains one or more peaks at approximately 4.2, 14.7, 15.1 and 16.9° 2θ. In one embodiment, the XRPD diagram further contains a peak at approximately 4.2° 2θ. In one embodiment, the XRPD pattern further contains a peak at approximately 14.7°

2θ. In one embodiment, the XRPD diagram further contains a peak at approximately 15.1° 2θ. In one embodiment, the XRPD pattern further contains a peak at approximately 16.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 15.9 and 16.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.4, 22.7 and 26.6° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 4.2, 10.3, 12.3, 12.7, 14.7, 15.1, 15.9, 16.1, 16.9, 17.4, 17.8, 19.3,

22.7, 23.2, 24.6 and 26.6° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram including peaks at

10.3, 19.3 and 24.6 ±0.04° 2θ. In one embodiment, the XRPD diagram further contains one or more peaks at 4.2, 14.7, 15.1 and 16.9 ±0.04° 2θ. In one embodiment, the XRPD diagram further contains a peak at 4.2 ±0.04° 2θ. In one embodiment, the XRPD diagram further contains a peak at 14.7 ±0.04° 2θ. In one embodiment, the diagram

XRPD additionally contains a peak at 15.1 ±0.04° 2θ. In one embodiment, the diagram

XRPD additionally contains a peak at 16.9 ±0.04° 2θ. In one embodiment, the diagram

XRPD additionally contains peaks at 15.9 and 16.1 ±0.04° 2θ. In one embodiment, the XRPD pattern further contains peaks at 17.4, 22.7 and 26.6 ±0.04° 2θ. In one embodiment, the XRPD chart contains peaks at 4.2, 10.3, 12.3, 12.7, 14.7, 15.1, 15.9, 16.1, 16.9, 17.4, 17 .8, 19.3, 22.7, 23.2, 24.6 and 26.6 ±0.04° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at 10.3, 19.3 and 24.6 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains one or more peaks at 4.2, 14.7, 15.1 and 16.9 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains a peak at 4.2 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains a peak at 14.7 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains a peak at 15.1 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains a peak at 16.9 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 15.9 and 16.1 ±0.02° 2θ. In one embodiment, the XRPD diagram further contains peaks at 17.4, 22.7 and 26.6 ±0.02° 2θ. In one embodiment, the XRPD chart contains peaks at 4.2, 10.3, 12.3, 12.7, 14.7, 15.1, 15.9, 16.1, 16.9, 17.4,

17.8, 19.3, 22.7, 23.2, 24.6 and 26.6 ±0.02° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at 10.3, 19.3 and 24.6° 2θ. In one embodiment, the XRPD pattern further contains one or more peaks at 4.2, 14.7, 15.1 and 16.9° 2θ. In one embodiment, the XRPD diagram further contains a peak at 4.2° 2θ. In one embodiment, the XRPD diagram further contains a peak at 14.7° 2θ. In one embodiment, the XRPD diagram further contains a peak at 15.1° 2θ. In one embodiment, the XRPD diagram further contains a peak at 16.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at 15.9 and 16.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at 17.4, 22.7 and 26.6° 2θ. In one embodiment, the XRPD chart contains peaks at 4.2, 10.3, 12.3, 12.7, 14.7, 15.1, 15.9, 16.1, 16.9, 17.4, 17 ,8, 19.3, 22.7, 23.2, 24.6 and 26.6° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 142.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical differential scanning calorimetry (DSC) thermogram of Compound 1 hydrochloride salt Form M is shown in FIG. 143. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits a thermal phenomenon as characterized by DSC with an initial temperature of about 259°C. In one embodiment, the thermal event also has a peak temperature of about 265°C. In one embodiment, without being limited to any particular theory, the thermal phenomenon corresponds to the melting of Form M. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by a thermogram

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DSC, which corresponds to the DSC thermogram shown in FIG. 143.

In one embodiment, Compound 1 hydrochloride salt Form M is prepared by a process comprising heating Compound 1 hydrochloride salt Form L to about 160°C. In one embodiment, the method further comprises exposing the hydrochloride salt of Compound 1 to about 160° C. for about 10 minutes and cooling it to about room temperature.

In one embodiment, provided herein is a solid form containing the hydrochloride salt form M of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising a hydrochloride salt Form M of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing a hydrochloride salt Form M of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form M of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form N of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form N is provided herein.

In one embodiment, form N is crystalline. In one embodiment, Form N is substantially crystalline. In one embodiment, Form N is moderately crystalline. In one embodiment, Form N is partially crystalline.

In one embodiment, Form N is the hydrochloride salt hydrate of Compound 1.

A typical XRPD diagram of Form N of the hydrochloride salt of Compound 1 is shown in FIG. 144.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 9.9, 11.8, 15.4, 17.2, 17.8, 18.3, 19.6, 19.9, 21.9 , 22.2, 23.2, 23.8, 24.2, 25.4, 25.8, 27.2, 27.8, 28.2, 28.7 and 29.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 9.9, 15.4 and 18.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.2, 25.8 and 27.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.8, 19.9 and 23.8° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 9.9, 11.8, 15.4, 17.2, 17.8, 18.3, 19.9, 22.2, 23.2, 23.8, 25.4, 25.8 and 27.8° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 144.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical TG-MS thermogram of Compound 1 hydrochloride salt Form N is shown in FIG. 145. In one embodiment, provided herein is a solid form containing the hydrochloride salt of Compound 1 that exhibits a weight loss of about 2.8% when heated from about 25 to about 100°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of water. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 145.

A typical differential scanning calorimetry (DSC) thermogram of Form N hydrochloride salt of Compound 1 is shown in FIG. 146. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 44°C, a second thermal event with an initial temperature of about 128°C, a third thermal an event with an initial temperature of about 256°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 66°C, the second thermal event also has a peak temperature

TURU is about 133°C, and the third heat event also has a peak temperature of about 263°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to dehydration, the second thermal event corresponds to solid-to-solid transition, and the third thermal event corresponds to melting. In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 146.

In one embodiment, Compound 1 hydrochloride salt Form N is prepared by heating Compound 1 hydrochloride salt Form L in a solvent mixture of acetone and water (e.g., 20% acetone/water v/v) at approximately 60° C. for a specified period of time (e.g. , at night).

In one embodiment, provided herein is a solid form containing the N hydrochloride salt form of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the N hydrochloride salt form of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the N hydrochloride salt form of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form N of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form O of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt Form O of Compound 1 is provided herein.

In one embodiment, Form O is crystalline. In one embodiment, Form O is substantially crystalline. In one embodiment, Form O is moderately crystalline. In one embodiment, Form O is partially crystalline.

In one embodiment, Form O is the hydrochloride salt solvate of Compound 1. In one embodiment, Form O is the hydrochloride salt solvate of Compound 1 in THF.

A typical XRPD diagram of Form O of the hydrochloride salt of Compound 1 is shown in FIG. 147.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the peaks located at approximately the following positions: 5 ,8, 7.6, 9.6, 14.2, 15.6, 16.9, 18.1, 19.4, 20.0, 23.3, 24.2 and 25.3° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.6, 16.9 and 18.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 9.6 and 15.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.8, 19.4 and 20.0° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.8, 7.6, 9.6, 14.2, 15.6, 16.9, 18.1, 19.4, 20.0, 23.3, 24.2 and 25.3° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 147.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form O is prepared by suspending Compound 1 hydrochloride salt Form L in THF at room temperature for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the O hydrochloride salt form of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form O hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form O hydrochloride salt of Compound 1.

- 59 044284 and one or more other crystalline forms of the hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form O of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form P of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form P is provided herein.

In one embodiment, form P is crystalline. In one embodiment, Form P is substantially crystalline. In one embodiment, Form P is moderately crystalline. In one embodiment, Form P is partially crystalline.

In one embodiment, Form P is the hydrochloride salt solvate of Compound 1. In one embodiment, Form P is the DMAc hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form P of the hydrochloride salt of Compound 1 is shown in FIG. 148.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6 or all peaks located at approximately the following positions: 4.8, 9.5, 14.1 , 16.6, 18.9, 22.3 and 23.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 9.5, 16.6 and 18.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.1 and 23.6° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 9.5, 14.1, 16.6, 18.9, 22.3 and 23.6° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 148.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form P is prepared by subjecting a suspension of Compound 1 hydrochloride salt Form L in DMAc to a temperature cycle (eg, about 4 to about 80° C.) for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt form P of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing a hydrochloride salt Form P of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein containing a hydrochloride salt Form P of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form P of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form Q of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form Q is provided herein.

In one embodiment, Form Q is crystalline. In one embodiment, Form Q is substantially crystalline. In one embodiment, Form Q is moderately crystalline. In one embodiment, Form Q is partially crystalline.

In one embodiment, Form Q is the hydrochloride salt solvate of Compound 1. In one embodiment, Form Q is a mixed DMSO and ethyl acetate solvate of the hydrochloride salt of Compound 1.

A representative XRPD diagram of Form Q of the hydrochloride salt of Compound 1 is shown in FIG. 149.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9 or all of the peaks located at approximately the following positions: 5,6, 7 ,6, 14.1, 15.5, 16.8, 17.7, 20.0, 23.1, 24.0 and 26.0° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one version

- 60 044284 implementation of the solid form is characterized by 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.6, 15.5 and 17.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.8 and 20.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.6 and 14.1° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.6, 7.6, 14.1, 15.5, 16.8, 17.7, 20.0, 24.0 and 26.0° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 149.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form Q of the hydrochloride salt of Compound 1 is prepared by adding a solution of the hydrochloride salt of Compound 1 in DMSO in ethyl acetate and keeping the resulting suspension at approximately room temperature for a period of time (eg, overnight). In one embodiment, a DMSO solution of the hydrochloride salt of Compound 1 is prepared by dissolving Form L of the hydrochloride salt of Compound 1 in DMSO.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form Q of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form Q of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form Q of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form Q of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form R of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt of Compound 1, Form R, is provided herein.

In one embodiment, Form R is crystalline. In one embodiment, Form R is substantially crystalline. In one embodiment, Form R is moderately crystalline. In one embodiment, Form R is partially crystalline.

In one embodiment, Form R is a hydrochloride salt solvate of Compound 1. In one embodiment, Form R is a mixed DMSO and MTBE hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form R of the hydrochloride salt of Compound 1 is shown in FIG. 150.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8 or all peaks located at approximately the following positions: 5.4, 16.2 , 17.7, 18.8, 20.1, 21.6, 22.1, 23.8 and 25.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 17.7, 20.1 and 21.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.4 and 22.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.2 and 18.8° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.4, 16.2, 17.7, 18.8, 20.1, 21.6, 22.1 and 23.8° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 150.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form R of the hydrochloride salt of Compound 1 is prepared by adding a solution of the hydrochloride salt of Compound 1 in DMSO in MTBE and keeping the resulting suspension at approximately room temperature for a specified period of time (eg, overnight). In one embodiment, a solution of the hydrochloride salt of Compound 1 in DMSO

- 61 044284 is prepared by dissolving Form L of the hydrochloride salt of compound 1 in DMSO.

In one embodiment, provided herein is a solid form containing the hydrochloride salt form R of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form R of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form R of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form R of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form S of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt of Compound 1, Form S, is provided herein.

In one embodiment, Form S is crystalline. In one embodiment, Form S is substantially crystalline. In one embodiment, Form S is moderately crystalline. In one embodiment, Form S is partially crystalline.

In one embodiment, Form S is a hydrochloride salt solvate of Compound 1. In one embodiment, Form S is a mixed DMSO and toluene hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form S of the hydrochloride salt of Compound 1 is shown in FIG. 151.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4 or all peaks located at approximately the following positions: 5.6, 9.9, 16.6, 18.6 and 22.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 16.6, 18.6 and 22.4° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.6, 9.9, 16.6, 18.6 and 22.4° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 151.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form S of the hydrochloride salt of Compound 1 is prepared by adding a solution of the hydrochloride salt of Compound 1 in DMSO to toluene and keeping the resulting suspension at approximately room temperature for a specified period of time (eg, overnight). In one embodiment, a DMSO solution of the hydrochloride salt of Compound 1 is prepared by dissolving Form L of the hydrochloride salt of Compound 1 in DMSO.

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form S of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form S of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form S of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form S of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form T of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form T is provided herein.

In one embodiment, Form T is crystalline. In one embodiment, Form T is substantially crystalline. In one embodiment, Form T is moderately crystalline. In one embodiment, Form T is partially crystalline.

In one embodiment, Form T is a solvate of the hydrochloride salt of Compound 1. In one embodiment, Form T is an isopropylacetate solvate

- 62 044284 hydrochloride salt of compound 1.

A typical XRPD diagram of Form T of the hydrochloride salt of Compound 1 is shown in FIG. 152.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the peaks located at approximately the following positions: 5 ,8, 7.7, 9.7, 14.1, 15.6, 16.9, 17.8, 19.4, 23.4, 24.3, 25.3 and 28.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.7, 16.9 and 17.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.8 and 15.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 9.7 and 19.4° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.8, 7.7, 9.7, 14.1, 15.6, 16.9, 17.8, 19.4, 23.4, and 24.3° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 152.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form T hydrochloride salt of Compound 1 is prepared by suspending the amorphous hydrochloride salt of Compound 1 in isopropyl acetate at about room temperature for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt form T of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrochloride salt Form T of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the hydrochloride salt Form T of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form T of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form U of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt form U of Compound 1 is provided herein.

In one embodiment, the U form is crystalline. In one embodiment, the U form is substantially crystalline. In one embodiment, the U form is moderately crystalline. In one embodiment, the U form is partially crystalline.

In one embodiment, Form U is the hydrochloride salt solvate of Compound 1. In one embodiment, Form U is the acetic acid solvate of the hydrochloride salt of Compound 1

A typical X-ray diffraction pattern of Form U of the hydrochloride salt of compound 1 is shown in FIG. 153.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the peaks located at approximately the following positions: 7,2 , 9.1, 9.6, 13.7, 16.8, 19.2, 20.2, 23.0, 24.4, 25.9 and 28.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 9.1, 19.2 and 24.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 9.6 and 23.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.2 and 20.2° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 7.2, 9.1, 9.6, 13.7, 16.8, 19.2, 20.2, 23.0 and 24.4° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 153.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form U hydrochloride salt of Compound 1 is prepared by suspending the amorphous hydrochloride salt of Compound 1 in acetic acid at about room temperature for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the U hydrochloride salt form of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising the U hydrochloride salt form of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the U hydrochloride salt form of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form U of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form V of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form V is provided herein.

In one embodiment, Form V is crystalline. In one embodiment, Form V is substantially crystalline. In one embodiment, Form V is moderately crystalline. In one embodiment, Form V is partially crystalline.

In one embodiment, Form V is the hydrochloride salt solvate of Compound 1. In one embodiment, Form V is the NMP hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form V hydrochloride salt of Compound 1 is shown in FIG. 154.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the peaks located at approximately the following positions: 7,2 , 9.5, 14.3, 16.7, 18.0, 19.3, 21.5, 22.1, 24.0, 25.2 and 26.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 7.2, 9.5 and 14.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 19.3 and 25.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.7 and 18.0° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 7.2, 9.5, 14.3, 16.7, 18.0, 19.3, 21.5, 22.1, 24.0, and 25.2° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 154.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form V is prepared by suspending the amorphous Compound 1 hydrochloride salt in NMP at about room temperature for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form V of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form V of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form V of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form V of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form W of the hydrochloride salt of compound 1.

In some embodiments, Form W of the hydrochloride salt of Compound 1 is provided herein.

In one embodiment, form W is crystalline. In one embodiment, Form W is substantially crystalline. In one embodiment, Form W is moderately crystalline. In one embodiment, Form W is partially crystalline.

In one embodiment, Form W is the hydrochloride salt solvate of Compound 1. In one embodiment, Form W is the anisole hydrochloride salt solvate of Compound 1.

A typical XRPD diagram of Form W of the hydrochloride salt of Compound 1 is shown in FIG. 155.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all peaks located approximately in the following positions: 5.7, 7.5, 9.6, 14.1, 15.4, 16.8, 17.6, 18.9, 19.6, 19.9, 23.5, 24 ,2, 25.0, 25.9 and 28.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 9.6, 16.8 and 17.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.5 and 15.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.7, 19.6 and 19.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.7, 7.5, 9.6, 14.1, 15.4, 16.8, 17.6, 18.9, 19.6, 19.9, and 24.2° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 155.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form W is prepared by suspending the amorphous Compound 1 hydrochloride salt in anisole at about 50° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form W of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the W hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing the W hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form W of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form X of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form X is provided herein.

In one embodiment, Form X is crystalline. In one embodiment, Form X is substantially crystalline. In one embodiment, Form X is moderately crystalline. In one embodiment, Form X is partially crystalline.

In one embodiment, Form X is the hydrochloride salt solvate of Compound 1. In one embodiment, Form X is the CPME hydrochloride salt solvate of Compound 1. In one embodiment, Form X and Form Y of the hydrochloride salt of Compound 1 are isomorphic solvate forms. In one embodiment, Form X and Form O are also isomorphic solvate forms.

A typical XRPD pattern of Form X of the hydrochloride salt of Compound 1 is shown in FIG. 156.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all peaks located approximately at the following positions: 5.7, 7.6, 9.5, 12.7, 14.1, 15.4, 16.8, 17.6, 18.0, 19.5, 19.9, 23.2, 24.1, 25.1, 26.0, 26.6 and 28.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one version

- 65 044284 implementation of the solid form is characterized by 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 9.5, 16.8 and 17.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.6, 15.4 and 19.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.7 and 19.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.7, 7.6, 9.5, 14.1, 15.4, 16.8, 17.6, 18.0, 19.5, 19.9, 23.2, 24.1 and 26.0° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 156.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form X is prepared by suspending the amorphous Compound 1 hydrochloride salt in CPME at about 50° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form X of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form X of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form X of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form X of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form Y of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form Y is provided herein.

In one embodiment, Form Y is crystalline. In one embodiment, Form Y is substantially crystalline. In one embodiment, Form Y is moderately crystalline. In one embodiment, Form Y is partially crystalline.

In one embodiment, Form Y is the hydrochloride salt solvate of Compound 1. In one embodiment, Form Y is the MTBE hydrochloride salt solvate of Compound 1. In one embodiment, Form Y and Form X of the hydrochloride salt of Compound 1 are isomorphic solvate forms. In one embodiment, Form Y and Form O are also isomorphic solvate forms.

A typical X-ray diffraction pattern of Form Y of the hydrochloride salt of Compound 1 is shown in FIG. 157.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all peaks located in approximately the following positions: 5.8, 7.6, 9.6, 14.3, 15.6, 16.7, 18.2, 19.5, 23.2, 24.1, 25.1, 26.1, 26.7 and 28.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 7.6, 16.7 and 18.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.8 and 19.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 15.6 and 26.1° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.8, 7.6, 9.6, 14.3, 15.6, 16.7, 18.2, 19.5, 24.1, and 26.1° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 157.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form Y of the hydrochloride salt of Compound 1 is prepared by suspending the amorphous hydrochloride salt of Compound 1 in MTBE at about 50° C. for a period

- 66 044284 time (for example, approximately 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form Y of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form Y of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form Y of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form Y of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form Z of the hydrochloride salt of compound 1.

In some embodiments, Compound 1 hydrochloride salt Form Z is provided herein.

In one embodiment, Form Z is crystalline. In one embodiment, Form Z is substantially crystalline. In one embodiment, Form Z is moderately crystalline. In one embodiment, Form Z is partially crystalline.

In one embodiment, Form Z is a hydrochloride salt solvate of Compound 1. In one embodiment, Form Z is a hydrochloride solvate of Compound 1 with n-butanol.

A typical XRPD diagram of Form Z of the hydrochloride salt of Compound 1 is shown in FIG. 158.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all peaks located approximately at the following positions: 5.9, 7.5, 8.0, 9.7, 11.3, 12.4, 14.1, 16.4, 17.3, 18.8, 20, 4, 21.9, 23.2, 24.0, 25.4 and 25.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 17.3, 18.8 and 20.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.5 and 24.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.9, 8.0 and 9.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.9, 7.5, 8.0, 9.7, 11.3, 12.4, 14.1, 16.4, 17.3, 18.8, 20.4 and 24.0° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 158.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form Z is prepared by suspending the amorphous Compound 1 hydrochloride salt in n-butanol at about 50° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt Form Z of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form Z of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form Z of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form Z of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form AA of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt form AA of Compound 1 is provided herein.

In one embodiment, form AA is crystalline. In one embodiment, Form AA is substantially crystalline. In one embodiment, Form AA is moderately crystalline. In one embodiment, Form AA is partially crystalline.

In one embodiment, Form AA is a hydrochloride salt solvate of Compound 1. In one embodiment, Form AA is a mixed acetone and aqueous solvate of Compound 1 hydrochloride salt.

A typical XRPD diagram of Form AA of the hydrochloride salt of Compound 1 is shown in FIG. 159.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all peaks located at about the following positions : 5.5, 7.2, 8.3, 11.3, 14.5, 15.5, 17.2, 18.2, 19.2, 21.7, 22.2, 23.3 and 26 .9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD pattern including peaks at approximately 8.3, 15.5 and 18.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.2 and 22.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.5 and 26.9° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.5, 7.2, 8.3, 11.3, 14.5, 15.5, 17.2, 18.2, 19.2, 22.2, and 26.9° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 159.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form AA is prepared by suspending Compound 1 hydrochloride salt Form L in a mixed solvent of acetone and water (e.g., about 97:3 v/v) at approximately room temperature for a period of time (e.g., about 14 days).

In one embodiment, provided herein is a solid form comprising the AA hydrochloride salt form of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising Form AA of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form AA of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form AA of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form AB of the hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt form AB of Compound 1 is provided herein.

In one embodiment, form AB is crystalline. In one embodiment, form AB is substantially crystalline. In one embodiment, Form AB is moderately crystalline. In one embodiment, form AB is partially crystalline.

In one embodiment, Form AB is the hydrochloride salt solvate of Compound 1. In one embodiment, Form AB is the ethyl acetate solvate of the hydrochloride salt of Compound 1.

A typical XRPD pattern of the AB form of the hydrochloride salt of compound 1 is shown in FIG. 160.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7 or all peaks located at approximately the following positions: 5.9, 7.7, 10 ,4, 14.2, 18.2, 20.9, 24.5 and 25.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 7.7, 18.2 and 20.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.9 and 14.2° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.9, 7.7, 10.4, 14.2, 18.2, 20.9 and 25.9° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 160.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form AB is prepared by suspending the amorphous Compound 1 hydrochloride salt in ethyl acetate at about 50° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form containing the hydrochloride salt form AB of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form AB of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, provided herein is a solid form containing Form AB of the hydrochloride salt of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form AB of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form AC hydrochloride salt of compound 1.

In some embodiments, the hydrochloride salt form AC of Compound 1 is provided herein.

In one embodiment, the form of AC is crystalline. In one embodiment, the AC form is substantially crystalline. In one embodiment, the AC form is moderately crystalline. In one embodiment, the AC form is partially crystalline.

In one embodiment, Form AC is the hydrochloride salt solvate of Compound 1. In one embodiment, Form AC is the hydrochloride solvate of Compound 1 with toluene.

A typical XRPD diagram of the AC form of the hydrochloride salt of compound 1 is shown in FIG. 161.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the peaks located approximately in the following positions: 5.8, 7.8, 9.9, 14.1, 15.6, 17.0, 18.2, 20.0, 23.4, 24.2, 25.8, 26 .5, 27.0, 27.7 and 28.3° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 14.1, 18.2 and 25.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.8 and 15.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.8 and 20.0° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.8, 7.8, 9.9, 14.1, 15.6, 17.0, 18.2, 20.0, 23.4, 24.2, and 25.8° 2θ.

In one embodiment, provided herein is a solid form containing a hydrochloride salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 161.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrochloride salt Form AB is prepared by suspending the amorphous Compound 1 hydrochloride salt in toluene at about 50° C. for a period of time (eg, about 7 days).

In one embodiment, provided herein is a solid form comprising the AC hydrochloride salt form of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the AC hydrochloride salt form of Compound 1 and an amorphous hydrochloride salt form of Compound 1. In one embodiment, provided herein is a solid form containing the AC hydrochloride salt form of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising the AC hydrochloride salt form of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Mesylate salt of compound 1.

In some embodiments, a mesylate salt of Compound 1 is provided herein. It is contemplated that the mesylate salt of Compound 1 may exist in a variety of solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline mesylate salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form comprising a mesylate salt of Compound 1. In one embodiment, the solid form is a mesylate salt solvate of Compound 1. In one embodiment, the solid form is a hydrate of the mesylate salt of Compound 1. In one embodiment, a solid the form is the unsolvated form of the mesylate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the mesylate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the mesylate salt of Compound 1. In one embodiment, the solid form is is the dehydrated form of the mesylate salt of compound 1.

In some embodiments, the molar ratio of Compound 1 to methanesulfonic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-mesylate salt). In another embodiment, the molar ratio is about 1:1 (ie, monomesylate salt).

Form A of the mesylate salt of compound 1.

In some embodiments, Compound 1 mesylate salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

In one embodiment, the molar ratio of Compound 1 to methanesulfonic acid in Form A is about 1:1. In one embodiment, Form A is the monomesylate salt of Compound 1.

In one embodiment, Form A is the mesylate salt solvate of Compound 1. In one embodiment, Form A is the ethyl acetate solvate of the mesylate salt of Compound 1.

A typical X-ray diffraction pattern of Compound 1 mesylate salt Form A is shown in FIG. 70.

In one embodiment, provided herein is a solid form containing the mesylate salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 5.5, 9.1, 12.1, 12.7, 13.2, 14.3, 15.2, 15 ,9, 16.6, 16.9, 17.7, 18.3, 19.0, 21.4, 21.7, 22.2, 22.7, 23.3, 23.9, 24.6 , 25.6, 27.1, and 28.0° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the mesylate salt of compound 1, characterized by an XRPD pattern including peaks at approximately 16.9, 17.7 and 22.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 15.2 and 23.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 9.1 and 16.6° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 9.1, 13.2, 14.3, 15.2, 16.6, 16.9, 17.7, 21.4, 22.7, 23.3, and 23.9° 2θ.

In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 70.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Compound 1 mesylate salt Form A is shown in FIG. 71. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 that exhibits a weight loss of about 9.6% when heated from about 25 to about 180°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of ethyl acetate (and trace amounts of water). In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 71.

A typical differential scanning calorimetry (DSC) thermogram of Compound 1 mesylate salt Form A is shown in FIG. 72. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 that exhibits, as characterized by DSC, a first (broad) thermal event with a peak temperature of about 69°C, a second thermal event with an onset temperature of about 132°C , and a third thermal event with an initial temperature of about 228°C. In one embodiment, the second thermal event also has a peak temperature of about 155°C, and the third thermal event also has a peak temperature of about 264°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to partial desolvation and the second thermal event corresponds to melting and desolvation. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 72.

A typical dynamic vapor sorption (DVS) isotherm plot of Compound 1 mesylate salt Form A is shown in FIG. 73. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 that exhibits a weight increase of about 20.8% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 73. In one embodiment, Form A is hygroscopic.

In one embodiment, Compound 1 mesylate salt Form A is prepared by subjecting a mixture of Compound 1 and methanesulfonic acid (e.g., about 1:1 molar ratio) in ethyl acetate to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 5 days). In one embodiment, the resulting product is optionally dried (eg, under vacuum at 40° C.) for a specified period of time (eg, about 4.5 hours).

In one embodiment, provided herein is a solid form comprising the mesylate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the mesylate salt Form A of Compound 1 and an amorphous mesylate salt of Compound 1. In one embodiment, a solid form is provided herein containing the mesylate salt Form A of Compound 1 and one or more crystalline mesylate salt forms salts of Compound 1. In one embodiment, provided herein is a solid form comprising Form A of the mesylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form B of the mesylate salt of compound 1.

In some embodiments, the mesylate salt Form B of Compound 1 is provided herein.

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is moderately crystalline. In one embodiment, Form B is partially crystalline.

In one embodiment, Form B is the mesylate salt solvate of Compound 1. In one embodiment, Form B is the 1,4-dioxane mesylate salt solvate of Compound 1.

A typical XRPD pattern of Form B of the mesylate salt of compound 1 is shown in FIG. 134.

In one embodiment, provided herein is a solid form containing the mesylate salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all peaks located approximately at the following positions: 5.7, 7.8, 9.1, 10.1, 11.7, 14.2, 14.5, 15.5, 16.1, 17.1, 17.7, 19.3, 22.6, 23.5, 26.1, 26.7 and 28.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 characterized by an XRPD diagram containing peaks at approximately 5.7, 9.1 and 26.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.2, 19.3 and 26.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.5 and 16.1° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.7, 7.8, 9.1, 11.7, 14.2, 14.5, 16.1, 19.3, 26.1, and 26.7°

2θ.

In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 134.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Representative thermograms of TG/DTA form B of the mesylate salt of compound 1 are shown in FIG. 135. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 which exhibits a first weight loss of about 1.5% when heated from about 25 to about 80°C and a second weight loss of about 1.4% when heating from about 80 to about 160°C. In one embodiment, without being limited to any particular theory, the first mass loss corresponds to the loss of unbound solvent, and the second mass loss corresponds to possible dehydration. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 135.

In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 that exhibits, as characterized by DTA, a thermal event (or series of small thermal events) at a temperature of from about 222 to about 249°C. In one embodiment, without being limited to any particular theory, the thermal phenomenon corresponds to decomposition. In one embodiment, provided herein is a solid form containing the mesylate salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 135.

In one embodiment, Compound 1 mesylate salt Form B is prepared by subjecting a suspension containing Compound 1 and methanesulfonic acid in 1,4-dioxane to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40°C for for approximately 4 hours) over a specified period of time (eg 72 hours).

In one embodiment, provided herein is a solid form comprising the mesylate salt Form B of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising the mesylate salt Form B of Compound 1 and an amorphous mesylate salt of Compound 1. In one embodiment, a solid form is provided herein containing the mesylate salt Form B of Compound 1 and one or more other crystalline forms mesylate salt of Compound 1. In one embodiment, provided herein is a solid form comprising Form B of the mesylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Hydrobromide salt of compound 1.

In some embodiments, the hydrobromide salt of Compound 1 is provided herein. It is contemplated that the hydrobromide salt of Compound 1 may exist in a variety of solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline hydrobromide salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1. In one embodiment, the solid form is the hydrobromide salt solvate of Compound 1. In one embodiment, the solid form is the hydrobromide salt hydrate of Compound 1. In one embodiment, the solid the form is the unsolvated form of the hydrobromide salt of Compound 1. In one embodiment, the solid form is the desolvated form of the hydrobromide salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the hydrobromide salt of Compound 1. In one embodiment, the solid form is is the dehydrated form of the hydrobromide salt of compound 1.

In some embodiments, the molar ratio of Compound 1 to hydrobromic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-hydrobromide salt). In another embodiment, the molar ratio is about 1:1 (ie, monohydrobromide salt).

Form B of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form B is provided herein.

- 72 044284

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is moderately crystalline. In one embodiment, Form B is partially crystalline.

In one embodiment, Form B is the hydrobromide salt hydrate of Compound 1.

A typical XRPD pattern of Form B of the hydrobromide salt of Compound 1 is shown in FIG. 74.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or all peaks located approximately at the following positions: 3.8, 5.8, 7.6, 9.9, 10.5, 11.7, 13.9, 14.8, 15.5, 17 ,1, 18.0, 19.9, 20.6, 25.3, 26.0, 26.6, 27.3, 27.9, and 29.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 5.8, 13.9 and 25.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 3.8 and 7.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.8, 19.9 and 26.0° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 3.8, 5.8, 7.6, 10.5, 13.9, 14.8, 19.9, 20.6, 25.3, 26.0, and 27.9° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 74.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical thermograms of TG/DTA form B of the hydrobromide salt of compound 1 are shown in FIG. 75. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight loss of about 12.7% when heated from about 25 to about 190°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of water (eg, about 5 water equivalents). In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 75.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 169°C. In one embodiment, the thermal event also has a peak temperature of about 193°C. In one embodiment, without being limited to any particular theory, the thermal phenomenon corresponds to decomposition. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 75.

In one embodiment, Compound 1 hydrobromide salt Form B is prepared by subjecting a mixture of Compound 1 and hydrobromic acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 7 days). In one embodiment, the solvent is acetone, anisole, ethyl formate, iPrOAc, MEK, TBME, toluene, a mixture of DMA and iPrOAc (for example, 1:9 v/v), or a mixture of DMF and toluene (for example, 1:9 v/v). /about.). In one embodiment, the solvent is TBME.

In one embodiment, Form B of the hydrobromide salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and hydrobromic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is 1,4-dioxane, acetone, ethyl acetate, MEK, THF, a mixture of THF and water (eg, about 1:1 v/v), toluene, or water. In one embodiment, the solvent is MEK.

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form B of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising hydrobromide salt Form B of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing hydrobromide salt Form B of Compound 1 and one or more than other crystalline forms of the hydrobromide salt of Compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form B of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form A of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

In one embodiment, the molar ratio of Compound 1 to hydrobromic acid in Form A is approximately 1:1. In one embodiment, Form A is the monohydrobromide salt of Compound 1.

In one embodiment, Form A is the unsolvated form of the hydrobromide salt of Compound 1. In one embodiment, Form A is the anhydrate of the hydrobromide salt of Compound 1.

A typical XRPD diagram of Compound 1 hydrobromide salt Form A is shown in FIG. 76.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or all peaks located approximately at the following positions: 4.3, 10.3, 11.9, 12.8, 14.4, 15.6, 15.9 , 17.1, 17.6, 18.8, 19.3, 20.2, 20.7, 22.4, 22.8, 23.3, 24.0, 26.0, 26.4, 26 .9, 27.7, 28.5, 29.6 and 31.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or all peaks located approximately in the following positions: 4.3, 10.3, 11.9, 12.8, 15.7, 15.9, 17.1, 17.2, 17.7, 18.8, 19 ,3, 19.5, 19.6, 20.2, 20.3, 20.7, 22.5, 22.8, 23.3, 23.9, 24.1, 26.0, 26.3 , 26.8, 27.7 and 31.2° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 10.3, 19.3 and 24.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.1 and 20.7° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 12.8 and 15.6° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 10.3, 12.8, 15.6, 15.9, 17.1, 17.6, 19.3, 20.7, 24.0, and 26.0° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 76.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Representative TG/DSC thermograms of Compound 1 hydrobromide salt Form A are shown in FIG. 77. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight loss of about 0.1% when heated from about 25 to about 150°C. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 77.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, which exhibits a thermal phenomenon as characterized by DSC with an initial temperature of about 283°C. In one embodiment, the thermal event also has a peak temperature of about 285°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to melting. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by a DSC thermogram that corresponds to the DTA thermogram shown in FIG. 77.

In one alternative embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, which exhibits a weight loss of about 1.8% when heated from about 25 to about 270°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of unbound solvent.

In one alternative embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 277°C. In one embodiment, the thermal event also has a peak temperature of about 282°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to melting.

A typical dynamic vapor sorption (DVS) isotherm plot of Compound 1 hydrobromide salt Form A is shown in FIG. 78. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight increase of about 0.7% as relative humidity (RH) increases from about 0% to about 95%. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 78. In one embodiment, Form A is slightly hygroscopic. In one embodiment, Form A remains as Form A after the DVS cycle.

In one alternative embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight increase of about 0.7% as relative humidity (RH) increases from about 5 to about 90%. In one embodiment, Form A is slightly hygroscopic. In one embodiment, Form A remains as Form A after the DVS cycle.

In one embodiment, Compound 1 hydrobromide salt Form A is prepared by subjecting a suspension containing Compound 1 and hydrobromic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is IPA, a mixture of acetone and water (for example, about 1:1 v/v), a mixture of acetonitrile and water (for example, about 1:1 v/v), ethanol, or a mixture of ethanol and water (for example, approximately 1:1 v/v).

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising hydrobromide salt Form A of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing hydrobromide salt Form A of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form A of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form C of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form C is provided herein.

In one embodiment, Form C is crystalline. In one embodiment, Form C is substantially crystalline. In one embodiment, Form C is moderately crystalline. In one embodiment, Form C is partially crystalline.

In one embodiment, Form C is the anhydrous hydrobromide salt form of Compound 1.

A typical XRPD pattern of Form C of the hydrobromide salt of Compound 1 is shown in FIG. 79.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or all peaks located approximately at the following positions: 5.7, 7.5, 9.6, 9.7, 10.1, 10.9, 11.5, 12.1, 13.5, 15 ,0, 16.5, 17.2, 18.7, 20.4, 22.0, 23.1, 24.6, 25.8, and 28.2° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form

- 75 044284 is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 9.7, 10.1 and 12.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 5.7, 7.5 and 24.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 15.0 and 25.8° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 5.7, 7.5, 9.7, 10.1, 11.5, 12.1, 15.0, 17.2, 24.6, and 25.8° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 79.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form C of the hydrobromide salt of Compound 1 are shown in FIG. 80. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight loss of about 1.1% when heated from about 25 to about 250°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of unbound solvent. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 80.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, which exhibits a thermal phenomenon as characterized by DTA with an initial temperature of about 275°C. In one embodiment, the thermal event also has a peak temperature of about 279°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to melting. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 80.

In one embodiment, Compound 1 hydrobromide salt Form C is prepared by subjecting a suspension containing Compound 1 and hydrobromic acid in acetonitrile to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form C of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising the hydrobromide salt Form C of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrobromide salt Form C of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form C of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form D of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form D is provided herein.

In one embodiment, Form D is crystalline. In one embodiment, Form D is substantially crystalline. In one embodiment, Form D is moderately crystalline. In one embodiment, Form D is partially crystalline.

In one embodiment, Form D is the hydrobromide salt solvate of Compound 1. In one embodiment, Form D is the methanol solvate of the hydrobromide salt of Compound 1.

A typical XRPD pattern of Form D of the hydrobromide salt of Compound 1 is shown in FIG. 81.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 6.2, 7.8, 11.1, 12.2, 12.4, 13.3, 13.8, 14.5, 15.5 , 15.7, 17.0, 17.2, 17.6, 19.8, 20.0, 22.5, 23.4, 24.5, 25.7, and 27.5° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 12.2, 12.4 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 11.1 and 15.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 6.2, 17.0 and 25.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 6.2, 11.1, 12.2, 12.4, 13.3, 13.8, 15.5, 15.7, 17.0, 24.5, 25.7 and 27.5° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 81.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Representative TG/DTA thermograms of Form D hydrobromide salt of Compound 1 are shown in FIG. 82. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight loss of about 0.95% when heated from about 25 to about 60° C., a weight loss of about 2.2% when heated from about 60°C to about 140°C and a weight loss of about 7.8% when heated from about 140 to about 220°C. In one embodiment, without being limited to any particular theory, the first mass loss corresponds to the loss of unbound solvent, the second mass loss corresponds to desolvation or dehydration, and the third mass loss corresponds to decomposition. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 82.

In one embodiment, provided herein is a solid form containing a hydrobromide salt of Compound 1 that exhibits, as characterized by DTA, a first (broad) thermal event (or two overlapping thermal events) with a peak temperature of about 192°C to about 210°C, a second a thermal event with an initial temperature of about 216°C and a third thermal event with an initial temperature of about 268°C. In one embodiment, the second thermal event also has a peak temperature of about 221°C, and the third thermal event also has a peak temperature of about 274°C. In one embodiment, without being limited to any particular theory, the thermal event corresponds to recrystallization and the third thermal event corresponds to melting. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 82.

In one embodiment, Compound 1 hydrobromide salt Form D is prepared by subjecting a suspension containing Compound 1 and hydrobromic acid in methanol to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours ) for a certain period of time (for example, 72 hours).

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form D of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrobromide salt Form D of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing the hydrobromide salt Form D of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form D of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form E of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form E is provided herein.

In one embodiment, Form E is crystalline. In one embodiment, Form E is substantially crystalline. In one embodiment, Form E is moderately crystalline. In one embodiment, Form E is partially crystalline.

In one embodiment, Form E is the hydrobromide salt solvate of Compound 1. In one embodiment, Form E is an isomorphic hydrobromide salt solvate of Compound 1. In one embodiment, Form E is the DMAc hydrobromide salt solvate of Compound 1. In one embodiment, Form E is is a solvate of the hydrobromide salt of compound 1 in DMF.

- 77 044284

A typical XRPD pattern of Form E of the hydrobromide salt of Compound 1 is shown in FIG. 162.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or all peaks located approximately at the following positions: 5.5, 6.7, 8.1, 9.8, 10.9, 12 ,1, 13.5, 14.4, 15.2, 16.4, 16.7, 17.4, 18.5, 18.8, 19.2, 20.0, 20.5, 21.9 , 22.5, 23.1, 23.9, 24.4, 25.1, 25.8, 26.6, 28.1 and 28.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 8.1, 13.5 and 24.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 21.9 and 25.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.4 and 18.5° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.5, 6.7, 8.1, 13.5, 16.4, 17.4, 18.5, 19.2, 21.9, 23.9, 24.4 and 25.8° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 162.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form E of the hydrobromide salt of Compound 1 is prepared by slowly (eg, over a period of time overnight or longer) evaporating a solution of the hydrobromide salt of Compound 1 in DMAc or DMF.

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form E of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form E of the hydrobromide salt of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing Form E of the hydrobromide salt of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form E of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form F of the hydrobromide salt of compound 1.

In some embodiments, the hydrobromide salt of Compound 1, Form F, is provided herein.

In one embodiment, Form F is crystalline. In one embodiment, Form F is substantially crystalline. In one embodiment, Form F is moderately crystalline. In one embodiment, Form F is partially crystalline.

In one embodiment, Form F is the hydrobromide salt solvate of Compound 1. In one embodiment, Form F is the NMP hydrobromide salt solvate of Compound 1.

A typical XRPD pattern of Form F of the hydrobromide salt of Compound 1 is shown in FIG. 163.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or all peaks located approximately at the following positions: 7.3, 9.4, 10.0, 11.3, 11.8, 12.9, 13 ,7, 14.6, 15.3, 16.5, 17.9, 18.4, 19.4, 20.0, 20.6, 22.1, 22.8, 23.6, 24.1 , 24.5, 24.9, 25.3, 25.9, 26.7 and 27.2° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 18.4, 23.6 and 24.5° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.6 and 24.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 10.0 and 20.0° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 10.0, 11.3, 14.6, 15.3, 18.4, 20.0, 23.6, 24.5,

- 78 044284

24.9, 25.3, 25.9, 26.7 and 27.2° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 163.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrobromide salt Form F is prepared by slowly (eg, over a period of time overnight or longer) evaporating a solution of Compound 1 hydrobromide salt in NMP.

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form F of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrobromide salt Form F of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing the hydrobromide salt Form F of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form F of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form G of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form G is provided herein.

In one embodiment, Form G is crystalline. In one embodiment, Form G is substantially crystalline. In one embodiment, Form G is moderately crystalline. In one embodiment, Form G is partially crystalline.

In one embodiment, Form G is the hydrobromide salt solvate of Compound 1. In one embodiment, Form G is the toluene solvate of the hydrobromide salt of Compound 1. In one embodiment, Form G is the toluene solvate hydrobromide salt hydrate of Compound 1.

A typical XRPD pattern of Form G of the hydrobromide salt of Compound 1 is shown in FIG. 164.

In one embodiment, provided herein is a solid form containing a hydrobromide salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all peaks located approximately at the following positions: 6.0, 7.7, 8.8, 9.1, 10.6, 11.8, 12.7, 13.9, 14.7, 16.4, 18, 1, 20.1, 21.5, 25.1, 25.8 and 27.9° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of compound 1 characterized by an XRPD diagram containing peaks at approximately 10.6, 18.1 and 25.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.7 and 13.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 6.0 and 11.8° 2θ. In one embodiment, the XRPD pattern contains peaks at approximately 6.0, 7.7, 8.8, 10.6, 11.8, 13.9, 14.7, 16.4, 18.1, and 25.1° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 164.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Form G of the hydrobromide salt of Compound 1 is prepared by subjecting a suspension of the amorphous hydrobromide salt of Compound 1 in toluene to one or more temperature cycles (e.g., from about room temperature to about 50° C.) for a period of time (e.g., about 7 days) .

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form G of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising the hydrobromide salt Form G of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrobromide salt Form G of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1, represented by

- 79 044284 in this document. In one embodiment, provided herein is a solid form comprising Form G of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form H of the hydrobromide salt of compound 1.

In some embodiments, Compound 1 hydrobromide salt Form H is provided herein.

In one embodiment, Form H is crystalline. In one embodiment, Form H is substantially crystalline. In one embodiment, Form H is moderately crystalline. In one embodiment, Form H is partially crystalline.

In one embodiment, Form H is the hydrobromide salt solvate of Compound 1. In one embodiment, Form H is the hydrobromide salt hydrate of Compound 1. In one embodiment, Form H is the hydrobromide salt tetrahydrate of Compound 1.

A typical XRPD pattern of Form H of the hydrobromide salt of Compound 1 is shown in FIG. 165.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all peaks located approximately at the following positions: 7.5, 8.1, 11.7, 13.4, 15.1, 15.6, 16.9, 18.0, 19.3, 20.6, 22.6, 24.4, 25.0, 25.8, 26.5, 27.5 and 28.4° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1, characterized by an XRPD pattern including peaks at approximately 7.5, 15.1 and 18.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 20.6 and 24.4° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 22.6 and 27.5° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.5, 8.1, 11.7, 15.1, 15.6, 16.9, 18.0, 20.6, 22.6, 24.4, and 27.5° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 165.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A representative thermogravimetric (TGA) thermogram of Form H is shown in FIG. 166. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 that exhibits a weight loss of about 10.5% when heated from about 25 to about 100°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of water (about 4 equivalents). In one embodiment, the solid form further exhibits a weight loss of about 0.5% when heated from about 100 to about 210°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of residual solvent chloroform. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 166.

A representative differential scanning calorimetry (DSC) thermogram of Form H is shown in FIG. 167. In one embodiment, provided herein is a solid form containing a hydrobromide salt of Compound 1 that exhibits, as characterized by DSC, a first thermal event with a peak temperature of about 70°C and a second thermal event with an initial temperature of about 171°C. In one embodiment, the second thermal event also has a peak temperature of about 178°C. In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 167.

In one embodiment, Compound 1 hydrobromide salt Form H is prepared by drying (e.g., drying at room temperature overnight) Compound 1 hydrobromide salt Form I.

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form H of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrobromide salt Form H of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrobromide salt Form H of Compound 1 and one or several other crystalline forms of the hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form containing Form H of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form I of the hydrobromide salt of compound 1.

In some embodiments, Form I of the hydrobromide salt of Compound 1 is provided herein.

In one embodiment, Form I is crystalline. In one embodiment, Form I is substantially crystalline. In one embodiment, Form I is moderately crystalline. In one embodiment, Form I is partially crystalline.

In one embodiment, Form I is the hydrobromide salt solvate of Compound 1. In one embodiment, Form I is the hydrobromide salt chloroform solvate of Compound 1.

A typical XRPD pattern of Form I hydrobromide salt of Compound 1 is shown in FIG. 168.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all peaks located approximately at the following positions: 7.2, 14.4, 15.0, 17.2, 18.0, 18.8, 19.8, 20.6, 21.4, 22.1 , 23.7, 25.4, 25.8, 26.2, 27.7, 28.5, 29.5, and 30.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 18.8, 21.4 and 25.4° 2θ. In one embodiment of the invention, the XRPD diffraction pattern further contains peaks at approximately 15.0 and 17.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.4 and 19.8° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.2, 14.4, 15.0, 17.2, 18.0, 18.8, 19.8, 20.6, 21.4, 22.1, 23.7 and 25.4° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 168.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrobromide salt Form I is prepared by subjecting a suspension of the amorphous compound 1 hydrobromide salt in chloroform to one or more temperature cycles (e.g., from about room temperature to about 50° C.) for a period of time (e.g., about 7 days) .

In one embodiment, provided herein is a solid form containing Form I hydrobromide salt of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising Form I of the hydrobromide salt of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, provided herein is a solid form containing Form I of the hydrobromide salt of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form I of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form J of the hydrobromide salt of compound 1.

In some embodiments, the hydrobromide salt of Compound 1, Form J, is provided herein.

In one embodiment of the invention, Form J is crystalline. In one embodiment of the invention, Form J is substantially crystalline. In one embodiment of the invention, Form J is moderately crystalline. In one embodiment of the invention, Form J is partially crystalline.

In one embodiment, Form J is the hydrobromide salt solvate of Compound 1. In one embodiment, Form J is the 1,4-dioxane hydrobromide salt solvate of Compound 1.

A typical XRPD diagram of Compound 1 hydrobromide salt Form J is shown in FIG. 169.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or all peaks located approximately at the following positions: 5.9, 7.8, 8.1, 11.6, 13.6, 14.9, 16.9, 17.2, 17.8, 18.4 , 19.4, 21.1, 22.2, 25.2, 25.9, 26.4, 27.4, and 28.7° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 19.4, 25.2 and 25.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.8 and 21.1° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 16.9 and 18.4° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.9, 7.8, 8.1, 13.6, 14.9, 16.9, 17.2, 17.8, 18.4, 19.4, 21.1, 25.2 and 25.9° 2θ.

In one embodiment, provided herein is a solid form containing the hydrobromide salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 169.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

In one embodiment, Compound 1 hydrobromide salt Form J is prepared by subjecting a suspension of the amorphous Compound 1 hydrobromide salt in 1,4-dioxane to one or more temperature cycles (e.g., from about room temperature to about 50° C.) for a period of time (e.g., about 7 days).

In one embodiment, provided herein is a solid form containing the hydrobromide salt Form J of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the hydrobromide salt Form J of Compound 1 and an amorphous hydrobromide salt of Compound 1. In one embodiment, a solid form is provided herein containing the hydrobromide salt Form J of Compound 1 and one or more other crystalline forms hydrobromide salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form J of the hydrobromide salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Besylate salt of compound 1.

In some embodiments, a besylate salt of Compound 1 is provided herein. It is contemplated that the besylate salt of Compound 1 may exist in a variety of solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline besylate salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form comprising a besylate salt of Compound 1. In one embodiment, the solid form is a solvate of the besylate salt of Compound 1. In one embodiment, the solid form is a hydrate of the besylate salt of Compound 1. In one embodiment, the solid the form is the unsolvated form of the besylate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the besylate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the besylate salt of Compound 1. In one embodiment, the solid form is is a dehydrated form of the besylate salt of compound 1.

In some embodiments, the molar ratio of Compound 1 to benzenesulfonic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-besylate salt). In another embodiment, the molar ratio is approximately 1:1 (ie, monobesylate salt).

Form A of the besylate salt of compound 1.

In some embodiments, Compound 1 besylate salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

A typical XRPD pattern of Form A of the besylate salt of Compound 1 is shown in FIG. 83.

In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all peaks located approximately at the following positions: 8.8, 8.9, 13.0, 13.2, 13.7, 13.9, 14.9, 15.1, 15.6 , 16.5, 16.9, 18.9, 20.8, 21.1, 24.3, 24.5, 25.0, 25.3, 27.6 and 30.8° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 characterized by an XRPD pattern including peaks at approximately 13.2, 21.1 and 24.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 15.1 and 27.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 14.9, 16.5 and 20.8° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 8.9, 13.2, 14.9, 15.1, 15.6, 16.5, 20.8, 21.1, 24.3, 24.5, and 27.6° 2θ.

In one embodiment, provided herein is a solid form containing the besylate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 83.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Representative TG/DTA thermograms of Form A of the besylate salt of Compound 1 are shown in FIG. 84. In one embodiment, provided herein is a solid form containing the besylate salt of Compound 1 that exhibits a weight loss of about 5.8% when heated from about 25 to about 80°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to a loss of 1,4-dioxane (eg, about 0.5 equivalents). In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 84.

In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 that exhibits, as characterized by DTA, a first (broad) thermal event with a peak temperature of about 50°C and a second thermal event with an initial temperature of about 272°C. In one embodiment, the second thermal event also has a peak temperature of about 306°C. In one embodiment, without being limited to any particular theory, the first thermal event corresponds to desolvation and the second thermal event corresponds to decomposition. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 84.

In one embodiment, Compound 1 besylate salt Form A is prepared by subjecting a mixture of Compound 1 and benzenesulfonic acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 7 days). In one embodiment, the solvent is a mixture of acetone and water (eg, about 1:1 v/v), a mixture of THF and water (eg, about 1:1 v/v), or 1,4-dioxane.

In one embodiment, provided herein is a solid form containing the besylate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing besylate salt Form A of Compound 1 and an amorphous besylate salt of Compound 1. In one embodiment, provided herein is a solid form containing besylate salt Form A of Compound 1 and one or more other crystalline forms besylate salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form A of the besylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Form B besylate salt of compound 1.

In some embodiments, the besylate salt Form B of Compound 1 is provided herein.

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is moderately crystalline. In one embodiment, Form B is partially crystalline.

In one embodiment, the molar ratio of Compound 1 to benzenesulfonic acid in Form B is about 1:1. In one embodiment, Form B is the monobesylate salt of Compound 1.

In one embodiment, Form B is the unsolvated form of the besylate salt of Compound 1. In one embodiment, Form B is the anhydrate of the besylate salt of Compound 1.

A typical XRPD pattern of Form B of the besylate salt of compound 1 is shown in FIG. 85.

In one embodiment, provided herein is a solid form containing a besylate salt of compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or all peaks located approximately at the following positions: 7.3, 10.3, 10.9, 11.2, 13.9 , 14.3, 14.7, 16.2, 16.6, 16.9, 17.2, 17.6, 17.7, 18.5, 19.5, 19.7, 20.1, 20 ,8, 21.7, 21.9, 22.5, 23.0, 23.3, 23.5, 24.6, 25.4, 26.6 and 28.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a besylate salt of compound 1 characterized by an XRPD pattern including peaks at approximately 16.9, 17.7 and 21.9° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 11.2, 17.6 and 23.0° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.3 and 25.4° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 7.3, 11.2, 16.2, 16.9, 17.6, 17.7, 20.8, 21.9, 23.0, 23.3, 24.6 and 25.4° 2θ.

In one embodiment, provided herein is a solid form containing the besylate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 85.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

A typical differential scanning calorimetry (DSC) thermogram of Form B besylate salt of Compound 1 is shown in FIG. 86A. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 that exhibits, as characterized by DSC, a first thermal event with an initial temperature of about 255°C and a second thermal event with an initial temperature of about 265°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 261°C, and the second thermal event also has a peak temperature of about 268°C. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram presented in FIG. 86A.

A typical thermogravimetric analysis (TGA) thermogram of Form B besylate salt of Compound 1 is shown in FIG. 86B. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 that exhibits a weight loss of about 0.37% when heated from about 25 to about 150°C or a weight loss of about 0.84% when heated from about 25 to about 150°C. approximately 200°C. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 86B.

A typical graph of the dynamic vapor sorption (DVS) isotherm of Form B besylate salt of Compound 1 is shown in FIG. 87. In one embodiment, provided herein is a solid form containing a besylate salt of Compound 1 that exhibits a weight increase of about 1.75% as relative humidity (RH) increases from about 5 to about 95%. In one embodiment, provided herein is a solid form containing the besylate salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot presented in FIG. 87. In one embodiment of the invention, Form B is slightly hygroscopic. In one embodiment, Form B remains as Form B after the DVS cycle.

In one embodiment, Compound 1 besylate salt Form B is prepared by crystallization from acetonitrile. In one embodiment, Compound 1 besylate salt Form B is prepared by suspending a mixture of Compound 1 and benzenesulfonic acid in acetonitrile at room temperature for a period of time (eg, overnight). In one embodiment, the besylate salt Form B of Compound 1 is prepared by adding benzenesulfonic acid to a suspension of Compound 1 in acetonitrile to form a solution, optionally seeding Form B, and stirring the mixture at room temperature for a period of time.

- 84 044284 (for example, overnight).

In one embodiment, provided herein is a solid form comprising the besylate salt Form B of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing the besylate salt Form B of Compound 1 and an amorphous besylate salt of Compound 1. In one embodiment, provided herein is a solid form containing the besylate salt Form B of Compound 1 and one or more other crystalline forms besylate salt of compound 1 presented herein. In one embodiment, provided herein is a solid form comprising Form B of the besylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

Glycolate salt of compound 1.

In some embodiments, a glycolate salt of Compound 1 is provided herein. It is contemplated that the glycolate salt of Compound 1 may exist in various solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline glycolate salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form comprising a glycolate salt of Compound 1. In one embodiment, the solid form is a glycolate salt solvate of Compound 1. In one embodiment, the solid form is a hydrate of a glycolate salt of Compound 1. In one embodiment, the solid the form is the unsolvated form of the glycolate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the glycolate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the glycolate salt of Compound 1. In one embodiment, the solid form is is a dehydrated form of the glycolate salt of compound 1.

In some embodiments, the molar ratio of Compound 1 to glycolic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-glycolate salt). In another embodiment, the molar ratio is approximately 1:1 (ie, monoglycolate salt).

Form A of the glycolate salt of compound 1.

In certain embodiments, Compound 1 Glycolate Salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

A typical XRPD diagram of Compound 1 glycolate salt Form A is shown in FIG. 88.

In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or all peaks located approximately at the following positions: 6.2, 6.6, 7.1, 7.3, 13.6, 14.0, 14.3 , 14.8, 15.2, 15.3, 16.4, 17.6, 18.1, 18.9, 19.7, 20.8, 21.0, 21.7, 22.2, 22 ,6, 24.2, 27.0, 27.3 and 28.1° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing a glycolate salt of compound 1 characterized by an XRPD pattern including peaks at approximately 13.6, 17.6 and 22.2° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 6.6, 14.8 and 20.8° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.3 and 21.7° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 6.2, 6.6, 7.1, 7.3, 13.6, 14.8, 16.4, 17.6, 20.8, 21.7, 22.2 and 24.2° 2θ.

In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 88.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Typical TG/DTA thermograms of Form A glycolate salt of Compound 1 are shown in FIG. 89. In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 that exhibits a weight loss of approximately 2.4% when heated from

- 85 044284 about 25 to about 60°C and a weight loss of about 1.0% when heated from about 60°C to about 140°C. In one embodiment, without being limited to any particular theory, the first weight loss corresponds to the loss of unbound solvent, and the second weight loss corresponds to the loss of ethanol and water. In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 89.

In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 that exhibits, as characterized by DTA, a first (broad) thermal event with a peak temperature of about 52°C and a second thermal event with an initial temperature of about 140°C. In one embodiment, the second thermal event also has a peak temperature of about 144°C. In one embodiment, provided herein is a solid form containing a glycolate salt of Compound 1 having a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 89.

In one embodiment, Compound 1 glycolate salt Form A is prepared by subjecting a mixture of Compound 1 and glycolic acid (e.g., about 1:1 molar ratio) in a solvent to a temperature cycle (e.g., between about 25 and about 35° C.) for a period of time ( e.g., from about 1 day to about 14 days, e.g., about 7 days). In one embodiment, the solvent is IPA. In one embodiment, the solvent is ethanol.

In one embodiment, provided herein is a solid form comprising glycolate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form comprising glycolate salt Form A of Compound 1 and an amorphous glycolate salt of Compound 1. In one embodiment, provided herein is a solid form containing glycolate salt Form A of Compound 1 and one or more other crystalline forms glycolate salt of Compound 1. In one embodiment, provided herein is a solid form comprising Form A of the glycolate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided herein.

L-malate (L-malic acid) salt of compound 1.

In some embodiments, an L-malate salt of Compound 1 is provided herein. It is contemplated that the L-malate salt of Compound 1 may exist in a variety of solid forms. Such solid forms include crystalline solids, such as polymorphs, solvates and hydrates of the crystalline L-malate salt of Compound 1, as well as amorphous solids or mixtures thereof.

In one embodiment, provided herein is a solid form comprising an L-malate salt of Compound 1. In one embodiment, the solid form is a solvate of the L-malate salt of Compound 1. In one embodiment, the solid form is a hydrate of the L-malate salt of Compound 1 In one embodiment, the solid form is the unsolvated form of the L-malate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the L-malate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of L- malate salt of Compound 1. In one embodiment, the solid form is the dehydrated form of the L-malate salt of Compound 1.

In some embodiments, the molar ratio of Compound 1 to L-malic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (ie, bis-L-malate salt). In another embodiment, the molar ratio is approximately 1:1 (ie, MOHO-L-malate salt).

Form A of the L-malate salt of compound 1.

In some embodiments, Compound 1 L-malate salt Form A is provided herein.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is moderately crystalline. In one embodiment, Form A is partially crystalline.

A typical XRPD pattern of Form A of the L-malate salt of Compound 1 is shown in FIG. 90.

In one embodiment, provided herein is a solid form containing the L-malate salt of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or all peaks located approximately at the following positions: 5.1, 5.7, 7.2, 8.1, 11.4, 13.0, 13.8 , 14.4, 14.7, 15.3, 15.5, 16.4, 17.9, 18.1, 18.6, 19.5, 20.6, 21.9, 22.9, 23 ,6, 25.3, 25.8 and 26.6° 2θ. In one embodiment, the solid form is characterized by 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, provided herein is a solid form containing the L-malate salt of Compound 1, characterized by an XRPD pattern containing peaks at approximately 8.1, 14.7 and 25.3° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 17.9, 20.6 and 26.6° 2θ. In one embodiment, the XRPD diagram further contains peaks at approximately 7.2 and 14.4° 2θ. In one embodiment, the XRPD chart contains peaks at approximately 5.7, 7.2, 8.1, 14.4, 14.7, 15.3, 16.4, 17.9, 18.1, 19.5, 20.6, 25.3 and 26.6° 2θ.

In one embodiment, provided herein is a solid form containing the L-malate salt of Compound 1 having an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 90.

In one embodiment, XRPD patterns are obtained using Cu Ka radiation.

Representative TG/DTA thermograms of Form A of the L-malate salt of Compound 1 are shown in FIG. 91. In one embodiment, provided herein is a solid form containing the L malate salt of Compound 1 that exhibits a weight loss of about 2.1% when heated from about 25 to about 75°C. In one embodiment, without being limited to any particular theory, the weight loss corresponds to the loss of unbound solvent. In one embodiment, provided herein is a solid form containing the L-malate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 91.

In one embodiment, provided herein is a solid form containing an L-malate salt of Compound 1 that exhibits, as characterized by DTA, a first thermal event with an initial temperature of about 105°C and a second thermal event with an initial temperature of about 185°C. In one embodiment of the invention, the first thermal event also has a peak temperature of about 111°C, and the second thermal event also has a peak temperature of about 206°C. In one embodiment, provided herein is a solid form containing the L-malate salt of Compound 1 characterized by a DTA thermogram that corresponds to the DTA thermogram presented in FIG. 91.

In one embodiment, Compound 1 L-malate salt Form A is prepared by subjecting a mixture of Compound 1 and L-malic acid (e.g., about 1:1 molar ratio) in DCM to a temperature cycle (e.g., between about 25 and about 35° C.) over a period of time (eg, from about 1 day to about 14 days, such as about 7 days).

In one embodiment, provided herein is a solid form comprising L-malate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, provided herein is a solid form containing Form A of the L-malate salt of Compound 1 and an amorphous L-malate salt of Compound 1. In one embodiment, provided herein is a solid form containing Form A of the L-malate salt of Compound 1. 1 and one or more other crystalline forms of the L-malate salt of Compound 1. In one embodiment, provided herein is a solid form comprising Form A of the L-malate salt of Compound 1 and one or more forms (e.g., amorphous or crystalline) salts of the compound 1 presented in this document.

Other salts of compound 1.

In one embodiment, provided herein is a napadisylate salt of Compound 1. In one embodiment, provided herein is Form A of a napadisylate salt of Compound 1. In one embodiment, provided herein is a solid form containing a napadisylate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 92. In one embodiment of the invention, Form A of the napadisylate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 1,5-naphthalenedisulfonic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a specified period of time (eg 72 hours). In one embodiment, the solvent is 1,4-dioxane, 2-propanol, acetone, a mixture of acetone and water (for example, about 50:50 v/v), acetonitrile, a mixture of acetonitrile and water (for example, about 50:50: 50 v/v), dichloromethane, diisopropyl ether, ethanol, ethanol/water mixture (e.g. about 50:50 v/v), ethyl acetate, heptane, isopropyl acetate, methanol, methyl ethyl ketone, tert-butyl methyl. ether, tetrahydrofuran, a mixture of tetrahydrofuran and water (for example, about 50:50 v/v), toluene or water.

In one embodiment, provided herein is a sulfate salt of Compound 1. In one embodiment, provided herein is

- 87 044284 amorphous sulfate salt of compound 1.

In one embodiment, a tosylate salt of Compound 1 is provided herein. In one embodiment, a tosylate salt of Compound 1 is provided herein, Form A. In one embodiment, a solid form is provided herein containing a tosylate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 93. In one embodiment of the invention, Compound 1 tosylate salt Form A is prepared by subjecting a suspension containing Compound 1 and toluenesulfonic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is 1,4-dioxane.

In one embodiment, provided herein is an oxalate salt of Compound 1. In one embodiment, provided herein is Form A of an oxalate salt of Compound 1. In one embodiment, provided herein is a solid form containing an oxalate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 94. In one embodiment of the invention, Form A of the oxalate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and oxalic acid in a solvent to a temperature cycle (for example, at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is a mixture of acetone and water (for example, about 50:50 v/v), a mixture of acetonitrile and water (for example, about 50:50 v/v), methanol, or a mixture of tetrahydrofuran and water (eg about 50:50 v/v). In one embodiment of the invention, isopropyl acetate is added as an antisolvent.

In one embodiment, provided herein is an isethionate salt of Compound 1. In one embodiment, provided herein is Form A of an isethionate salt of Compound 1. In one embodiment, provided herein is a solid form containing an isethionate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 95. In one embodiment of the invention, Form A of the isethionate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and isethionic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is acetone.

In one embodiment, provided herein is Form B of the isethionate salt of Compound 1. In one embodiment, provided herein is a solid form containing the isethionate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 96. In one embodiment of the invention, Form B of the isethionate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and isethionic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is diisopropyl ether or heptane.

In one embodiment, provided herein is a maleate salt of Compound 1. In one embodiment, provided herein is Form A of a maleate salt of Compound 1. In one embodiment, provided herein is a solid form containing a maleate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 97. In one embodiment of the invention, Form A of the maleate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and maleic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is a mixture of acetone and water (eg, about 50:50 v/v) or a mixture of acetonitrile and water (eg, about 50:50 v/v). In one embodiment of the invention, isopropyl acetate is added as an antisolvent. In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is Form B of the maleate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the maleate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 98. In one embodiment of the invention, Maleate Salt Form B of Compound 1 is prepared by subjecting a suspension containing Compound 1 and maleic acid in a solvent to a temperature cycle (e.g., at room

- 88 044284 temperature for about 4 hours, and then for about 4 hours at about 40°C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is methanol.

In one embodiment, provided herein is a phosphate salt of Compound 1. In one embodiment, provided herein is Form A of a phosphate salt of Compound 1. In one embodiment, provided herein is a solid form containing a phosphate salt of Compound 1 characterized by an XRPD diagram , which corresponds to the XRPD diagram presented in Fig. 99. In one embodiment, Compound 1 phosphate salt Form A is prepared by subjecting a suspension containing Compound 1 and phosphoric acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° for about 4 hours C) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is a mixture of acetone and water (eg, about 50:50 v/v).

In one embodiment, provided herein is a malonate salt of Compound 1. In one embodiment, provided herein is Form A of a malonate salt of Compound 1. In one embodiment, provided herein is a solid form containing a malonate salt of Compound 1, characterized by an XRPD diagram, which corresponds to the XRPD diagram shown in FIG. 100. In one embodiment of the invention, Malonate Salt Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and malonic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is water.

In one embodiment, provided herein is a gentisate salt of Compound 1. In one embodiment, provided herein is Form A of a gentisate salt of Compound 1. In one embodiment, provided herein is a solid form containing a gentisate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 101. In one embodiment of the invention, gentisate salt Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 2,5-dihydroxybenzoic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours). h at about 40°C) for a certain period of time (for example, 72 h). In one embodiment of the invention, the solvent is 1,4-dioxane, a mixture of acetone and water (for example, about 50:50 v/v), a mixture of acetonitrile and water (for example, about 50:50 v/v), a mixture ethanol and water (eg, about 50:50 v/v), tetrahydrofuran, or a mixture of tetrahydrofuran and water (eg, about 50:50 v/v). In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is Form B of the gentisate salt of Compound 1. In one embodiment, provided herein is a solid form containing the gentisate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 102. In one embodiment of the invention, gentisate salt Form B of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 2,5-dihydroxybenzoic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours). h at about 40°C) for a certain period of time (for example, 72 h). In one embodiment of the invention, the solvent is acetonitrile, dichloromethane, ethanol, ethyl acetate, methyl ethyl ketone, or water.

In one embodiment, provided herein is Form C of the gentisate salt of Compound 1. In one embodiment, provided herein is a solid form containing the gentisate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 103. In one embodiment of the invention, Form C of the gentisate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 2,5-dihydroxybenzoic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a specified period of time (eg 72 hours). In one embodiment of the invention, the solvent is methanol.

In one embodiment, the L-tartrate salt of Compound 1 is provided herein. In one embodiment, the L-tartrate salt of Compound 1 is provided herein in Form A. In one embodiment, the L-tartrate salt of Compound 1 is provided herein as a solid form. the salt of compound 1, characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 104. In one embodiment of the invention, L-tartaric acid Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and L-tartaric acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours). h at about 40°C) for a certain period of time (for example, 72 h). In one embodiment of the invention

- 89 044284 the solvent is 1,4-dioxane, tetrahydrofuran or a mixture of tetrahydrofuran and water (for example, about 50:50 v/v). In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is a fumarate salt of Compound 1. In one embodiment, provided herein is Form A of a fumarate salt of Compound 1. In one embodiment, provided herein is a solid form containing a fumarate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 105. In one embodiment of the invention, Form A of the fumarate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and fumaric acid in a solvent to a temperature cycle (for example, at room temperature for about 4 hours, and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is dichloromethane.

In one embodiment, the citrate salt of Compound 1 is provided herein. In one embodiment, the amorphous citrate salt of Compound 1 is provided herein.

In one embodiment, provided herein is the R-mandelic acid salt of Compound 1. In one embodiment, provided herein is Form A of the R-mandelic acid salt of Compound 1. In one embodiment, provided herein is a solid form containing R-mandelic acid the salt of compound 1, characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 106. In one embodiment of the invention, Compound 1 R-mandelic acid Form A is prepared by subjecting a suspension containing Compound 1 and R-mandelic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a specified period of time (eg 72 hours). In one embodiment of the invention, the solvent is water.

In one embodiment, provided herein is an L-ascorbate salt of Compound 1. In one embodiment, provided herein is Form A of an L-ascorbate salt of Compound 1. In one embodiment, provided herein is a solid form containing L-ascorbate the salt of compound 1, characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 107. In one embodiment of the invention, Compound 1 L-ascorbic salt Form A is prepared by subjecting a suspension containing Compound 1 and L-ascorbic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a specified period of time (eg 72 hours). In one embodiment of the invention, the solvent is 1,4-dioxane. In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is a succinate salt of Compound 1. In one embodiment, provided herein is Form A of a succinate salt of Compound 1. In one embodiment, provided herein is a solid form containing a succinate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 108. In one embodiment of the invention, Form A of the succinate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and succinic acid in a solvent to a temperature cycle (for example, at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is 1,4-dioxane. In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is a nitrate salt of Compound 1. In one embodiment, provided herein is Form A of a nitrate salt of Compound 1. In one embodiment, provided herein is a solid form containing a nitrate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 109. In one embodiment of the invention, Form A of the nitrate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and nitric acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is 2-propanol, acetone, a mixture of acetone and water (for example, about 50:50 v/v), acetonitrile, dichloromethane, diisopropyl ether, ethanol, a mixture of ethanol and water (for example, about 50: 50 v/v), ethyl acetate, heptane, isopropyl acetate, methanol, methyl ethyl ketone, tert-butyl methyl ether, tetrahydrofuran, a mixture of tetrahydrofuran and water (for example, about 50:50 v/v), toluene, or water.

In one embodiment, provided herein is a salicylate salt of Compound 1. In one embodiment, provided herein is

- 90 044284 Form A of the salicylate salt of Compound 1. In one embodiment, the invention provides herein a solid form containing the salicylate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 110. In one embodiment of the invention, Form A of the salicylate salt of Compound 1 is prepared by subjecting a suspension containing

Compound 1 and salicylic acid in a solvent, temperature cycled (eg, at room temperature for about 4 hours, then at about 40°C for about 4 hours) for a certain period of time (eg, 72 hours). In one embodiment, the solvent is acetonitrile, dichloromethane, heptane, tert-butyl methyl ether, tetrahydrofuran, a mixture of tetrahydrofuran and water (eg, about 50:50 v/v) or water.

In one embodiment, provided herein is Form B of the salicylate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the salicylate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 111. In one embodiment of the invention, Salicylate Salt Form B of Compound 1 is prepared by subjecting a suspension containing Compound 1 and salicylic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is ethanol or ethyl acetate.

In one embodiment, provided herein is Form C of the salicylate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the salicylate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 112. In one embodiment of the invention, Form C of the salicylate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and salicylic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is acetone or methyl ethyl ketone.

In one embodiment, provided herein is the edisylate salt of Compound 1. In one embodiment, provided herein is Form A of the edisylate salt of Compound 1. In one embodiment, provided herein is a solid form containing the edisylate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 113. In one embodiment of the invention, Compound 1 edisylate salt Form A is prepared by subjecting a suspension containing Compound 1 and 1,2-ethanedisulfonic acid in solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours). h at about 40°C) for a certain period of time (for example, 72 h). In one embodiment of the invention, the solvent is 1,4-dioxane.

In one embodiment, provided herein is Form B of the edisylate salt of Compound 1. In one embodiment, provided herein is a solid form containing the edisylate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 114. In one embodiment of the invention, Form B of the edisylate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 1,2-ethanedisulfonic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a specified period of time (eg 72 hours). In one embodiment, the solvent is a mixture of acetone and water (for example, about 50:50 v/v), acetonitrile, a mixture of acetonitrile and water (for example, about 50:50 v/v), diisopropyl ether, a mixture ethanol and water (eg, about 50:50 v/v), heptane, isopropyl acetate, methyl ethyl ketone, t-butyl methyl ether, tetrahydrofuran or toluene. In one embodiment of the invention, isopropyl acetate is added as an antisolvent. In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is the cyclamate salt of Compound 1. In one embodiment, provided herein is Form A of the cyclamate salt of Compound 1. In one embodiment, provided herein is a solid form containing the cyclamate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 115. In one embodiment of the invention, Form A of the cyclamate salt of compound 1 is prepared by subjecting a suspension containing compound 1 and cyclamic acid in a solvent to a temperature cycle (for example, at room temperature for about 4 hours, and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is 1,4-dioxane, methyl ethyl ketone or tetrahydrofuran.

- 91 044284

In one embodiment, provided herein is Form B of the cyclamate salt of Compound 1. In one embodiment, provided herein is a solid form containing the cyclamate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 116. In one embodiment of the invention, Form B of the cyclamate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and cyclamic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then for about 4 hours at about 40°C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is acetonitrile.

In one embodiment, provided herein is Form C of the cyclamate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the cyclamate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 117. In one embodiment of the invention, Form C of the cyclamate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and cyclamic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is dichloromethane.

In one embodiment, provided herein is Form D of the cyclamate salt of Compound 1. In one embodiment, provided herein is a solid form containing the cyclamate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 118. In one embodiment of the invention, Form D of the cyclamate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and cyclamic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is a mixture of acetone and water (eg, about 50:50 v/v). In one embodiment of the invention, isopropyl acetate is added as an antisolvent.

In one embodiment, provided herein is Form E of the cyclamate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the cyclamate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 119. In one embodiment of the invention, Form E of the cyclamate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and cyclamic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then for about 4 hours at about 40 °C) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is methanol. In one embodiment of the invention, isopropyl acetate is added as an antisolvent.

In one embodiment, provided herein is the zylate salt of Compound 1. In one embodiment, provided herein is Form A of the esylate salt of Compound 1. In one embodiment, provided herein is a solid form containing the esylate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 120. In one embodiment of the invention, Compound 1 esylate salt Form A is prepared by subjecting a suspension containing Compound 1 and ethanesulfonic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then at about 40° C. for about 4 h) for a specified period of time (for example, 72 h). In one embodiment of the invention, the solvent is 1,4-dioxane.

In one embodiment, provided herein is Form B of the esylate salt of Compound 1. In one embodiment, provided herein is a solid form comprising the esylate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 121. In one embodiment of the invention, Compound 1 esylate salt Form B is prepared by subjecting a suspension containing Compound 1 and ethanesulfonic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then at about 40° C. for about 4 h) for a specified period of time (for example, 72 h). In one embodiment, the solvent is a mixture of acetone and water (for example, about 50:50 v/v), a mixture of acetonitrile and water (for example, about 50:50 v/v), tetrahydrofuran, or a mixture of tetrahydrofuran and water (eg about 50:50 v/v). In one embodiment of the invention, isopropyl acetate is added as an antisolvent. In one embodiment of the invention, the solvent is evaporated.

In one embodiment, provided herein is a D-glucuronate salt of Compound 1. In one embodiment, provided herein

- 92 044284 that provides Form A of the D-glucuronate salt of Compound 1. In one embodiment of the invention, provided herein is a solid form containing the D-glucuronate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 122. In one embodiment of the invention, Form A of the D-glucuronate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and D-glucuronic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is a mixture of tetrahydrofuran and water (eg, about 50:50 v/v).

In one embodiment, provided herein is a 4-aminosalicylate salt of Compound 1. In one embodiment, provided herein is Form A of a 4-aminosalicylate salt of Compound 1. In one embodiment, provided herein is a solid form containing a 4-aminosalicylate salt of Compound 1, characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 123. In one embodiment of the invention, Form A of the 4-aminosalicylate salt of Compound 1 is prepared by subjecting a suspension containing Compound 1 and 4-aminosalicylic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40°C for for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is water.

In one embodiment, the caproate salt of Compound 1 is provided herein. In one embodiment, the caproate salt of Compound 1 is provided herein, Form A. In one embodiment, the caproate salt of Compound 1 is provided herein as a solid form containing the caproate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram shown in FIG. 124. In one embodiment of the invention, caproic salt Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and caproic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then at about 40° C. for about 4 h) for a specified period of time (for example, 72 h). In one embodiment of the invention, the solvent is a mixture of tetrahydrofuran and water (eg, about 50:50 v/v).

In one embodiment, provided herein is the cinnamate salt of Compound 1. In one embodiment, provided herein is Form A of the cinnamate salt of Compound 1. In one embodiment, provided herein is a solid form containing the cinnamate salt of Compound 1, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 125. In one embodiment of the invention, Compound 1 cinnamate salt Form A is prepared by subjecting a suspension containing Compound 1 and cinnamic acid in a solvent to a temperature cycle (eg, at room temperature for about 4 hours and then at about 40° C. for about 4 h) for a specified period of time (for example, 72 h). In one embodiment of the invention, the solvent is tert-butyl methyl ether.

In one embodiment, provided herein is Form B of the cinnamate salt of Compound 1. In one embodiment, provided herein is a solid form containing the cinnamate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 126. In one embodiment, Compound 1 cinnamate salt Form B is prepared by subjecting a suspension containing Compound 1 and cinnamic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is a mixture of tetrahydrofuran and water (eg, about 50:50 v/v).

In one embodiment, the caprylate salt of Compound 1 is provided herein. In one embodiment, the caprylate salt of Compound 1 is provided herein, Form A. In one embodiment, the caprylate salt of Compound 1 is provided herein as a solid form, characterized by the diagram XRPD, which corresponds to the XRPD diagram presented in FIG. 127. In one embodiment of the invention, caproic salt Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and caproic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is a mixture of tetrahydrofuran and water (eg, about 50:50 v/v).

In one embodiment, provided herein is a camphor salt of Compound 1. In one embodiment, provided herein is Camphor Salt Form A of Compound 1. In one embodiment, provided herein is a solid form containing a camphor salt of Compound 1, characterized by

- 93 044284 XRPD diagram, which corresponds to the XRPD diagram presented in FIG. 128. In one embodiment of the invention, Camphor Salt Form A of Compound 1 is prepared by subjecting a suspension containing Compound 1 and camphoric acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C. for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is acetonitrile or methanol.

In one embodiment, provided herein is the D-aspartate salt of Compound 1. In one embodiment, provided herein is D-aspartate salt Form A of Compound 1. In one embodiment, provided herein is a solid form containing the D-aspartate salt of Compound 1. 1, characterized by an XRPD diagram that corresponds to the XRPD diagram shown in FIG. 129. In one embodiment of the invention, Compound 1 D-aspartate salt Form A is prepared by subjecting a suspension containing Compound 1 and D-aspartic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment, the solvent is a mixture of acetone and water (eg, about 50:50 v/v).

In one embodiment, provided herein is the D-aspartate salt Form B of Compound 1. In one embodiment, provided herein is a solid form containing the D-aspartate salt of Compound 1 characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. . 130. In one embodiment of the invention, Compound 1 D-aspartate salt Form B is prepared by subjecting a suspension containing Compound 1 and D-aspartic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40 °C for about 4 hours) over a specified period of time (e.g. 72 hours). In one embodiment of the invention, the solvent is diisopropyl ether or heptane.

In one embodiment, provided herein is a D-glutamate salt of Compound 1. In one embodiment, provided herein is Form A of a D-glutamate salt of Compound 1. In one embodiment, provided herein is a solid form containing D-glutamate the salt of compound 1, characterized by an XRPD diagram that corresponds to the XRPD diagram presented in FIG. 131. In one embodiment of the invention, Compound 1 D-glutamine salt Form A is prepared by subjecting a suspension containing Compound 1 and D-glutamic acid in a solvent to a temperature cycle (e.g., at room temperature for about 4 hours and then at about 40° C for about 4 hours) for a certain period of time (for example, 72 hours). In one embodiment of the invention, the solvent is a mixture of tetrahydrofuran and water (eg, about 50:50 v/v).

5.3. Methods of application.

In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient a solid form or salt of Compound 1 provided herein. In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient a solid form containing Compound 1 provided herein. In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient a salt of Compound 1 provided herein. In one embodiment, provided herein is a solid form or salt of Compound 1 provided herein for use in a method of treating multiple myeloma, wherein the method includes administering said solid form or salt to a patient.

In one embodiment, provided herein is a method for preventing multiple myeloma, which includes administering to a patient a solid form or salt of Compound 1 provided herein. In one embodiment, provided herein is a method for preventing multiple myeloma, which includes administering to a patient a solid form containing Compound 1 provided herein. In one embodiment, provided herein is a method for preventing multiple myeloma, which includes administering to a patient a salt of Compound 1 provided herein. In one embodiment, a solid form or salt of Compound 1 provided herein is provided herein for use in a method for preventing multiple myeloma, wherein said method includes said compound for a patient.

In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient a solid form or salt of Compound 1 provided herein. In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient

- 94 044284 solid form containing compound 1 presented herein. In one embodiment, provided herein is a method of treating multiple myeloma, which includes administering to a patient a salt of Compound 1 provided herein. In one embodiment, a solid form or salt of Compound 1 provided herein is provided herein for use in a method of treating multiple myeloma, wherein the method includes administering said compound to a patient.

In one embodiment of the invention, methods for inducing a therapeutic response assessed by the International Unified Response Criteria for Multiple Myeloma (IURC) in a patient are also provided herein (see Durie BGM, Harousseau J-L, Miguel JS, et al., International Unified Response Criteria for multiple myeloma. Leukemia, 2006;(10)10:1-7), comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for achieving a strict complete response, a complete response, or a very good partial response, as defined by the International Unified Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a solid form or salt of Compound 1 represented by herein, to a patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression or disease-free survival in a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to the patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for achieving an increase in overall survival of a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma. In another embodiment, provided herein are methods of increasing progression-free survival in a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for achieving an increase in event-free survival in a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for achieving an increase in time to progression in a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma. In another embodiment of the invention, methods are provided herein for increasing disease-free survival of a patient, comprising administering an effective amount of a solid form or salt of Compound 1 provided herein to a patient suffering from multiple myeloma.

This document also provides treatments for patients who have previously been treated for multiple myeloma but do not respond to standard treatments, as well as for patients who have not previously been treated. Treatment options are also covered for patients who have undergone surgery to attempt treatment for multiple myeloma, as well as those who have not. This document also presents treatments for patients who have previously undergone transplant therapy, as well as those who have not yet undergone transplant therapy.

The methods provided herein include the treatment of multiple myeloma that is relapsed, refractory or refractory. Methods provided herein include the prevention of multiple myeloma that is relapsed, refractory or resistant. The methods provided herein include the treatment of multiple myeloma that is relapsed, refractory or refractory. In some such embodiments, the myeloma is primary, secondary, tertiary, quadruple or quintuple multiple myeloma. In one embodiment of the invention, the methods presented herein reduce, maintain or eliminate minimal residual disease (MRD). In one embodiment of the invention, the methods provided herein cover the treatment, prevention or management of various types of multiple myeloma, such as monoclonal gammopathy of undetermined significance (MGUS), low, intermediate and high risk multiple myeloma, newly diagnosed multiple myeloma (including multiple myeloma low, intermediate and high risk), transplant eligible and transplant ineligible multiple myeloma, smoldering (smoldering) multiple myeloma (including low, intermediate and high risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia , multiple myeloma of the central nervous system, light chain myeloma, nonsecretory myeloma, immunoglobulin D myeloma and immunoglobulin E myeloma by administering a therapeutically effective amount of solids

- 95 044284 doy form or salt of compound 1 presented herein. In another embodiment, the methods provided herein include the treatment, prevention or management of multiple myeloma characterized by genetic abnormalities such as cyclin D translocations (eg, t(11;14)(q13;q32); t(6;14) )(p21;32); t(12;14)(p13;q32); or t(6;20);); MMSET translocations (e.g. t(4;14)(p16;q32)); MAF translocations (e.g. t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (eg, deletion of 17p13 or chromosome 13; del(17/17p), non-hyperdiploidy and amplification (1q)) by administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In some embodiments, the methods include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as induction therapy. In some embodiments, the methods include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as consolidation therapy. In some embodiments, the methods include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as maintenance therapy.

In one specific embodiment of the methods described herein, multiple myeloma is a plasma cell leukemia.

In one embodiment of the methods described herein, the multiple myeloma is high-risk multiple myeloma. In some such embodiments, the high-risk multiple myeloma is relapsed or refractory. In one embodiment of the invention, high-risk multiple myeloma is multiple myeloma that recurs within 12 months of initial treatment. In yet another embodiment, high-risk multiple myeloma is multiple myeloma that is characterized by genetic abnormalities, such as one or more of del(17/17p) and t(14;16)(q32;q32). In some such embodiments, high-risk multiple myeloma has relapsed or is refractory to one, two, or three previous courses of treatment.

In one embodiment of the invention, multiple myeloma is characterized by a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is the R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is an R337 mutation. In one embodiment, the p53 mutation is the R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is an S261 mutation. In one embodiment, the p53 mutation is an S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is an R175 mutation. In one embodiment, the p53 mutation is the R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

In one embodiment of the invention, multiple myeloma is characterized by a homozygous deletion of p53. In one embodiment of the invention, multiple myeloma is characterized by a homozygous deletion of wild-type p53.

In one embodiment of the invention, multiple myeloma is characterized by wild-type p53.

In one embodiment of the invention, multiple myeloma is characterized by activation of one or more oncogenic factors. In one embodiment, the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, Cyclin D1, and Cyclin D. In one embodiment, multiple myeloma is characterized by activation of C-MAF. In one embodiment of the invention, multiple myeloma is characterized by activation of MAFB. In one embodiment of the invention, multiple myeloma is characterized by activation of FGFR3 and MMset. In one embodiment of the invention, multiple myeloma is characterized by activation of C-MAF, FGFR3 and MMset. In one embodiment of the invention, multiple myeloma is characterized by activation of cyclin D1. In one embodiment of the invention, multiple myeloma is characterized by activation of MAFB and cyclin D1. In one embodiment of the invention, multiple myeloma is characterized by activation of cyclin D.

In one embodiment of the invention, multiple myeloma is characterized by one or

- 96 044284 several chromosomal translocations. In one embodiment of the invention, the chromosomal translocation is t(14;16). In one embodiment of the invention, the chromosomal translocation is t(14;20). In one embodiment of the invention, the chromosomal translocation is t(4;14). In one embodiment of the invention, the chromosomal translocations are t(4;14) and t(14;16). In one embodiment of the invention, the chromosomal translocation is t(11;14). In one embodiment of the invention, the chromosomal translocation is t(6;20). In one embodiment of the invention, the chromosomal translocation is t(20;22). In one embodiment of the invention, the chromosomal translocations are t(6;20) and t(20;22). In one embodiment of the invention, the chromosomal translocation is t(16;22). In one embodiment of the invention, the chromosomal translocations are t(14;16) and t(16;22). In one embodiment of the invention, the chromosomal translocations are t(14;20) and t(l 1;14).

In one embodiment, multiple myeloma is characterized by a Q331 p53 mutation, C-MAF activation, and a chromosomal translocation at t(14;16). In one embodiment of the invention, multiple myeloma is characterized by a homozygous deletion of p53, activation of C-MAF and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by a p53 K132N mutation, MAFB activation, and a chromosomal translocation at t(14;20). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by wild-type p53, CMAF activation, and a chromosomal translocation at t(14;16). In one embodiment, multiple myeloma is characterized by homozygous deletion of p53, activation of FGFR3, MMset and C-MAF and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, multiple myeloma is characterized by a homozygous deletion of p53, activation of cyclin D1 and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by a p53 R337L mutation, cyclin D1 activation, and a chromosomal translocation at t(11;14). In one embodiment, multiple myeloma is characterized by a p53 W146 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by the S261T p53 mutation, MAFB activation, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, multiple myeloma is characterized by a p53 E286K mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by a p53 R175H mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, multiple myeloma is characterized by the p53 E258K mutation, C-MAF activation, and chromosomal translocations at t(14;16) and t(16;22). In one embodiment, multiple myeloma is characterized by wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14). In one embodiment, multiple myeloma is characterized by a p53 A161T mutation, cyclin D activation, and a chromosomal translocation at t(l 1;14).

In some embodiments of the methods described herein, the multiple myeloma is a newly diagnosed multiple myeloma suitable for transplantation. In another embodiment of the invention, the multiple myeloma is a recently diagnosed multiple myeloma ineligible for transplantation.

In other embodiments, multiple myeloma is characterized by early progression (eg, less than 12 months) after initial treatment. In other embodiments, multiple myeloma is characterized by early progression (eg, less than 12 months) after autologous stem cell transplantation. In another embodiment of the invention, multiple myeloma is resistant to lenalidomide. In another embodiment of the invention, multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is assumed to be resistant to pomalidomide (eg, based on molecular characteristics). In another embodiment, the multiple myeloma is recurrent or resistant to 3 or more treatments and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprosomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide), or exhibits dual resistance to a proteasome inhibitor and an immunomodulatory compound. In other embodiments, the multiple myeloma is relapsed or refractory to 3 or more prior treatments, including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib) and an immunomodulatory compound (eg, thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide) or exhibits dual resistance to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is resistant to a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprosomib, or marizomib), an immunomodulatory compound (for example, thalidomide, lenalidomide, pomalidomide, iberdomide, or Vadomide ) and another active agent as described herein.

In certain embodiments, provided herein are methods of treating, preventing, and/or managing multiple myeloma, including relapsed/refractory multiple myeloma in patients with impaired renal function or symptoms thereof, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to the patient with relapsed/refractory multiple myeloma with impaired renal function.

In certain embodiments, provided herein are methods of treating, preventing, and/or managing multiple myeloma, including relapsed or refractory multiple myeloma in a debilitated patient or a symptom thereof, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a debilitated patient. with multiple myeloma. In some such embodiments, the frail patient is unsuitable for induction therapy or intolerant to dexamethasone treatment. In some such embodiments, the frail patient is elderly, such as over 65 years of age.

In some embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein, wherein the multiple myeloma is fourth-line relapsed/refractory multiple myeloma.

In some embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as induction therapy when multiple myeloma is newly diagnosed, suitable for multiple myeloma transplantation.

In some embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as maintenance therapy following another therapy or transplant, wherein the multiple myeloma - newly diagnosed multiple myeloma suitable for transplantation, before other therapy or transplantation.

In certain embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein as maintenance therapy following other therapy or transplantation. In some embodiments, multiple myeloma is newly diagnosed multiple myeloma eligible for transplantation, prior to other therapy and/or transplantation. In some embodiments, the other pre-transplant therapy is treatment with chemotherapy or Compound 1.

In certain embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein, wherein the multiple myeloma is high-risk multiple myeloma, that is, relapsing or unresponsive to one, two or three previous courses of treatment.

In certain embodiments, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 provided herein, wherein the multiple myeloma is newly diagnosed multiple myeloma not suitable for transplantation .

In some embodiments, the therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 25, from about 0.01 to about 10, from about 0.01 to about 5, from about 0.01 to about 2, from about 0.01 to about 1, about 0.01 to about 0.5, about 0.01 to about 0.25, about 0.1 to about 25, about 0.1 to about 10, about 0 .1 to about 5, from about 0.1 to about 2, from about 0.1 to about 1, from about 0.1 to about 0.5, from about 0.1 to about 0.25, from about 0, 5 to about 25, from about 0.5 to about 10, from about 0.5 to about 5, from about 0.5 to about 2, from about 0.5 to about 1, from about 1 to about 25, from about 1 to about 10, about 1 to about 5, about 1 to about 2.5, or about 1 to about 2 mg per day. In one embodiment of the invention, a therapeutically or prophylactically effective amount of Compound 1 is from about 0.1 to about 0.4 mg per day.

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In some embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8 , about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, or about 25 mg per day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, or about 0.7 mg per day.

In one embodiment of the invention, the recommended daily dosage range of Compound 1 for the conditions described herein is in the range of about 0.1 mg to about 25 mg per day, preferably administered as a single dose once daily or in divided doses during the day. In other embodiments, the dosage is from about 0.1 to about 10 mg per day. Specific daily doses include 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 mg per day. More specific daily doses include 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day.

In a specific embodiment, the recommended starting dose may be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 25 mg per day . In another embodiment of the invention, the recommended starting dose may be 0.1, 0.2, 0.3, 0.4 or 0.5 mg per day. The dose can be increased to 1, 2, 3, 4 or 5 mg per day.

In some embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 5, from about 0.001 to about 4, from about 0.001 to about 3, from about 0.001 to about 2, from about 0.001 to about 1, from about 0.001 to about 0.05, about 0.001 to about 0.04, about 0.001 to about 0.03, about 0.001 to about 0.02, about 0.001 to about 0.01, or about 0.001 to about 0.005 mg/kg /day.

The dose administered may also be expressed in units other than mg/kg/day. For example, doses for parenteral administration may be expressed in mg/m/day. One skilled in the art will readily recognize how to convert doses from mg/kg/day to mg/m/day based on the subject's height or weight, or both (see www.fda.gov/cder/cancer/ animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg person is approximately 38 mg/m /day.

In some embodiments, the patient to be treated with one of the methods provided herein has not been treated with multiple myeloma therapy prior to administration of the solid or salt form of Compound 1 provided herein. In some embodiments, a patient to be treated with one of the methods provided herein has been treated with multiple myeloma therapy prior to administration of the solid or salt form of Compound 1 provided herein. In some embodiments, a patient being treated with one of the methods provided herein has developed drug resistance to multiple myeloma therapy. In some such embodiments, the patient has developed resistance to one, two, or three multiple myeloma drugs, wherein the treatments selected from a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and an immunomodulatory compound (eg thalidomide, lenalidomide, pomalidomide, iberdomide or avadomide).

The methods presented herein cover treatment of a patient regardless of the age of the patient. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is over 65 years of age. In one embodiment, the subject is an elderly subject with multiple myeloma, such as a subject over 65 years of age. In one embodiment, the subject is an elderly subject with multiple myeloma, such as a subject over 75 years of age.

Depending on the condition of the disease being treated and the condition of the subject, the solid form or salt of Compound 1 provided herein may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, IV, intracystemal injection or infusion, subcutaneous injection, or implant ), inhalation, nasal, vaginal, rectal, sublingual, or topical (eg, transdermal or topical) route of administration. The solid form or salt of Compound 1 provided herein may be formulated alone or together in a suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles suitable for each route of administration.

In one embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered orally. In another embodiment, the solid form or salt of Compound 1 provided herein is administered parenterally. In yet another embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered intravenously.

The solid form or salt of Compound 1 provided herein may be delivered as a single dose, such as, for example, a single bolus injection or orally

- 99 044284 tablets or pills; or over time, such as continuous infusion over time or divided bolus doses over time. The compounds described herein may be re-administered as necessary, for example, until the patient exhibits stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or absence thereof is determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, tumor imaging visualized by X-ray, CAT, PET or MRI, and other conventional assessment methods.

The solid form or salt of Compound 1 provided herein may be administered once daily (QD or qd) or divided into multiple daily doses such as twice daily (BID or bid), three times daily (TID or tid ) and four times a day (QID or qid). In addition, administration may be continuous (ie, daily for consecutive days or every day), intermittent, such as cyclic (ie, including days, weeks or months of rest without drug). As used herein, the term daily is intended to mean that the therapeutic compound is administered one or more times each day, for example, over a period of time. The term continuous is intended to mean that the therapeutic compound is administered daily for a continuous period of at least 7 days to 52 weeks. The term intermittent or intermittent as used in this document is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the solid form or salt of Compound 1 provided herein is one to six days per week, administered in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period without administration for up to one week) or administration every other day. The term cycling as used herein is intended to mean that the therapeutic compound is administered daily or continuously but with a rest period. In some such embodiments, administration is once daily for two to six days, followed by a rest period without administration for five to seven days.

In some embodiments, the frequency of administration ranges from about a daily dose to about a monthly dose. In some embodiments, administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks or once every four weeks. In one embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered once daily. In another embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered twice daily. In yet another embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered three times daily. In yet another embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered four times daily.

In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 20 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 15 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 10 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 7 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 5 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 4 days followed by a rest period. In one embodiment of the invention, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered in a treatment cycle that includes an administration period of up to 3 days followed by a rest period.

In one embodiment of the invention, the treatment cycle includes an administration period of up to 14 days followed by a rest period. In one embodiment of the invention, the treatment cycle includes an administration period of up to 10 days followed by a rest period. In one embodiment of the invention, the treatment cycle includes an administration period of up to 7 days followed by a rest period. In one embodiment of the invention, the treatment cycle includes an administration period of up to 5 days followed by a rest period. In one embodiment of the invention, the treatment cycle includes an administration period of up to 4 days followed by a rest period. In one embodiment of the invention, the treatment cycle includes an administration period of up to 3 days followed by a rest period.

In one embodiment of the invention, the rest period is from about 2 to about 11 days. In one embodiment of the invention, the rest period is from about 2 to about 10 days. In one embodiment of the invention, the rest period is about 2 days. In one embodiment of the invention, the rest period is about 3 days. In one embodiment of the invention, the rest period is about 4 days. In one embodiment of the invention, the rest period is about 5 days. In one embodiment of the invention, the rest period is about 6 days. In another embodiment of the invention, the rest period is about 7 days. In another embodiment of the invention, the rest period is about 8 days. In another embodiment of the invention, the rest period is about 9 days. In another embodiment of the invention, the rest period is about 10 days. In another embodiment of the invention, the rest period is about 11 days.

In one embodiment of the invention, the treatment cycle includes an administration period of up to 15 days, followed by a rest period of about 2 to about 10 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 10 days, followed by a rest period of about 2 to about 10 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 7 days, followed by a rest period of about 2 to about 10 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 5 days, followed by a rest period of about 2 to about 10 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 10 to about 15 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 3 days, followed by a rest period of about 3 to about 15 days.

In one embodiment of the invention, the treatment cycle includes an administration period of up to 15 days followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 5 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 4 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 3 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 2 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 7 days followed by a rest period of 7 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 5 days. In one embodiment of the invention, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 11 days. In another embodiment of the invention, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 9 days. In another embodiment of the invention, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 2 days. In another embodiment of the invention, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 4 days.

In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 5 of a 28-day cycle. In another embodiment of the invention, the treatment cycle includes administration of a solid form or salt of Compound 1 provided herein on days 1 to 10 of a 28-day cycle. In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 21 of a 28-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 5 of a 7-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 7 of a 7-day cycle. In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 10 and days 15 to 24 of a 28-day cycle (referred to herein as treatment cycle 20/ 28). In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1-3 and days 15-18 of a 28-day cycle. In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 7 and days 15 to 21 of a 28-day cycle (herein referred to as treatment cycle 14/ 28). In one embodiment of the invention, the treatment cycle includes administering a therapeutically effective amount of a solid form or

- 101 044284 salts of compound 1 presented herein, on days 1 to 5 and days 15 to 19 of a 28-day cycle (referred to herein as the 10/28 treatment cycle). In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 3 and days 15 to 17 of a 28-day cycle (referred to herein as treatment cycle 6/ 28).

In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 14 of a 21-day cycle. In another embodiment of the invention, a treatment cycle includes administration of a solid form or salt of Compound 1 provided herein on days 1 to 4 and 8 to 11 of a 21-day cycle. In one embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 5 and 8 to 12 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 5 and 11 to 15 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 5, 8 to 12, and 15 to 19 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 4, 8 to 11, and 15 to 18 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 4, 8 to 10, and 15 to 17 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 3 and 8 to 11 of a 21-day cycle. In another embodiment of the invention, a treatment cycle comprises administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 to 3 and 11 to 13 of a 21-day cycle.

Any treatment cycle described herein may be repeated for at least 2, 3, 4, 5, 6, 7, 8 or more cycles. In some cases, a treatment cycle as described herein comprises from 1 to about 24, from about 2 to about 16, or from about 2 to about 4 cycles. In some cases, the treatment cycle described herein includes from 1 to about 4 cycles. In some embodiments, cycles 1 through 4 are all 28-day cycles. In some embodiments, a therapeutically effective amount of the solid form or salt of Compound 1 provided herein is administered over 1 to 13 cycles of 28 days (eg, about 1 year). In some cases, cyclic therapy is not limited to the number of cycles, and therapy continues until the disease progresses. Cycles may in some cases include varying the length of the administration periods and/or rest periods described herein.

In one embodiment of the invention, the treatment cycle comprises administering a solid form or salt of Compound 1 provided herein at a dosage of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0. 7, 0.8, 0.9, 1.0, 5.0, or 10 mg/day administered once daily. In one embodiment of the invention, the treatment cycle comprises administering a solid form or salt of Compound 1 provided herein at a dosage of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0. 7 or 0.8 mg/day administered once daily. In some such embodiments, the treatment cycle comprises administering a solid form or salt of Compound 1 provided herein once daily at a dosage of about 0.1, 0.2, 0.3, 0.4, or 0.5 mg per days 1 to 10 of the 28-day cycle. In some such embodiments, the treatment cycle comprises administering a solid form or salt of Compound 1 provided herein once daily at a dosage of about 0.1, 0.2, 0.3, 0.4, or 0.5 mg per days 1 to 10 and 15-24 of the 28-day cycle. In some such embodiments, the treatment cycle comprises administering the solid or salt form of Compound 1 provided herein once daily at a dosage of about 0.1 mg on days 1 to 10 and 15 to 24 of a 28-day cycle. In other embodiments, the treatment cycle comprises administering a solid or salt form of Compound 1 provided herein twice daily at a dosage of about 0.1, 0.2, 0.3, 0.4 or 0.5 mg per day from 1 to 3 of the 28-day cycle. In other embodiments, the treatment cycle comprises administering a solid or salt form of Compound 1 provided herein twice daily at a dosage of about 0.1, 0.2, 0.3, 0.4 or 0.5 mg per day from 1 to 3 and from 15 to 19 of the 28-day cycle. In other embodiments, the treatment cycle comprises administering a solid or salt form of Compound 1 provided herein twice daily at a dosage of about 0.1, 0.2, 0.3, 0.4 or 0.5 mg per day from 1 to 3 and from 15 to 17 of the 28-day cycle. In other embodiments, the treatment cycle includes administration of the solid or salt form of Compound 1 provided herein twice daily at a dosage of about 0.2 mg on days 1 to 3 and 15 to 17 of a 28-day cycle. In one such embodiment, the compound is administered on days 1 to 3 (morning and evening), day 14 (evening only), days 15 and 16 (morning and evening), and day 17

- 102 044284 (morning only) 28-day cycle, for example in cycle 1.

For clarity, it should be noted that, unless otherwise stated, the doses of Compound 1 mentioned herein refer to the amount of Compound 1 in its free base form. In the case where, for example, a pharmaceutically acceptable salt of Compound 1 is used, the above amounts will need to be adapted accordingly.

5.4. Combination therapy with a second active agent.

The solid form or salt of Compound 1 provided herein may also be combined with or used in combination with (e.g., before, during, or after) conventional therapy, including, but not limited to, surgery, biological therapy (including immunotherapy, e.g. with checkpoint inhibitors), radiation therapy, chemotherapy, stem cell transplantation, cell therapy or other non-drug therapy currently used to treat, prevent or cure multiple myeloma. The combined use of a compound presented herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective for some patients. Without being limited by theory, it is believed that the solid form or salt of Compound 1 provided herein may provide additive or synergistic effects when administered concomitantly with conventional therapy.

As discussed elsewhere herein, included herein is a method of reducing, treating, and/or preventing adverse or undesirable effects associated with conventional therapies, including, but not limited to, surgery, chemotherapy, radiation therapy, biological therapy, and immunotherapy. The solid form or salt of Compound 1 provided herein and the other active ingredient may be administered to a patient before, during, or after the occurrence of an adverse effect associated with conventional therapy.

The solid form or salt of Compound 1 provided herein may also be combined or used in combination with other therapeutic agents useful for the treatment and/or prevention of multiple myeloma described herein.

In one embodiment, provided herein is a method of treating, preventing, or managing multiple myeloma, comprising administering to a patient a solid form or salt of Compound 1 provided herein in combination with one or more second active agents and, optionally, in combination with therapy radiation, blood transfusion or surgery.

As used herein, the term combination includes the use of more than one therapy (eg, one or more prophylactic and/or therapeutic agents). However, use of the term in combination does not limit the order in which therapies (eg, prophylactic and/or therapeutic agents) are administered to a patient with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent such as a solid form or salt of Compound 1 provided herein may be administered before (e.g., 5 min, 15, 30, 45 min, 1 hour, 2, 4, 6 , 12, 24, 48, 72, 96 hours, 1 week, 2, 3, 4, 5, 6, 8, or 12 weeks before, simultaneously with, or after (for example, after 5, 15, 30, 45 minutes, 1 hour, 2, 4, 6, 12, 24, 48, 72, 96 hours, 1 week, 2, 3, 4, 5, 6, 8, or 12 weeks) administration of a second therapy (e.g., prophylactic or therapeutic agent) to the subject Triple therapy is also contemplated herein, as is quadruple therapy.In one embodiment of the invention, the second therapy is dexamethasone.

Administration of the solid form or salt of Compound 1 provided herein and one or more second active agents to a patient may occur simultaneously or sequentially by the same or different routes of administration. The suitability of the particular route of administration used for a particular active agent will depend on the active agent itself (eg, whether it can be administered orally without degradation before entering the bloodstream).

The route of administration of the solid or salt form of Compound 1 provided herein is independent of the route of administration of the second therapy. In one embodiment, the solid form or salt of Compound 1 provided herein is administered orally. In another embodiment, the solid form or salt of Compound 1 provided herein is administered intravenously. Thus, in accordance with these embodiments, the solid form or salt of Compound 1 provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally , buccal, intranasal, liposomal, inhalation, vaginal, intraocular, local delivery via catheter or stent, subcutaneous, intrafatty, intra-articular, intrathecal or slow-release dosage form. In one embodiment of the invention, the solid form or salt of Compound 1 provided herein and the second therapy are administered by the same route of administration, orally or intravenously. In another embodiment of the invention, the solid form or salt of Compound 1 provided herein is administered by one route of administration, for example, intravenously, while the second agent (anti-multiple myeloma agent)

- 103 044284 is administered by another route of administration, for example orally.

In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of about 1 to about 1000, about 5 to about 500, about 10 to about 350, or about 50 to 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of multiple myeloma being treated or controlled, the severity and stage of the disease, and the amount of solid or salt form of Compound 1 provided herein and any optional additional active agents simultaneously administered to the patient.

One or more second active ingredients or agents can be used together with the solid form or salt of Compound 1 provided herein in the methods and compositions provided herein. The second active agents may be large molecules (eg, proteins), small molecules (eg, synthetic inorganic, organometallic, or organic molecules), or cellular therapeutic agents (eg, CAR cells).

Examples of second active agents that may be used in the methods and compositions described herein include one or more of the following: melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, obinutuzmab, a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib , oprosomib or marizomib), histone deacetylase inhibitor (eg, panobinostat, ACY241), BET inhibitor (eg, GSK525762A, OTX015, BMS986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 89 4999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy )-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)one, EP11313 and EP11336), BCL2 inhibitor (e.g. venetoclax or navitoclax), MCL-1 inhibitor (e.g. AZD5991, AMG176, MIK665, S64315 or S63845), LSD-1 inhibitor (e.g. ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-aminopiperidin-1-yl)-5 -(3-fluoro-4methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile or its salt), corticosteroid (for example, prednisone), dexamethasone; an antibody (eg, a CS1 antibody such as elotuzumab; an anti-CD38 antibody such as daratumumab or isatuximab; or a BCMA antibody or an antibody conjugate such as GSK2857916 or BI 836909), a checkpoint inhibitor (as described herein), or cells CAR (as described here).

In one embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is dexamethasone.

In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of cycle 1.

In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1.4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 3, 14, and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone

- 104 044284 is administered at a dose of 10 mg on days 1, 3, 14 and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 3, 14, and 17 of cycle 1.

In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 10, 15, and 22 of cycle 1. In certain other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, 11, 15, and 18. -day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 3, 15 and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 3, 14, and 17 of cycle 1.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is bortezomib. In yet another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is daratumumab. In some such embodiments, the methods further comprise administering dexamethasone. In some embodiments, the methods include administering a solid form or salt of Compound 1 provided herein with a proteasome inhibitor described herein, a CD38 inhibitor described herein, and a corticosteroid described herein.

In another embodiment, the second active agent used in conjunction with the solid or salt form of Compound 1 provided in the methods and compositions described herein is panobinostat. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is ACY241. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is vincristine. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided in the methods and compositions described herein is cyclophosphamide. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is etoposide. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid or salt form of Compound 1 provided in the methods and compositions described herein is doxorubicin. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is venetoclax. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is AMG176. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is MIK665. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is GSK525762A. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is OTX015. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid form or salt of Compound 1 provided herein in the methods and compositions described herein is 4-[2-(cyclopropylmethoxy)-5(methanesulfonyl)phenyl] -2-methylisoquinolin-1(2H)-one. In some such embodiments, the methods further comprise administering dexamethasone.

In another embodiment, the second active agent used in conjunction with the solid or salt form of Compound 1 provided in the methods and compositions described herein is 4-[2-(4-aminopiperidin-1 -yl)-5-(3-fluoro -4-methoxyphenyl)-1-methyl-6-oxo-1,6dihydropyrimidin-4-yl]-2-fluorobenzonitrile or a salt thereof (eg besilate salt). In some such embodiments, the methods further comprise administering dexamethasone.

In some embodiments, the solid form or salt of Compound 1 provided herein is administered in combination with immune checkpoint inhibitors. In one embodiment of the invention, one immune checkpoint inhibitor is used in combination with a solid form or salt of Compound 1 provided herein in connection with the methods presented herein. In another embodiment of the invention, two immune checkpoint inhibitors are used in combination with a solid form or salt of Compound 1 provided herein in connection with the methods presented herein. In yet another embodiment, three or more immune checkpoint inhibitors are used in combination with a solid form or salt of Compound 1 provided herein in connection with the methods presented herein.

As used herein, the term immune checkpoint inhibitor or checkpoint inhibitor refers to molecules that completely or partially reduce, inhibit, interfere with, or modulate one or more immune checkpoint proteins. Without being limited to any particular theory, immune checkpoint proteins regulate T cell activation or function. Numerous immune checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). These proteins appear to be responsible for costimulatory or inhibitory interactions of T cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

In one embodiment of the invention, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment of the invention, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in US Pat. Nos. 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human IgG monoclonal antibody that binds to CTLA-4. Ipilimumab is sold under the trade name Yervoy™.

In one embodiment, the immune checkpoint inhibitor is a PD-1/PD-L1 inhibitor. Examples of PD-1/PD-L1 inhibitors include, but are not limited to, those described in US Pat. No. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8217149 and publications of PCT patent applications WO 2003042402, WO 2008156712, WO 2010089411, WO 2010036959, WO 2011066342, WO 2011159877, WO 2011082400 and WO 201116 1699, all of which are incorporated herein in their entirety.

In one embodiment of the invention, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment of the invention, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody

- 106 044284 is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558 or MDX1106) or pembrolizumab (also known as MK-3475, SCH 900475 or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 monoclonal antibody against PD-1 and is marketed under the brand name Opdivo™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized IgG4 monoclonal antibody marketed under the brand name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is a humanized CT-011 antibody. CT-011, administered alone, showed no response in the treatment of relapsed acute myeloid leukemia (AML). In yet another embodiment, the anti-PD-1 antibody is an AMP-224 fusion protein. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody that is specifically engineered to bind Fc gamma receptor I and has a unique PD-1 binding signature with high affinity and excellent target specificity.

In one embodiment of the invention, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment of the invention, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and Tecentriq®).

In one embodiment of the invention, the immune checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment of the invention, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment of the invention, the anti-PDL2 antibody is rHIgM12B7A.

In one embodiment of the invention, the immune checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment of the invention, the LAG-3 inhibitor is BMS-986016.

In one embodiment of the invention, the immune checkpoint inhibitors are a B7 inhibitor. In one embodiment of the invention, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-I3 inhibitor is MGA271, an anti-B7-I3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).

In one embodiment of the invention, the immune checkpoint inhibitors are a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).

In one embodiment of the invention, the immune checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment of the invention, the immune checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is an anti-OX-40 antibody. In another embodiment, the anti-OX40 antibody is MEDI6469.

In one embodiment of the invention, the immune checkpoint inhibitor is a GITR agonist. In one embodiment of the invention, the immune checkpoint inhibitor is an anti-GITR antibody. In one embodiment of the invention, the anti-GITR antibody is TRX518.

In one embodiment of the invention, the immune checkpoint inhibitor is a CD137 agonist. In one embodiment of the invention, the immune checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

In one embodiment of the invention, the immune checkpoint inhibitor is a CD40 agonist. In one embodiment of the invention, the immune checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

In one embodiment of the invention, the immune checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

In one embodiment of the invention, the immune checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment of the invention, the IDO inhibitor is

- 107 044284 is indoximod.

In some embodiments, the combination therapies provided herein include two or more immune checkpoint inhibitors described herein (including immune checkpoint inhibitors of the same or a different class). Moreover, the combination therapies described herein can be used in combination with one or more second active agents, as described herein, where appropriate for the treatment of diseases described herein and understood in the art.

In some embodiments, a solid form or salt of Compound 1 provided herein may be used in combination with one or more immune cells expressing one or more chimeric antigen receptors (CARs) on their surface (eg, a modified immune cell). Typically, CARs include an extracellular domain of a first protein (eg, antigen binding protein), a transmembrane domain, and an intracellular signaling domain. In some embodiments, once the extracellular domain binds to a target protein, such as tumor associated antigen (TAA) or tumor specific antigen (TSA), a signal is generated via the intracellular signaling domain that activates the immune cell, for example, to target and kill the cell expressing the target protein.

Extracellular Domains: The extracellular domains of CARs bind to the antigen of interest. In some embodiments, the extracellular domain of the CAR includes a receptor or portion of a receptor that binds to the antigen. In some embodiments, the extracellular domain includes or represents an antibody or an antigen-binding portion thereof. In certain embodiments, the extracellular domain comprises or is a single chain Fv(scFv) domain. A single chain Fv domain may include, for example, a _VL linked to a VH by a flexible linker, wherein said VL and VH are derived from an antibody that binds the antigen.

In some embodiments, the antigen recognized by the extracellular domain of a polypeptide described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor associated antigen or tumor specific antigen is, without limitation, Her2, prostate stem cell antigen (PSCA), alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125 ), CA19-9, calretinin, MUC-1, B-cell maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-associated antigen-24 (MAGE), CD19, CD22, CD27, CD30, CD34, CD45, CD70, CD99, CD117, EGFRvIII (epidermal growth factor III variant), mesothelin, PAP (prostate acid phosphatase), prostein, TARP (T cell alternative reading frame protein), Trp- p8, STEAPI (six transmembrane epithelial antigen of prostate 1), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), liquid macrogenic cystic disease protein (GCDFP-15), HMB-45 antigen, melan-A protein (melanoma antigen recognized T-lymphocytes; MART-I), myo-DI, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, dimeric form of pyruvate kinase isoenzyme type M2 (tumor M2-PK), abnormal ras protein or abnormal p53 protein. In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is αΎβ3 integrin (CD61), galactin, or Ral-B.

In some embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a cancer/testis antigen (CT), e.g., BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ES0-1, NY-SAR-35, OY-TES-1, SPANXBI, SPA17, SSX, SYCPI or TPTE.

In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a carbohydrate or ganglioside, for example, fuc-GMI, GM2 (oncofetal antigen-immunogenic-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, etc.

In some other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, beta-catenin, CA 125, CA 15-3 (CA 27.29YBCAA), CA 195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-1, dek-can fusion protein, EBNA, EF2, Epstein-Barr virus antigens, ETV6- AML1 fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAA0205, Mart2, Mum-1, 2 and 3, neo-PAP, class I myosin, OS-9, pml-RARa fusion protein, PTPRK, K- ras, N-ras, triosephosphate isomerase, Gage 3,4,5,6,7, GnTV, HervK-mel, Lage-1, NA-88, NY-Eso-1/Lage-2, SP17, SSX-2, TRP2 -M2, gp100 (Pmel17), tyrosinase, TRP-1, TRP2, MAGE-1, MAGE-3, RAGE, GAGE-1, GAGE-2, p15 (58), RAGE, SCP-1, Hom/Mel-40 , PRAME, p53, HRas, HER-2/neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, human papillomavirus (HPV) E6 and E7 antigens, TSP-180, MAGE-4, MAGE- 5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72- 108 044284

4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-race, 13-Catenin, Mom-1, p16, TAGE, P SMA, CT7, telomerase,

43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68/KP1, C0-029, FGF-5, G250, Ga733 (EpCAM), HTgp175, M344, MA-50, MG7-Ag, MOV18, NB/70K , NY-C0-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72,

TLP or TPS.

In various specific embodiments, the tumor-associated antigen or tumor-specific antigen are tumor antigens associated with AML, as described in S. Anguille et al., Leukemia (2012), 26, 2186-2196.

Other tumor-associated and tumor-specific antigens are known to those skilled in the art.

Receptors, antibodies and scFvs that bind to TSA and TAA useful for constructing chimeric antigen receptors are known in the art as the nucleotide sequences that encode them.

In some specific embodiments, the antigen recognized by the extracellular domain of the chimeric antigen receptor is an antigen that is not typically considered a TSA or TAA, but that is nonetheless associated with tumor cells or tumor-induced damage. In some embodiments, for example, the antigen is, for example, a growth factor, cytokine or interleukin, for example, a growth factor, cytokine or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines or interleukins may include, for example, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF) or interleukin -8(IL-8). Tumors can also create a local hypoxic environment. Thus, in other specific embodiments, the antigen is a hypoxia-associated factor, for example, HTF-1a, HTF-1e, HTF-2a, HIF-2e, HTF-3a, or HTF-3e. Tumors can also cause local damage to normal tissue by causing the release of molecules known as damage-associated molecular pattern molecules (DAMPs; also known as alarmins). Therefore, in some other specific embodiments, the antigen is a DAMP, e.g., heat shock protein, chromatin-associated protein, high mobility group box 1 (FDVIGB 1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B ), serum amyloid A(SAA), or may be deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparin sulfate.

Transmembrane domain: In some embodiments, the extracellular domain of the CAR is attached to the transmembrane domain of the polypeptide via a linker, spacer, or hinge polypeptide sequence, such as a CD28 sequence or a CTLA4 sequence. The transmembrane domain may be derived from or derived from the transmembrane domain of any transmembrane protein and may include all or part of such transmembrane domain. In specific embodiments of the invention, the transmembrane domain may be derived from, for example, CD8, CD16, cytokine receptor and interleukin receptor, or growth factor receptor or the like.

Intracellular Signaling Domains: In some embodiments, a CAR intracellular domain is or includes an intracellular domain or protein motif that is expressed on the surface of T cells and triggers the activation and/or proliferation of said T cells. Such a domain or motif is capable of transmitting the primary antigen-binding signal, which is necessary for T-lymphocyte activation in response to antigen binding to the extracellular part of the CAR. Typically this domain or motif includes or is an ITAM (immunoreceptor tyrosine activation motif). ITAM-containing polypeptides suitable for CAR include, for example, CD3 zeta chain (CD3Z or ITAM-containing portions thereof. In a particular embodiment, the intracellular domain is a CD3Z intracellular signaling domain. In other specific embodiments, the intracellular domain is derived from a receptor chain lymphocytes, a TCR/CD3 complex protein, an Fe receptor subunit, or an IL-2 receptor subunit. In some embodiments, the CAR further comprises one or more costimulatory domains or motifs, for example, as part of an intracellular domain of a polypeptide. The one or more costimulatory domains or motifs may contain or may be one or more CD27 costimulatory polypeptide sequences, CD28 costimulatory polypeptide sequences, OX40 costimulatory polypeptide sequence (CD134), co-stimulatory polypeptide sequence 4-1BB (CD137) or costimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence, or another co-stimulatory domain or motif, or any combination thereof.

CAR may also contain a T cell survival motif. A T cell survival motif can be any polypeptide sequence or motif that promotes the survival of a T lymphocyte following antigen stimulation. In some embodiments, the T cell survival motif is or is derived from CD3, CD28, intracellular signaling

- 109 044284 IL-7 receptor (IL-7R) domain, IL-12 receptor intracellular signaling domain, IL-15 receptor intracellular signaling domain, IL-21 receptor intracellular signaling domain, or transforming growth factor β (TGFP) receptor intracellular signaling domain.

Modified immune cells expressing CARs may be, for example, T lymphocytes (T cells, e.g. CD4+T cells or CD8+T cells), cytotoxic lymphocytes (CTL) or natural killer (NK) cells. The T lymphocytes used in the compositions and methods provided herein can be naïve T lymphocytes or MHC-restricted T lymphocytes. In some embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In some embodiments, T lymphocytes were isolated from a tumor biopsy or were expanded from T lymphocytes isolated from a tumor biopsy. In some other embodiments, T cells have been isolated or expanded from T lymphocytes isolated from peripheral blood, umbilical cord blood, or lymph. Immune cells to be used to generate modified CAR-expressing immune cells can be isolated using conventional methods well known in the art, such as blood collection followed by apheresis and, optionally, antibody-mediated cell isolation or sorting.

The modified immune cells are preferably autologous to the individual to whom the modified immune cells are to be administered. In some other embodiments, the modified immune cells are allogeneic to the individual to whom the modified immune cells are to be administered. If allogeneic T lymphocytes or NK cells are used to produce engineered T lymphocytes, it is preferable to select T lymphocytes or NK cells that will reduce the likelihood of graft-versus-host disease (GVHD) in the individual. For example, in some embodiments, virus-specific T lymphocytes are selected to produce modified T lymphocytes; such lymphocytes are expected to have a significantly reduced natural ability to bind to and thus be activated by any recipient antigens. In some embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by coadministration of one or more immunosuppressive drugs, such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, or the like, to the host.

T lymphocytes, such as unmodified T lymphocytes or T lymphocytes expressing CD3 and CD28, or containing a CD3Z signaling domain-containing polypeptide and a CD28 co-stimulatory domain, can be expanded using antibodies to CD3 and CD28, e.g. balls; see, for example, US Patent Nos. 5,948,893; 6,534,055; 6,352,694; 6,692,964; 6,887,466; and 6,905,681.

Modified immune cells, such as modified T lymphocytes, may optionally contain a suicide gene or safety switch that allows virtually all modified immune cells to be killed if desired. For example, the modified T lymphocytes in some embodiments may contain the HSV thymidine kinase (HSV-TK) gene, which causes the modified T lymphocytes to die when exposed to ganciclovir. In another embodiment, the modified T lymphocytes contain an inducible caspase, for example, inducible caspase 9 (icaspase9), for example, a fusion protein between caspase 9 and human binding protein FK506, allowing dimerization using a specific small molecule pharmaceutical. See Straathof et al., Blood 1 05(11):4247-4254 (2005).

In some embodiments, the solid form or salt of Compound 1 provided herein is administered to patients with various types or stages of multiple myeloma in combination with chimeric antigen receptor (CAR) T cells. In some embodiments, the CAR T cell in combination targets B-cell maturation antigen (BCMA), and in more specific embodiments, the CAR T cell is bb2121 or bb21217. In some embodiments, the CAR T cell is JCARH125.

5.5. Pharmaceutical compositions.

The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more compounds provided herein, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

The compounds may be formulated as suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or as sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patches and dry powder inhalers. Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts are mixed with a suitable pharmaceutical carrier or excipient. In some embodiments, the concentrations of the compounds in the compositions are effective to deliver an amount when administered that treats, prevents, or alleviates one or more symptoms and/or progression of multiple myeloma.

Typically the compositions are formulated for single dose administration. To formulate the composition, a mass fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the condition being treated is alleviated or improved. Pharmaceutical carriers or carriers suitable for administration of the compounds presented herein include any such carriers known to those skilled in the art as suitable for the particular route of administration.

In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in a composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. They can be prepared by methods known to those skilled in the art. For example, liposome compositions can be prepared by methods known in the art. Briefly, liposomes such as multilayer vesicles (MLVs) can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) inside a flask. Add a solution of the compound provided herein in divalent cation-free phosphate buffered saline (PBS) and shake the flask until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation and then resuspended in PBS.

The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to provide a therapeutically beneficial effect without causing undesirable side effects in the patient being treated. The therapeutically effective concentration can be determined empirically by testing compounds in the in vitro and in vivo systems described herein and then extrapolated from there to human dosages.

The concentration of the active compound in the pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, metabolism and elimination of the active compound, the physicochemical characteristics of the compound, the dosage regimen and amount administered, as well as other factors known to those skilled in the art. For example, the amount delivered is sufficient to relieve one or more symptoms of cancer, including solid tumors and blood-borne tumors.

Solutions or suspensions used for parenteral, intradermal, subcutaneous or topical use may include any of the following: a sterile diluent such as water for injection, saline, fatty oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents such as benzyl alcohol and methylparabens; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates and phosphates; and tone-regulating agents such as sodium chloride or dextrose. Formulations for parenteral administration may be contained in ampoules, pens, disposable syringes, or single-dose or multiple-dose vials made of glass, plastic, or other suitable material.

In cases where compounds exhibit insufficient solubility, methods for solubilizing the compounds can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), the use of surfactants such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

When the compound(s) are mixed or added, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a number of factors, including the intended route of administration and the solubility of the compound in the chosen vehicle or base. The effective concentration is sufficient to relieve the symptoms of the disease, disorder or condition being treated and can be determined empirically.

The pharmaceutical compositions are intended for administration to humans and animals in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-in-water emulsions, containing suitable amounts of the compounds or their pharmaceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in single dosage forms or multiple dosage forms. Unit dose forms used herein refer to physically discrete units suitable for human and animal administration and packaging.

- 111 044284 individually forged, as is known in the art. Each unit dose contains a predetermined amount of a therapeutically active compound sufficient to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier, carrier or diluent. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dose forms can be administered in fractional or multiple doses. A multiple-dose form is a plurality of identical unit dosage forms packaged in a single container for administration in separate unit dosage forms. Examples of multiple dose forms include vials, tablet or capsule bottles, or pint or gallon bottles. Therefore, a multiple dose form is a plurality of unit doses that are not separated within the package.

Dosage forms or compositions can be prepared containing the active ingredient in the range of 0.005 to 100%, with the balance being a non-toxic carrier. For oral administration, a pharmaceutically acceptable non-toxic composition is prepared by including any of the commonly used excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starches, magnesium stearate, talc, cellulose derivatives, crosscarmellose sodium, glucose, sucrose, magnesium carbonate or sodium saccharin . Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable, biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparing these compositions are known to those skilled in the art.

The active compounds or pharmaceutically acceptable salts can be formulated with carriers that protect the compound from rapid elimination from the body, such as sustained release formulations or coatings.

The compositions may include other active compounds to provide the desired combinations of properties. The compounds provided herein, or their pharmaceutically acceptable salts described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be valuable in the treatment of one or more of the diseases or medical conditions in question. speech as above, such as diseases associated with oxidative stress. It should be understood that such combination therapy constitutes an additional aspect of the compositions and methods of treatment presented herein.

6. Examples

Some embodiments of the invention are illustrated by the following non-limiting examples.

6.1. Synthesis of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl) -3-fluorobenzonitrile (compound 1).

ABOUT

tert-Butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate. To a solution of (2S)-2(benzyloxycarbonylamino)-5-tert-butoxy-5-oxopentanoic acid (150 g, 445 mmol) in 1,4-dioxane (1.50 L) was added di-tert-butyl dicarbonate (155 g , 711 mmol), pyridine (70.3 g, 889 mmol) and ammonium bicarbonate (105 g, 1.33 mol). The reaction mixture was stirred at 18°C for 16 hours and then concentrated. The residue was dissolved in ethyl acetate (5.0 L) and water (5.0 L), the organic layer was separated and washed with HCl (3.0 ml, 1 N), saturated sodium bicarbonate (3.0 L), brine (3. 0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give crude tert-butyl (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate (450 g, crude) as a white solid, which was used in the next step without additional cleaning. 1H NMR 400 MHz DMSO-d ₆ δ: 7.35-7.30 (m, 5H), 7.02 (s, 1H), 5.01 (d, J=3.2 Hz, 1H), 3, 93-3.90 (m, 1H), 2.20 (t, J=8.0 Hz, 2H), 1.88-1.84 (m, 1H), 1.72-1.69 (m, 1H), 1.35 (s, 9H).

tert-Butyl (4S)-4,5-diamino-5-oxopentanoate. To a solution of tert-butyl (4S)-5-amino-4(benzyloxycarbonylamino)-5-oxopentanoate (112 g, 333 mmol) in methanol (1.0 L) was added 10% palladium on carbon (15 g) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under an atmosphere of hydrogen gas (40 psi) at 30°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude tert-butyl (4S)-4,5diamino-5-oxopentanoate as a colorless oil. ¹ H NMR 400 MHz DMSO-d ₆ δ: 7.30 (s, 1H), 6.95 (s, 1H), 3.10-3.07 (m, 1H), 2.27-2.23 ( m, 2H), 1.69-1.78 (m, 1H), 1.59-1.55 (m, 1H), 1.38 (s, 9H).

- 112 044284

Methyl 3-hydroxy-2-methylbenzoate. Four batches (200 g each) were processed in parallel. To a solution of 3-hydroxy-2-methylbenzoic acid (200 g, 1.31 mol) in methanol (4.0 L) was added concentrated sulfuric acid (47.7 g, 486 mmol). The reaction mixture was stirred at 60°C for 17 hours. The reaction mixture was concentrated to 800 ml. The resulting mixture was cooled to 20°C and slowly poured into water (400 ml) over 30 minutes. Water (1200 ml) was added at 20°C for 3 hours and the resulting mixture was stirred at 20°C for 1 hour. The precipitated solid was collected by vacuum filtration (four batches combined) and washed three times with water/methanol (1000 ml, 9: 1) or until the filtrate reaches pH>3. The solid was dried in vacuo at 45°C to give methyl 3-hydroxy-2-methyl benzoate (700 g, 80.4% yield) as a gray solid. 1H NMR: 400 MHz DMSO-d ₆ δ: 9.70 (s, 1H), 7.18 (t, J=6.8 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H ), 7.00 (t, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H).

Methyl 3-[tert-butyl(dimethyl)silyl]oxy-2-methylbenzoate. Two batches (240 g each) were processed in parallel. To a solution of methyl 3-hydroxy-2-methylbenzoate (240 g, 1.44 mol) in N,Ndimethylformamide (1.40 L) was added imidazole (246 g, 3.61 mol) and tert-butyldimethylsilyl chloride (238 g, 1 .58 mol) at 5°C. After addition, the mixture was heated to 20°C and stirred for 6 hours. Isopropyl acetate (1700 ml) was added and then water (2000 ml) was added slowly, maintaining the temperature below 30°C. The resulting mixture was stirred, followed by separation of the organic phase. The combined organic layers (two batches combined) were washed with water (1700 mlx3) and concentrated to ~1500 ml (KF < 0.05%). The product was stored as an isopropyl acetate solution, which was used in the next step without further purification.

Methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxybenzoate. Two batches (~375 g each) were processed in parallel. N-bromosuccinimide (274 g, 1.54 mol) and azobisisobutyronitrile (4.40 g, 26 .8 mmol). The reaction mixture was heated to 70°C for at least 1 hour and stirred at 70°C for 4 hours. The reaction mixture was cooled to 20°C and kept at 20°C for at least 1 hour. Two batches of the solid (succinimide) were removed filtration and washed with isopropyl acetate (700 ml). The filtrate is washed with a saturated solution of sodium sulfite (700 g) in water (6000 ml), then with water (1500 ml). The organic layer was distilled in vacuo at 45°C to dryness to obtain methyl 2(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxybenzoate (920 g, 95.5% yield) as a dark orange oil. ^1H NMR: 400 MHz DMSO-d6 δ: 7.45 (d, J=6.8 Hz, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.13 (t, J =7.2 Hz, 1H), 4.95 (s, 2H), 1.02 (s, 9H), 0.29 (s, 6H).

tert-Butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxoisoindolin-2-yl]-5oxopentanoate. To a solution of tert-butyl (4S)-4,5-diamino-5-oxopentanoate (130 g, 643 mmol) in acetonitrile (4.0 L) was added methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl) silyl]oxybenzoate (210 g, 584 mmol) and diisopropylethylamine (113 g, 877 mmol). The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated to remove most of the acetonitrile, the residue was dissolved in methyl tert-butyl ether (2.0 L) and water (1.5 L), the organic layer was washed with saturated monophosphate potassium (1.0 Lx2), brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give crude tert-butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl )silyl]oxy1-oxoisoindolin-2-yl]-5-oxopentanoate (524 g), which was used in the next step without further purification.

tert-Butyl (4S)-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of tert-butyl (4S)-5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxoisoindolin-2-yl]-5-oxopentanoate (275 g, 613 mmol) in methanol (2 .0 L) tetrabutylammonium fluoride trihydrate (38.7 g, 123 mmol) was added. The mixture was stirred at 18°C for 16 hours. The reaction mixture was concentrated to remove most of the methanol, and the residue was dissolved in dichloromethane/water (3 L/2 L). The organic layer was separated and washed with brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by a silica gel column to give the product (260 g). The product was added to acetonitrile (750 ml) and the mixture was stirred at 60°C for 2 hours, cooled to 18°C and stirred for a further 2 hours. The solid was filtered and the precipitate was dried to give tert-butyl (4S)-5amino-4 -(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (248 g, 60.5% yield) as a gray solid. 1H NMR 400 MHz DMSO-d ₆ δ: 10.00 (s, 1H), 7.54 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.14 (d, J=4.8 Hz, 2H), 4.72-4.68 (m, 1H), 4.49-4.28 (m, 2H), 2.17-1.97 (m, 4H), 1 .31(s,9H).

4-(4-(4-(Chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 1,4-bis(chloromethyl)benzene (51.2 g, 292 mmol) was placed in a flask with acetonitrile (195 ml) and N,N-dimethylformamide (195 ml). The reaction mixture was stirred at ambient temperature until all solids had dissolved. Diisopropylamine (51.1 mL, 292 mmol) was then added along with 3-fluoro-4-(piperazin-1-yl)benzonitrile (20 g, 97 mmol). The reaction mixture was heated to 60°C for 1 hour. Acetonitrile was removed under reduced pressure. The remaining mixture was partitioned between ethyl acetate (1.0 L), water (700 ml) and brine (300 ml). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. Volatile organic compounds were combined and removed under reduced pressure. The solid was dissolved

- 113 044284 in a minimal amount of dichloromethane and purified on a silica gel column (0-100% ethyl acetate in hexane, more than 3 l). Fractions containing the desired product were combined and volatile organic compounds were removed under reduced pressure. The residue was dissolved in a minimal amount of dichloromethane and purified a second time on a silica gel column (10% isocratic ethyl acetate in hexane over 800 ml, then 20-80% ethyl acetate in hexane over 4 L). Fractions containing the desired product were combined and VOCs were removed under reduced pressure to give 4-(4-(4(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (22.7 g, 66.0 mmol, yield 67.7%) as an off-white solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.33-7.39 (m, 5H) 7.29 (d, J=1.96 Hz, 1H) 7.25 (d, J=1.96 Hz , 1H) 6.91 (t, J=8.56 Hz, 1H) 4.60 (s, 2H) 3.58 (s, 2H) 3.19-3.27 (m, 4H) 2.58- 2.66 (m, 4H). MS (ESI) m/z 344.2 [M+1]+.

(S)-tert-butyl-5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1oxoisoindoline-2 -yl)-5-oxopentanoate. (S)-tert-Butyl-5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)5-oxopentanoate (22.05 g, 65.9 mmol) was placed in a flask with 4-(4- (4-(chloromethyl)benzyl)piperazin-1-yl)-3fluorobenzonitrile (22.67 g, 65.9 mmol), potassium carbonate (18.23 g, 132 mmol) and N,Ndimethylformamide (330 ml). The reaction mixture was heated to 45°C for 16 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and filtered. The filtrate was partitioned between ethyl acetate (900 ml), water (600 ml) and brine (200 ml). The organic layer was separated and washed with water (600 ml). The organic layer was dried over sodium sulfate and volatiles were removed under reduced pressure. The residue was treated with 20% ethyl acetate in hexane and the volatiles were removed under reduced pressure to give (S)-tert-butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazine -1yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (44.02 g, 68.6 mmol, 104% yield) as an off-white solid. The yield was slightly higher than quantitative because some DMF remained. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 7.43-7.49 (m, 2H) 7.40 (s, 4H) 7.36 (dd, J=8.38, 1.28 Hz, 1H) 7.29 (d, J=1.96 Hz, 1H) 7.26 (d, J=1.83 Hz, 1H) 7.11 (dd, J=7.64, 1.16 Hz, 1H) 6 .92 (t, J=8.50 Hz, 1H) 6.23 (br s, 1H) 5.24-5.32 (m, 1H) 5.15 (s, 2H) 4.86-4.94 (m, 1H) 4.38-4.55 (m, 2H) 3.61 (s, 2H) 3.18-3.32 (m, 4H) 2.58-2.70 (m, 4 H) 2.09-2.47 (m, 4H) 1.43 (s, 8H). MS (ESI) m/z 642.4 [M+1] ⁺ .

(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin1-yl)-3- fluorobenzonitrile (compound 1). (S)-tert-butyl-5-amino-4-(4-((4-((4-(4-cyano-2fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindoline-2 -yl)-5-oxopentanoate (12.1 g, 18.86 mmol) was placed in a vial with acetonitrile (189 ml) and benzenesulfonic acid (3.96 g, 24.51 mmol). The reaction mixture was placed under vacuum and purged with nitrogen. This was repeated once more and then the mixture was heated to 85° C. overnight under a nitrogen atmosphere. The warm reaction mixture was poured directly into 2 separatory funnels containing dichloromethane (1000 ml) and ethyl acetate (300 ml). To this mixture were added saturated sodium bicarbonate solution (900 ml), water (100 ml) and brine (450 ml). The organic layer was isolated and the aqueous layer was extracted with dichloromethane (800 ml) and ethyl acetate (200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. Purification by standard methods yielded the title compound. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.96 (s, 1H) 7.68 (dd, J=13.45, 1.83 Hz, 1H) 7.56 (dd, J=8, 44, 1.83 Hz, 1H) 7.43-7.52 (m, 3H) 7.29-7.39 (m, 4H) 7.11 (t, J=8.80 Hz, 1 H) 5 .24 (s, 2H) 5.11 (dd, J=13.20, 5.14 Hz, 1H) 4.22-4.46 (m, 2H) 3.54 (s, 2H) 3.12- 3.22 (m, 4H) 2.85-2.97 (m, 1H) 2.53-2.62 (m, 2H) 2.38-2.48 (m, 2H) 1.93-2, 03 (m, 1H). MS (ESI) m/z 568.2 [M+1] ⁺ .

Recrystallization to give form K of compound 1. (S)-4-(4-(4-(((2-(2,6-dioxopiperidin3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine -1-yl)-3-fluorobenzonitrile was dissolved in acetone (35 L/kg) and filtered to increase chiral purity. The filtrate was passed through a 0.45 μm filter into a clean reactor. After distillation (target volume 15 L/kg), water (2 L/kg) was added to create supersaturation. The batch was inoculated with form K and kept at constant temperature with wet grinding through a recirculation loop at 40°C. Water (6 L/kg) was loaded at a constant rate of 1 (L/kg)/h during wet grinding at a reduced tip speed. The batch was cooled to 25°C and then kept for 3 hours. The batch was filtered, washed and dried. Wet aging was performed followed by grinding to form (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazine -1-yl)-3-fluorobenzonitrile as form K. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.96 (s, 1H) 7.68 (dd, J=13.45, 1.83 Hz, 1 H) 7.56 (dd, J=8.44, 1.83 Hz, 1H) 7.437.52 (m, 3H) 7.29-7.39 (m, 4H) 7.11 (t, J=8.80 Hz, 1H) 5.24 (s, 2H) 5.11 (dd, J=13.20, 5.14 Hz, 1H) 4.22-4.46 (m, 2H) 3 .54 (s, 2H) 3.12-3.22 (m, 4H) 2.85-2.97 (m, 1H) 2.53-2.62 (m, 2H) 2.38-2.48 (m, 2H) 1.93-2.03 (m, 1H). MS (ESI) m/z 568.2 [M+1] ⁺ .

6.2. Antiproliferative effects in multiple myeloma.

Cell culture materials: Human multiple myeloma cell lines were purchased from suppliers and cultured at 37°C with 5% CO2 in medium as indicated in Table 1. 1. Lenalidomide- and pomalidomide-resistant cell lines were generated by methods as generally described previously (Lopez-Girona et al., Leukemia 2012; 26(11): 2335). All cell lines were maintained in log phase and cell density and viability were monitored by trypan blue exclusion

- 114 044284 using a Vicell XR Cell Viability Analyzer (Beckman Coulter, Brea, CA).

Table 1 _____Multiple myeloma cell lines tested____

Cell line MM NCI-H929 Supplier/Source ATCC (Manassas, VA) Catalog number CRL-9068 Cultivation conditions RPMI-1640, 10% FBS NCI-H929-1051 developed in-house, resistant to lenalidomide nd RPMI-1640, 10% FBS ORM2 DSMZ (Braunschweig, Germany) ACC-50 RPMI-1640, 10% FBS ORM2-R10 developed in-house, pomalidomide resistance 10 µM nd RPMI-1640, 10% FBS

Preparation of test drug solutions: Compound 1 was plated in black 384-well plates (Corning Inc.) to a final volume of 0.1% DMSO, assuming a maximum volume of 50 μL. A 10-point dose-response starting at 10 μM with a 1:3 dilution was printed in duplicate by acoustic dispensing using the EDC ATS-100 platform. Alternatively, a 10-point dose response was used, starting at 10 μM at a 1:10 dilution or starting at 100 nM at a 1:3 dilution.

Cell Proliferation Assays: The effect of Compound 1 on the proliferation/viability of hematological cell lines (Table 1) was assessed after 120 h of incubation using CTG (Promega) according to the manufacturer's instructions. Hematology cell lines were dispensed into compound plates using a Multidrop Combi Reagent Dispenser (Thermo Scientific, Waltham, MA) at a concentration of 0.1 x 10 ⁶ cells per ml in a total volume of 50 μl. After 120 h, 25 μl of CTG per well was dispensed using a Multidrop Combi Reagent Dispenser, and adenosine triphosphate (ATP) release from viable cells was measured as relative luminescence units after 30 min using the Envision platform.

Results.

Compound 1 demonstrates antiproliferative activity against MM cell lines. The MM cell lines selected for this study were those sensitive and resistant to lenalidomide and/or pomalidomide (Table 1), two agents approved for the treatment of patients with myeloma. Proliferation was assessed using the CellTitre-Glo® test. Results for cultures incubated with Compound 1 were normalized to results for control cultures for each cell line. The IC ₅₀ for cell growth inhibition by Compound 1 was determined for each cell line using ActivityBase software. Compound 1 strongly inhibited cell proliferation in four-cell lines, as determined by quantifying the levels of ATP present in the medium after 120 hours. The antiproliferative IC ₅₀ values of Compound 1 ranged from 0.07 to 4.3 nM (Table 2). Compound 1 showed very potent antiproliferative activity against multiple myeloma, even against cell lines resistant to lenalidomide and/or pomalidomide.

table 2

Inhibition of cell growth by compound 1 in MM cell lines in liquid culture

Conn. No. NCI-H929 120h IC 50 NCI-H929.1051 120h IC50 ORM-2 120h 1S ₅ o ORM-2.R10 120h IC50 1 0.07 nM 1.0 nM 0.07 nM 4.3 nM

6.3. Off-target effects of compound 1.

α1-Adrenergic receptors and dopamine D2 receptors.

Methods.

Binding and functional assays for α1-adrenergic and dopamine D2 receptors were performed by Eurofins Cerep according to their methods.

a1-Adrenergic receptor. Binding at 10 µM. The binding assay assessed the affinity of the test drug for the non-selective α1-adrenergic receptor in the rat cerebral cortex. Membrane homogenates of the cerebral cortex were incubated in duplicate for 60 min.

- 115 044284 at room temperature with 0.25 nM [ ³ H]prazosin in the absence or presence of test samples at 10 μM. After the incubation period, the samples were filtered through glass fiber filters, the filters were dried and then the radioactivity was counted using a scintillation counter. Results are expressed as the average percentage inhibition of control radioligand binding.

IC ₅₀ binding. To determine the IC ₅₀ of non-selective α1-adrenergic receptor binding, various concentrations of the test substance were incubated in duplicate with 0.25 nM [ ³ H]prazosin. The compound 3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidin-2,6-dione was previously reported (Example 5,285 in US Pat. No. 8,518,972) (Compound A) was tested at 0.01-30 µM. Compound B, the S-enantiomer of Compound A, was tested at 0.0003-10 µM. Compound 1 was analyzed at 0.03-100 µM. Radioactivity was measured as described above. IC ₅₀ was defined as the concentration causing half inhibition of control specific binding.

Antagonistic activity. The antagonistic effects of test compounds on a _1A and a _1B adrenergic receptors were measured using human receptor-transfected Chinese hamster ovary (CHO) cells. Antagonist activity was determined by measuring the effect of the compound on agonist (epinephrine)-induced calcium mobilization in the α _1A receptor assay or cAMP levels in the α _1B receptor assay. In these experiments, CHO cells were incubated in duplicate at room temperature with the test substance and epinephrine at 3 nM in the α _1A receptor assays or at 3000 nM in the α _1B receptor assay. Compound A was tested in the a _1A receptor assay at 0.01-30 μM. Compound B was tested in the a _1A and a _1B receptor assays at 0.000330 μM. Compound 1 was assayed at concentrations ranging from 0.03 to 30 μM in the α _1A receptor assay and from 0.03 to 100 μM in the α _1B receptor assay. In the a _1A receptor assay, cytosolic calcium levels were measured fluorometrically using the Fluo4 Direct fluorescent probe. Intracellular cAMP levels in the adrenergic receptor a _1B assay were measured using homogeneous time-resolved fluorescence (HTRF). The IC ₅₀ of antagonism was defined as the concentration that caused half the response of the control agonist.

Dopamine D2 receptor. Binding at 10 µM. The binding assay assessed the affinity of the test samples for the dopamine D2 receptor in transfected human embryonic kidney (HEK)-293 cells. To determine binding in the D _2S receptor assay, the test product was incubated with 0.3 nM [ ³ H]methylspiperone or 1 nM [ ³ H]7-hydroxy-2-N,N-dipropylaminotetralin (7-OHDPAT). [ ³ H]methylspiperone at a concentration of 0.3 nM was also used as a control ligand in the D _2L binding assay. Cell membrane homogenates were incubated in duplicate at room temperature for 60 min with ligand in the absence or presence of test samples at 10 μM. After the incubation period, the samples were filtered through glass fiber filters, the filters were dried and then the radioactivity was counted using a scintillation counter. Results are expressed as the average percentage inhibition of control radioligand binding.

IC ₅₀ binding. To determine IC ₅₀ binding in D2 receptor assays, HEK-293 was tested as described above, but with different concentrations of the test substance. Compound A was tested at 0.01-30 μM in a D _2S radioligand binding assay. Compound B was tested at 0.0003-10 μM in D _2S and D _2L binding assays. Compound 1 was tested at 0.03-100 µM in the D _2S assay and 0.01-100 µM in the D _2L assay. IC ₅₀ was defined as the concentration causing half inhibition of control specific binding.

Agonistic activity. The agonism of test compounds at the dopamine D _2S receptor was assessed using HEK-293 cells transfected with the human receptor. Agonist activity was determined by measuring the effect of the compound on impedance modulation. In these experiments, HEK-293 cells were incubated in duplicate at 28°C with the test article. Compound A was tested at 0.01-30 µM. Compound B was tested at 0.0003-10 μM, while Compound 1 was tested at 0.01-10 μM. Dopamine (3 μM) was used as an agonist control. Impedance measurements were monitored for 10 min after ligand addition using cellular dielectric spectroscopy. EC ₅₀ was defined as the concentration causing half the maximal response compared to the response to the control agonist (dopamine).

Results. Binding at 10 μM at α1 adrenergic receptors and dopamine D2 receptors was assessed for Compound 1, Compound A, Compound B, and a number of compounds exemplified in U.S. Patent No. 8,518,972 (as indicated by their example number pr.) (Table 3). While previously disclosed compounds completely inhibited ligand binding at both receptors, surprisingly, compound 1 showed a significantly reduced ability to inhibit ligand binding, showing only 67/62% (a1-adrenergic receptor) and 55/52% (dopamine D _2S ) binding inhibition ligand, respectively.

- 116 044284

Table 3

Effect of Compound A, Compound B, Compound 1 and Previously Described Compounds on the α1 Adrenergic Receptor and the Dopamine D2 Receptor

Conn. No. R ¹ R ² X Stereo Adrenergic "1 Dopamine D _2s % Ing. (@10 µM) % Ing. (@10 µM) 1 CN F dn ₂ S 62 52 A F F dn ₂ rac 102 99 IN F F dn ₂ S 98 99 Exp. 5.229 N N dn ₂ rac 98.3 98.7 Exp. 5.273 F N dn ₂ rac 100.3 94.7 Exp. 5.289 F N with rac 97.9 92.4

6.4. Analytical methods.

Typical measurement conditions are shown below.

Differential scanning calorimetry.

Thermal analysis of Q2000. Closed (hermetically sealed) gold crucibles or pinhole aluminum crucibles; sample filled under ambient conditions; heating rate 5 or 10 K min ^-1 ; range from -50 to 300°C (sometimes stops earlier).

Dynamic steam sorption.

Measurement technology project (now ProUmid) SPS11-100n. The sample was placed on an aluminum holder on top of the microbalance and allowed to equilibrate at 50% relative humidity before running one of the following predefined humidity programs (1 cycle):

maintain for 2 hours at 50% relative humidity, reduce humidity -5% relative. ow. h ^-1 for 10 hours (i.e. from 50 to 0%), maintain 5 hours at 0% relative humidity, increase humidity +5% relative humidity. humidity h ^-1 for 19 hours (i.e. from 0 to 95%), maintain 5 hours at 95% relative humidity, reduce humidity -5% relative humidity. ow. h ^-1 for 9 hours (i.e. from 95 to 50%), maintain 2 hours at 50% relative humidity or maintain 2 hours at 50% relative humidity, increase humidity +5% relative humidity. humidity h ^-1 for 9 hours (i.e. from 50 to 95%), maintain 5 hours at 95% relative humidity, reduce humidity -5% relative humidity. ow. h ^-1 for 19 hours (i.e. from 95 to 0%), maintain 5 hours at 0% relative humidity, increase humidity + 5% relative humidity. humid h ^-1 for 10 hours (i.e. from 0 to 50% RH), maintain for 2 hours at 50% RH.

The classification of hygroscopicity is based on the mass increase at 85% relative humidity relative to the initial mass as follows: deliquescent (the amount of adsorbed water sufficient to form a liquid), very hygroscopic (mass increase >15%), hygroscopic (mass increase <15%, but >2%), slightly hygroscopic (weight increase <2% but >0.2%) or non-hygroscopic (weight increase <0.2%).

Fourier-Raman spectroscopy.

Bruker MultiRAM (with OPUS 7.0 software). Nd: YAG, excitation 1064 nm, nominal laser power 300 mW, Ge detector, 64 scans, spectral range 3500-100 cm ^-1 used for analysis, resolution 2 cm ^-1 . Samples were measured through truncated glass NMR

- 117 044284 tubes.

^1H NMR.

Bruker DPX300. NMR 'll spectra were recorded using a proton frequency of 300.13 MHz, an excitation pulse of 30°, and a recycle delay of 1 s. Sixteen scans were collected and deuterated DMSO was used as the solvent.

HPLC.

Agilent Series 1100 HPLC instrument with Agilent 1260 Infinity degasser and Chromeleon software version 6.8.

Powder X-ray diffraction.

Stoe Stadi P. Copper radiation Kα1, 40 kV/40 mA. Mythen1K detector, transmission mode, curved Ge monochromator, step size 0.02° 2θ, step time 12 s, scanning range 1.5-50.5°2θ with detector step 1°2θ in step scanning mode.

Each sample (25-40 mg powder) was placed between two sheets of cellulose acetate foil, which were separated by a metal washer (0.4 mm thick, 12 mm inner diameter). This sandwich element was transferred to a special potent substance sample holder (SCell), which was again sealed with acetate foil. No special processing was used during sample preparation. An ambient atmosphere was used for all measurements and each sample was rotated during measurement.

X-ray diffraction patterns were indexed using the X'Pert HighScore Plus package from PANalytical. Peak tables for the diffraction patterns were created using Bruker EVA software (version 14, 0, 0, 0) and performing background subtraction followed by peak searching. Only peaks with °2θ values below 40°2θ that have significant intensity are reported.

Determination of solubility.

ml of buffer or ultrapure (resistivity >18.2 M 'Ω cm) water was added to a pre-weighed aliquot of approximately twenty milligrams of the substance being measured. The resulting suspensions were stirred for 15 min at room temperature using a magnetic stirrer. The suspensions were centrifuged and filtered through PVDF Millipore 0.2 μm filters and the concentration of each filtrate (ie, saturated solution) was determined using a conventional HPLC method. The pH of each saturated solution was measured using a Metrohm 713 pH meter.

TG-FTIR.

Thermal microbalance Netzsch TG 209 with IR-Fourier spectrometer Bruker IFS28 or Vector 22. Aluminum crucible (with micro-hole), N2 atmosphere, heating rate 10 K min ^-1 , range from 25°C to 350°C.

TG/DTA.

Approximately 5 mg of material was weighed into an open aluminum cup and loaded into a synchronous thermogravimetric/differential thermal analyzer (TG/DTA) and kept at room temperature. The sample was then heated at a rate of 10°C/min from 20 to 300°C, during which time the change in sample weight along with any differential thermal events (DTA) was recorded. Nitrogen was used as a purge gas at a flow rate of 300 cm ³ /min.

6.5. Free base polymorphism screening no. 1.

Searches for polymorphic forms of the free base of compound 1 were conducted from fifteen solvents and twenty-one solvent mixtures using methods such as suspension equilibration (at various temperatures), evaporation, cooling crystallization, precipitation, vapor diffusion, and vapor diffusion. In addition, many drying/desolvation experiments were undertaken, and mechanical and thermal treatments were also applied.

Suspension equilibration experiments were carried out using different solvents, temperatures and durations. Experiments at lower temperatures promote the formation of solvates, while experiments at higher temperatures can help overcome kinetic barriers to interconversion. After completion of the experiments, the freshly filtered samples were typically characterized by Raman spectroscopy, and selected samples were subsequently characterized by PXRD, TG-FTIR, ¹ H-NMR spectroscopy and/or DSC.

Evaporation experiments were carried out from five solvents and one mixture under laboratory conditions. Although very low evaporation rates were used, four products were amorphous.

Cooling Crystallization Experiments: Hot saturated solutions of compound 1 were prepared in seven different solvents/mixtures. With uncontrolled cooling, relatively rapid deposition (less than 24 hours) was observed in most experiments.

Precipitation experiments were undertaken both by adding antisolvent to concentrated solutions of compound 1 and by adding a concentrated solution of compound 1 to a bath of antisolvent. No immediate precipitation was observed in any of the cases. In one experiment (MEK as solvent and TBME as antisolvent), the final

- 118 044284 Precipitation (form H) was finally observed after eleven days of subsequent stirring at room temperature. In the remaining experiments, clear solutions were used as starting materials for vapor diffusion removal experiments.

Vapor diffusion experiments were performed by dissolving compound 1 in a solvent in an open vial and placing the vial in a bath of a more volatile antisolvent that was mixed with the solvent. The entire system was then closed to create an atmosphere saturated with antisolvent at room temperature. Diffusion of the volatile antisolvent into the solution should reduce the solubility of the compound and potentially lead to slow precipitation.

A remote vapor diffusion (reverse vapor diffusion) experiment was performed by dissolving compound 1 in a solvent/antisolvent mixture in which the solvent was the more volatile component. The sample was left open at ambient conditions to allow partial evaporation, and since the more volatile solvent evaporates faster, the solubility should decrease over time, resulting in precipitation.

Drying/Desolvation Experiments: Due to the solvophilic nature of Compound 1, most products contained residual solvent, making it difficult to distinguish solvates (stable or labile) from potential unsolvated forms that were not completely dried. In an attempt to identify true anhydrous forms, individual classes were reproduced and subsequently dried at 40°C in vacuum overnight. Samples were dried separately to avoid cross-contamination. The resulting products were analyzed by PXRD and TG-FTIR. The drying procedure was successful in many cases, but often resulted in loss of crystallinity and/or change in solid form, indicating that most of the starting samples were indeed solvates that were not stable under drying conditions. However, the form H solvates were found to be quite stable and did not change shape on drying, and the form K hydrate showed only small shifts in reflection positions consistent with dehydration to form K'.

Storage under controlled relative humidity: The following table describes the results of storing Form K and Form K' of Compound 1 at 17% relative humidity to help narrow the critical range of water activity for the interconversion of the hydrated and dehydrated forms. Later, the range was narrowed to a _H2O = 0.11-0.22, with the K' form being more stable at lower water activity (a _H2O <0.11), and the K form at higher water activity (a _H2O >0 ,22).

Table 4

Humidity-controlled storage experiments for compound 1

Starting material Storage conditions PXRD result

Form K ¹ stored humidity at relative 17% and k.t. 2.5 days form K Form K stored at relative form K humidity 17% and k.t. 5.5 days

Heat treatment of solid forms: The following table summarizes two experiments conducted using solvent-free heat treatment of forms of compound 1. The purpose of these experiments was to determine whether the 225°C endotherm observed in many DSC experiments corresponded to melting of the racemate of compound 1 or whether this is a polymorphic form of compound 1. Two experiments involved the preparation of various solid forms of compound 1, an amorphous form and form E. The resulting products were subsequently heated to temperatures at which exothermic phenomena were observed in DSC thermograms. Both experiments confirmed that the racemate was formed upon heating.

Table 5

Heat treatment of solid compound 1

Initial Heat treatment Result amorphous PXRD material is heated in a flow of N ₂ to 180°C and racemate

- 119 044284 stand for 10 minutes; quickly cool to room temperature; heat to 200 °C and hold for 10 minutes; quickly cool to room temperature.

Form E is heated in a stream of N ₂ to 200°C and the racemate is kept for several minutes; quickly cool the mold to room temperature.

racemate form

The racemization of compound 1 during DSC analysis was confirmed by heating samples to various temperatures and analyzing these samples by chiral HPLC, as well as comparing the melting point with a pure sample of the racemate of compound 1. When the sample was heated to 160°C, the chiral purity remained virtually unchanged (96.1 % area at 160°C compared to the original 97.1%). This supports the interpretation of the sharp endotherm observed in the DSC thermogram at about 152.6°C as a melt of the enantiomer. Between 160-218°C there is a gradual conversion of the enantiomer to the racemate together with recrystallization of the racemate. This explains the unstable baseline in this temperature range and the small, broad endotherm observed at about 197.1°C. Racemization is almost complete at 218°C, followed by melting of the racemate, corresponding to the second acute endotherm observed in the DSC thermogram at approximately 226.7°C. This melting point corresponds to the maximum melting temperature (about 225.6°C) of the pure racemate of compound 1.

Racemization of compound 1 during DSC analysis was also confirmed by hot stage microscopy. Microscopic images from heating a sample of Compound 1 on a hot stage showed the following: Individual particles of Compound 1 in the dry state were difficult to separate individually and were visualized as dark clumps. No noticeable changes were observed when the sample was heated to 151°C, when some of the smaller lumps began to melt. The compound melted completely when the temperature increased to 153°C. This corresponds to a melt of the enantiomer. Between 170 and 212°C, racemization and recrystallization of the drug occurred, as indicated in the DSC experiment. Upon further heating to 220°C, complete melting of the racemate was observed. The hot stage microscopy results are in fairly good agreement with the thermal phenomena observed by DSC and confirmed by the chiral chromatography described above.

Stress Experiment: The following table describes three experiments involving mechanical stress of Form A and/or Form B of Compound 1 free base by grinding in a mortar and pestle. When one polymorph was ground for two minutes, no changes in the polymorphic form were observed. When both polymorphs were ground together for ten minutes, the crystallinity decreased significantly, but the crystalline portion of the sample remained a mixture of the two forms.

Table 6

Machining connection 1

Feed material Mechanical processing PXRD result

Form A grind with a pestle into mortar for 2 minutes without changing the polymorphic form; a slight decrease is possible crystallinity Form B grind with a pestle into mortar for 2 minutes without changes in polymorphic form Form A and Form B grind with a pestle into mortar 10 min loss of crystallinity; what remains is a mixture of two polymorphs

Summary of the results of screening for free base polymorphism No. 1.

The endotherm around 225°C, which was observed in many DSC thermograms, is attributed to the melting of the racemate of compound 1. Such an endotherm is usually preceded by an exothermic event, which is presumably associated with crystallization of the racemate and possibly involves the racemization itself.

Free base form A of compound 1 is likely to be an anhydrous and slightly hygroscopic polymorph with a melting point of approximately 146.4°C (onset at 137.7°C, ΔΗ-49.7 J g ^-1 ). It converts to other forms when suspended in all solvent systems tested and was obtained only by desolvation of Form E solvate/hydrate (although other solid forms can also be obtained by desolvation of Form E samples). Grinding Form A with a mortar and pestle for two minutes does not result in a polymorphic transformation.

- 120 044284

Free base form B of compound 1 is likely to be a channel hydrate that is slightly hygroscopic. It is sometimes prepared in crystallization experiments, but probably only by desolvation of an intermediate solvate such as Form E, Form F, or Form G. DSC analyzes of Form B samples yielded melting points (of the dehydrated form) typically in the range of 122-129°C, but the driest sample of Form B observed in this project has a melting point of 138.0°C (start at 127.3°C, AN®23.1 J g ^-1 ). Grinding Form B with a pestle and mortar for two minutes does not result in a polymorphic transformation.

The free base form C of the compound is associated with a high melting point of 171.9°C (onset at 160.4°C, AN®41.1 J g ^-1 ), but is hygroscopic at high relative humidity. Although this often correlates with TG-FTIR thermograms with low solvent content (as little as 0.5 wt%), drying the Form C sample (obtained in the 2PgOH/ _H2O experiment) showed a loss of crystallinity. This suggests that form C likely arises from desolvation of solvated forms, even if these solvates were not always clearly observed.

Free base Form D of Compound 1 is a hydrated form that is relatively labile and converts toward Form B on drying. It was originally only derived from suspension equilibration experiments using ethanol and may include a transient solvated state. Form D has a melting point (after dehydration) of 136.1°C (start at 129.3°C, AH®17.7 J g ^-1 ). Although its DVS isotherm resembled that of the channel solvate, the sample converted to a mixture of forms B and E during the moisture cycle.

Form E of the free base of compound 1 is also likely to be the hydrated form, although it appears to be isomorphic with the MEK and ethyl formate solvates. A typical sample of Form E has a melting point (after partial dehydration/desolvation) of 132.0°C (start at 117.6°C, AH®64.1 J g ^-1 ).

Form F of the free base of compound 1 consists of nearly isomorphic solvates of many solvents, including anisole, toluene, ethyl formate, ethyl acetate, methyl acetate, isopropyl acetate, and possibly acetone and dioxane. Drying Form F samples either results in a loss of crystallinity and a shift in PXRD spectra (e.g. for anisole and toluene solvates) or, in cases such as the MeOAc solvate, conversion to Form B. Thus, despite the isomorphism of the various solvate structures form F, they undergo different desolvation mechanisms under the same conditions, presumably due to differences in the strength of host-guest interactions.

Form G of the free base of compound 1 appears to be acetonitrile monosolvate with a melting point of 139.5°C (start at 131.7°C, AH®19.2 J g ^-1 ). Desolvation of this form by vacuum drying at 40°C overnight resulted in transformation into the highly crystalline Form B sample.

Form H of the free base of compound 1 corresponds to the almost isomorphic solvates of TBME and THF with a desolvation/melting temperature of about 140 °C. Both solvates are relatively stable and do not desolvate even after drying in vacuum at 40°C overnight. THF solvates generally exhibit higher crystallinity than TBME solvates.

Compound 1 free base Form I is a DMSO solvate.

Form J of the free base of compound 1 is an acetic acid solvate that desolvates in two steps when the temperature is increased.

The free base form K of compound 1 is likely a channel hydrate that is slightly hygroscopic. The corresponding dehydrated/desolvated form was designated form K'. When dehydrated, its melting point is approximately 157.0°C (start at 152.9°C AH®73.4 J g ^-1 ). Form K is the most stable form in mixtures of water and organic solvents (such as acetone and 2PrOH) with a water activity a _H2O >0.17. Form K is also resistant to the DVS cycle. Its powder X-ray diffraction pattern appears to be indexable, meaning that the K form corresponds to a pure phase rather than a mixture of several solid forms. Indexing the diffraction pattern of the K' shape confirms that it is a slightly compressed version of the same lattice. The solubility of Form K and Form K' after fifteen minutes at pH 2.0 is essentially identical, suggesting that the two forms should have the same bioavailability.

Desolvation processes were not always predictable, and isomorphic solvates did not always produce the same product when dried, possibly due to differences in the strength of interactions between different types of solvent and compound molecules and details of the drying process that were not always easily controlled. Desolvation of Form E samples usually resulted in Form B, Form A, or a mixture of Forms A and B, but Form B could also be obtained by desolvation of Form G. Most Form F samples simply lost crystallinity when dried, but one (derived from MeOAc) became Form B, and the other (derived from 2PrOH) into form C.

Heating both amorphous and Form E samples to 180-200°C and holding for several minutes resulted in the formation of the racemate of compound 1, confirming that the melting peak at about 225°C in DSC endotherms was attributed to this racemate.

Both Forms A and B are mechanically stable to two minutes of grinding with a mortar and pestle. Grinding the mixture of Forms A and B for ten minutes resulted in partial amorphization but did not result in clear conversion in either direction.

6.6. Free base polymorphism screening no. 2.

A second search for polymorphic forms of the free base of compound 1 was carried out using twenty high molecular weight and/or sterically hindered solvents. The goal of these experiments was to determine whether the use of solvents that would not likely be incorporated into the host-guest structure as readily as previously tested solvents would result in the formation of a true anhydrous form (as opposed to a desolvated solvate). Most of the high molecular weight and hindered solvents used in this project resulted in the forms identified in the first screen, but three new solid forms were isolated.

Suspension (suspension) equilibration experiments were performed using twenty high molecular weight and/or hindered solvents. Experiments were carried out by preparing suspensions of approximately 55-68 mg of Compound 1 in 0.8-1.0 ml of the selected solvent using 4 ml Supelco glass vials. The suspensions were stirred with a magnetic stirrer for fourteen days at 40°C. Temperatures above room temperature were chosen to reduce the tendency to form solvates. Solid samples were recovered by filter centrifugation (20 min, 40°C, 5000 rpm, 0.45 μm PTFE membrane) and characterized by PXRD without further drying. This procedure should provide an indication of the most stable form in a given solvent. However, if a solvate or hydrate is formed, the solid form may change as the sample dries, and metastable forms may convert to more stable forms over time under laboratory environmental conditions. In two cases no solid product was obtained, so the solvents were subsequently evaporated.

For many products, diffraction patterns were obtained similar to several forms from the previous screen, suggesting that the use of high molecular weight and/or hindered solvents does not inhibit solvate formation. In addition, three new solid forms were identified (designated form L, form M and form N).

Due to the solvophilic nature of compound 1, most products contained residual solvent, making it difficult to distinguish solvates (stable or labile) from potential unsolvated forms that were not completely dried. In an attempt to either identify the true anhydrous forms or see if previously observed desolvation trends persisted for samples from the current screen that had similar lattice structures, selected solid forms were dried at elevated temperature under vacuum overnight. Samples were dried separately to avoid cross-contamination. The resulting products were analyzed by PXRD and TG-FTIR. Form N was stable with respect to drying, but the other three samples lost some crystallinity and sometimes also underwent conversion to a solid form.

Summary of the results of screening for free base polymorphism No. 2.

Samples of Form B, Form C, Form D, Form E and Form F were prepared from several high molecular weight and/or hindered solvents. Small shifts in the positions of the PXRD reflections of these products suggest that the crystal lattice frequently expanded to accommodate larger molecules.

Sample Form B was obtained from an experiment with glycerol.

Form C, the anhydrous or desolvated form, was prepared in experiments involving 50 w/v% choline dihydrogen phosphate in water, 50 w/v% choline acetate in water, and Tween 20.

Forms D and E have previously been associated with hydrated forms. Form D was obtained only from ethanol in the previous screen and contained only water, suggesting that it was a hydrate that formed in an intermediate solvated state. Form E was previously shown to be a hydrate that is likely isomorphic to the solvates of ethyl formate, DMA, NMP, and MEK. In the current screening, samples similar to Form D or an intermediate between Forms D and E were obtained from carbitol, diglyme, dodecane, isopropyl myristate, 1-octanol, and possibly propylene carbonate. No water was detected in any of these samples, although many contained large amounts of residual solvent, so it would have been impossible to detect water due to the dynamic range limitations of the TG-FTIR instrument.

Form F has previously been associated with nearly isomorphic solvates of anisole, toluene, and acetates (EtOAc, iPrOAc, and MeOAc), and also possibly with solvates of dioxane, DMF, and 2-propanol. In the current screen, it was also found to be associated with cumene, 1,3-dimethyl-2-imidazolidinone, triacetin, trifluorotoluene and n-xylene. The solvent 2-pentyl acetate can also form a solvate with this structure.

Form K was not obtained in any of the experiments in this screen. There was also no evidence of a true anhydrous solid free base form of compound 1 that was not obtained by desolvation or dehydration of the solvated form.

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Form L was obtained in a single experiment with tetrahydrofurfuryl alcohol. Tetrahydrofurfuryl alcohol is also associated with form H, which was previously known to correspond to the nearly isomorphic solvates of THF and TBME.

Form M was obtained from experiments with 2-pentyl acetate. This form is probably a hemisolvate.

Form N was obtained in a single experiment with hexamethylphosphoramide.

Additional forms of free base.

Throughout the salt screen described in section 6.9 below, 5 new diagrams were obtained from several different free base/acid salt forming combinations and in a range of solvents. Thus, these 5 new diagrams were likely new free base polymorphs. These 5 new diagrams were classified as Form O, Form P, Form Q, Form R and Form S of the free base of compound 1.

The properties of the solid free base forms of Compound 1 are summarized in the following table.

Table 7

Generalization of the solid forms of the free base of compound 1

Temperature

Form Melting solvation state Other aspects (approx.) anhydrous anhydrous starting material which

A 146.4 °C (desolvated easily turns into solvates;

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solvate) obtained by desolvation of selected IN channel hydrate 138.0 °C solvates form E obtained by desolvation of form G (MeCN solvate) and selected solvates WITH anhydrous (desolvated 171.9 °C Form E and Form F (e.g. MeOAc, u-xylene) solvophilic; obtained from 2propanol/water and ethyl formate, D solvate) hydrate or hygroscopic anhydrous form, 136.1 °C possibly by desolvation of labile solvates obtained from experiments with carbitol, diglyme, dodecane, EtOH, isopropyl myristate, 1-octanol and possibly E which is isomorphic with solvates hydrate isomorphic with solvates (for example, 132.0°C ^a) propylene carbonate; transforms towards Form B after drying in vacuum at 40°C overnight. obtained from experiments with ethyl formate, DMA, NMP and MEK; presumably isomorphic with solvates of some of these F MEK) almost isomorphic solvates of acetates (iPrOAc, EtOAc, MeOAc), acetone, anisole, cumene, 1,3dimethyl-2- inone azolide imide, toluene, triacetin, trifluorotoluene and p- 121.2°С ^b) solvents, but also exists in the form of a hydrate; converts to Form A or Form B when dried under vacuum at 40°C overnight moderately stable solvates that lose some crystallinity when dried in vacuum at 40°C overnight; possibly also forms solvates with dioxane, DMF, 2-propanol and 2-pentyl acetate.

xylene

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acetonitrile converts to Form B when dried in G (mono)solvate almost isomorphic 129.0 ^and C vacuum at 40°C overnight TVME and THF solvates relatively stable solvates, N (and maybe MIBK and 141.4°C ^c) which are not desolvated by drying in tetrahydrofurfuryl alcohol) vacuum at 40°C overnight I DMSO solvate „ ^d ) loses some crystallinity when J AcOH solvate 79.6 °C drying in vacuum at 40°C for nights stable when dried overnight; TO channel hydrate 157.0 °C more stable than forms B and C in mixtures of 2РгОН/ _Н2О with ango >0.3 and in mixtures of acetone/ _Н2О with ango >0.5 L solvate tetrahydrofurfuryl alcohol - a solvated form is possible, but TG-FTIR was not carried out M 2-pentyl acetate solvate 154.9°C ^e ' probable hemisolvated form N hexamethyl phosphorus amide solvate - possible solvate hexamethylphosphoramide ABOUT possible hydrate - derived from salt screen, highly crystalline R 132 °C derived from salt screen, highly crystalline Q possible hydrate - derived from salt screen, highly crystalline derived from salt screen, R possible hydrate — possibly highly hydrated and hygroscopic material S - derived from salt screen, highly crystalline

The sample on which DSC was measured was found to be a solvate of MEK.

The melting point was measured on anisole solvate.

This temperature probably corresponds to a combination of melting and dehydration processes.

The DMSO solvate was not further characterized due to the low vapor pressure and high boiling point of DMSO.

The melting point was not determined as a result of desolvation.

6.7. Salt screening No. 1.

A search for possible cocrystals and salts of compound 1 was conducted from four solvents (acetone, THF, MeCN, and DCM) and twenty-two potential salts/cocrystal formers (L-ascorbic acid, L-aspartic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, glutaric acid, glycolic acid, hippuric acid, hydrochloric acid, DL-lactic acid, L-malic acid, maleic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, L-tartaric acid and toluenesulfonic acid) in a 96-well microtiter plate. In all cases, a 1:1 ratio of free drug to salt/cocrystal former was used and then the solvents were evaporated. After completing Raman measurements of the products of the evaporation experiments, each solid residue was suspended in one of four solvents/mixtures (EtOAc, anisole, 95:5 (v/v) 2PgOH/ _H2O or TBME) and the temperature was varied between 25 and 35° C for thirty hours. The solvents were then evaporated and the solid residues were re-examined using Raman microscopy. Additionally, benzenesulfonic acid and αglycerophosphoric acid were tested in parallel laboratory experiments.

Based on these experiments, several potential leads were identified, including mesylate, D-gluconate, besylate, and hydrochloride. L-ascorbate, esylate, fumarate, glutarate, sulfate, and tosylate were possible amorphous forms that exhibited spectral changes that could be attributed to complexation.

Attempts have been made to increase the amount of hydrochloride salt. A total of five new diffraction patterns were obtained. Form A of the hydrochloride salt of compound 1 was found to be a TBME solvate and likely had a melting point (after in-situ desolvation) of 202.2°C (start at 189.1°C, AH®54.6 J g ^-1 ). Both elemental analysis and 1H NMR spectroscopy were consistent with the expected structure. Form A was found to be hygroscopic, but did not change to its solid form during the DVS cycle. Its solubility in water was 4.1 mg/ml (7.2 mM) for the free base component. Because the sample was converted to a solid form during the solubility measurement, this solubility value may not reflect Form A of the hydrochloride salt itself.

Form B of the hydrochloride salt of compound 1 was usually prepared from protic solvents, including alcohol/water mixtures. When dried overnight, the sample lost only part of its crystallinity, and its estimated melting point after (partial) desolvation was 209.8°C (start at 200.4°C, AH=48.8 J g ^-1 ). DVS shows that Form B is hygroscopic. 1H NMR is consistent with the expected structure.

Form C of the hydrochloride salt of compound 1 appears to be a monoacetone solvate. ¹ H-NMR spectroscopy confirmed the absence of decomposition.

Compound 1 hydrochloride salt Form D was prepared in a single evaporation experiment involving immiscible solvents DCM and water.

A sample of Form E of the hydrochloride salt of compound 1, derived from 1-propanol, contained a significant contribution of 2-propanol, suggesting that it is likely the solvated form. Another sample of Form E was prepared by equilibrating a suspension of sample Form C in acetonitrile. Form E probably corresponds to isomorphic solvates.

Attempts have been made to increase the amount of mesylate salt. Amorphous products were obtained in several experiments. The anisole solvate of the free base Form F was also often prepared. A degradation product was also observed in several experiments. Two experiments with ethyl acetate resulted in the formation of the ethyl acetate solvate of the mesylate salt. Both elemental analysis and ^1H -NMR spectroscopy of the ethyl acetate solvate confirmed the expected 1:1 stoichiometry of the mesylate salt. The ethyl acetate solvate of the mesylate salt showed a broad desolvation endotherm at 69°C followed by a second broad endotherm (presumably corresponding to melting of the desolvated solvate) around 154.9°C, but the sample was hygroscopic during the DVS measurement. Although a relatively high solubility value of 14.9 mg/mL (26.2 mM) was obtained for the free base component, the product formed a gel. Therefore, this measured value may not reflect the original shape.

6.8. Screening for polymorphism No. 1 of the hydrochloride salt of compound 1.

A search for polymorphic forms of the hydrochloride salt of compound 1 was carried out from sixteen solvents and ten solvent mixtures. The substance was found to have a tendency to be polymorphic, with at least eleven crystalline forms of the salt being identified. Most of these forms correspond to solvates, and in the case of several solvents (acetone, MeCN and NMP), multiple solvated forms are likely to exist.

Suspension (suspension) equilibration experiments were performed using thirteen solvents and seven solvent mixtures. All mixtures are stated in a volumetric ratio (v/v), and the organic component of each water mixture was pre-dried over molecular sieves to obtain the specific water activity for the mixture. Experiments were carried out by preparing suspensions of approximately 60-65 mg of compound 1 hydrochloride starting material batch (defined as a mixture of Form A and Form B) in 0.6-2.0 ml of the selected solvent using 4 ml Supelco glass vials. The suspensions were stirred with a magnetic stirrer for seven days at room temperature. Solid samples were recovered by filter centrifugation (5 min, 5000 rpm, 0.22 μm PTFE membrane) and characterized by PXRD without further drying. This procedure should provide an indication of the most stable form in a given solvent. However, if a solvate or hydrate is formed, the solid form may change as the sample dries, and metastable forms may convert to more stable forms over time under laboratory environmental conditions. Form A, Form B, Form F and Form G hydrochloride salt were prepared from suspensions.

Evaporation experiments were carried out from three solvents and three solvent mixtures under laboratory ambient conditions. While four evaporation experiments resulted in mostly amorphous material, new solid forms (Form I and Form H) were obtained in two

- 126 044284 cases.

Heating/cooling experiments: Hot, nearly saturated solutions of compound 1 hydrochloride were prepared in one solvent and three solvent mixtures. After at least thirty minutes of equilibration at 60°C, the samples were cooled to room temperature at an uncontrolled rate.

Generalization of the results of screening for hydrochloride salt polymorphism.

The most commonly obtained solid form from suspension equilibration experiments was Form A of the hydrochloride salt of compound 1, which appears to correspond to isomorphic solvates with several solvents including acetone, anisole, ethyl formate, isopropyl acetate, MEK, TBME, toluene, and probably DMA and DMF.

Form F of the hydrochloride salt of compound 1 was obtained in two experiments with acetonitrile/water mixtures. The sample corresponds to acetonitrile solvate.

Compound 1 hydrochloride salt Form G was prepared experimentally using an IPE/NMP mixture. This is probably an NMP solvate.

Form H of the hydrochloride salt of compound 1 was obtained from an experiment with cyclohexane and NMP and appears to be another NMP solvate with a different structure from that of form G.

Compound 1 hydrochloride salt Form I was prepared in a single experiment using an IPE/DMSO mixture. Most likely it is a DMSO solvate.

Neither Form J nor Form K of the hydrochloride salt of Compound 1 was obtained in this study. In other studies, Compound 1 hydrochloride salt form J was prepared from acetonitrile, dichloromethane, 95:5 (v/v) EtOAc/H2O and heptane; while the hydrochloride salt form K of compound 1 was prepared from hexane and TBME.

The anhydrous hydrochloride salt form of Compound 1 was not detected in this study. The hydrated hydrochloride salt form of Compound 1 was not isolated in this study, and equilibration of the suspension in pure water resulted in significant amorphization.

The following table shows the solid forms of the hydrochloride salt of Compound 1 (Form A through Form K).

Table 8

Summary of solid forms of the hydrochloride salt of compound 1 Name Description

Form A isomorphic solvates with acetone, anisole, ethyl formate, iPrOAc, MEK,

TVME, toluene and possibly DMA and DMF

Form B isomorphic solvates obtained from protic solvents (for example, water-alcohol mixtures)

Form C probable acetone solvate

Form D is obtained from a mixture of DCM/H ₂ O; hydrated form possible

Form E obtained from 2PgOH and from a suspension of form C in MeCN; probable isomorphic solvates

Form F probable solvate of MeCN

Form G probable NMP solvate

Form H probable solvate of NMP

Form I probable DMSO solvate

Form J prepared from MeCN, DCM, 95:5 EtOAc/H ₂ O and heptane

Form K derived from hexane and TBME

6.9. Salt screening No. 2.

A salt filter was performed for compound 1 using 48 different acid counterions (1 equiv.) and 20 different solvent systems in the following tables.

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Table 9

Acidic counterions used in salt filter

Counterion Counterion Hydrobromic acid DL-lactic acid Hydrochloric acid L-ascorbic acid 1,5-naphthalene disulphonic acid Benzoic acid Sulfuric acid succinic acid Toluenesulfonic acid Glutaric acid Methanesulfonic acid Adipic acid Benzenesulfonic acid Acetic acid Oxalic acid A nicotinic acid Isethionic acid Propionic acid L-aspartic acid Nitric acid Maleic acid Salicylic acid Phosphoric acid 1,2-Ethanesulfonic acid L-Glutamic acid Cyclamic acid Malonic acid Ethanesulfonic acid 2,5-Dihydroxybenzoic acid (gentisic Mucic acid L-Tartaric acid D-Glucuronic acid Fumaric acid 4-Aminosalicylic acid Lemon acid Caproic (Hexanoic) acid L-Pyroglutamic acid Cinnamic acid R-mandelic acid Capric (Decanoic) acid L-malic acid Caprylic (Octanoic) acid Hippuric acid Camphoric acid D-Gluconic acid D-Aspartic acid Glycolic acid D-Glutamic acid

Table 10

Selected solvents used in the salt filter

Solvent ICH Class Volume added (µL) 1 1,4-Dioxane 2 1000 2 2-Propanol 3 1000 3 Acetone 3 1000 4 Acetone/water (50:50 v/v) 3 1000 5 Acetonitrile 2 1000 6 Acetonitrile/water (50:50 v/v) 2 700 7 Dichloromethane 2 1000 8 Diisopropyl ether n/a 1000 9 Ethanol 3 1000 10 Ethanol/water (50:50 v/v) 3 1000 AND Ethyl acetate 3 1000 12 Heptane 3 1000 13 Isopropyl acetate 3 1000 14 Methanol 2 800 15 Methyl ethyl ketone 3 1000 16 tert-Butyl methyl ether 3 1000 17 Tetrahydrofuran 2 1000 18 Tetrahydrofuran/water (50:50 v/v) 2 800 19 Toluene 2 1000 20 Water n/a 1000

For the primary salt screen, 40 mg of free base per sample was used and 20 solvents were used for each free base/counterion combination. 21 samples were lyophilized and one sample was stored at 40°C/75% relative humidity for 72 hours after removal from the freeze dryer prior to XRPD analysis. The remaining 20 samples (per salt) were thermally cycled (with stirring) for 72 h after the addition of selected solvents to prepare suspensions/solutions. The thermal cycle was 4 h at room temperature and then 40°C for 4 h.

After removal from the temperature cycle, any solid material present was isolated by centrifugal filtration (0.2 μm) and retained for analysis. All solids were analyzed by XRPD. Any crystalline salts were analyzed by TG/DTA.

If no solid material was present after removal from the thermal cycle, the mother liquor was divided into 3 equal parts and stored under the following conditions: freezer (-18°C), evaporation, and addition of antisolvent (isopropyl acetate was used for all samples unless otherwise noted). Any recovered solids were analyzed by XRPD, and if crystal structures were identified, the solids were also analyzed by TG/DTA.

Of the 48 acidic counterions tested on the screen, salts were obtained from 34 acidic counterions, as shown in the following table.

Table 11

Summary of Salt Screening

Counterion Conclusion NVg 4 salts form B was the most common form Form A and Form C were found to be unsolvated forms. NS1 2 salts Napadisilate 1 salt derived from all solvent systems tested Sulfate Only amorphous solids are produced Tosylate 1 salt derived from 1,4-dioxane only Mesilate 1 salt derived from 1,4-dioxane only Besilat 1 salt formed by adding isopropyl acetate as an antisolvent to acetone/water (50:50 v/v) and THF/water (50:50 v/v) Oxalate 1 salt Isethionate 2 salts Form A may be the unsolvated form Maleate 2 salts Form A may be the unsolvated form Phosphate: Only 1 salt from acetone/water (50:50 v/v) Form A may be the unsolvated form

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Malonate 1 salt from water only Gentisat 3 salts most solids produced were either Form B or Form C Tartrate 1 salt Fumarate Only 1 salt from DCM Citrate Only amorphous solids are produced Almond and sour 1 salt from water only Malate Only 1 salt from DCM form A turned out to be the unsolvated form Glycolate Only 1 salt from IP A Ascorbate (from L-ascorbic acid) 1 salt from evaporation of 1,4-dioxane only Form A may be the unsolvated form Succinate 1 salt from evaporation of 1,4-dioxane only Form A may be the unsolvated form Nitrate 1 salt from all solvent systems tested except 1,4dioxane and MeCN/water (50:50 v/v) Salicylate 3 salts Form A was produced most often Form B may be the unsolvated form Edisilate 2 salts Form B was produced most often Cyclamate 5 salt Ezilat 2 salts Form B was produced most often form B turned out to be the unsolvated form Glucuronate (from D-glucuronic acid) 1 salt form A turned out to be the unsolvated form 4-amino salicylate 1 salt from water only Capronat Only 1 salt from THF/water (50:50 v/v) Cinnamat 2 salts Caprylate Camphorate Aspartate (from Daspartic acid) Only 1 salt from THF/water (50:50 v/v) 1 salt of MeCN and MeOH 2 salts Glutamate (from D- glutamic acid) 1 salt

6.10. Evaluation of forms.

Evaluation of Form A of the free base of compound 1.

Form A was not isolated directly as a wet precipitate, but was formed only after drying of Form E in polymorphism studies. Moreover, it appears that Form E can form either Form A or Form B, or a mixture of both, during drying, suggesting that the resulting

- 130 044284 shape depends on drying kinetics. Small amounts of Form A were prepared by dissolving crude compound 1 in MEK at high temperature, followed by rapid cooling to room temperature, filtration and drying. DSC and TGA data were obtained from Form A samples and after storage for 1 week at 60°C and 60°C/75% relative humidity. The DSC curve for the sample stored at 60°C was very similar to the original condition, however changes in physical shape were observed in the sample stored at 60°C/75% relative humidity. The melting endotherm in this sample was wider and had a peak temperature that was shifted by ~3.7°C to 140.7°C compared to 144.4°C in the original sample. In addition, another broad endotherm was observed in this sample in the temperature range of 50-75°C, which was absent in the original sample. TGA analysis confirmed that this broad endotherm was most likely caused by moisture absorption under accelerated storage conditions. Most of the 0.82% weight loss in this sample occurred in a single step at temperatures less than 75°C. In contrast, initially, weight loss was a two-step process. A weight loss of ~0.26% was observed between 25 and 75% relative humidity in the first stage and approximately 0.36% additional weight loss was observed in the second stage at the initial time point. The residual solvent initially present in the sample was lost when the sample was stored at 60°C (0.13% weight loss between 25 and 150°C).

Evaluation of Form B of the free base of compound 1.

Form B can be prepared by a method using methyl acetate. In the sample stored at 60°C, a color change was observed from the initially white sample to a light brown color. HPLC traces were taken from Form B samples and after storage for 2 weeks at 60°C and 60°C/75% RH. The area chemical purity of the sample was initially 98.4%, which decreased to 97.71 and 97.92% after storage for 2 weeks at 60°C and 60°C/75% RH, respectively. The growth of several small degradation products was observed, especially in the sample stored at 60°C. Chiral instability was also observed in the sample stored at 60°C/75% relative humidity. Chiral purity changed from an initial value of 97.96 area% to 96.54 area% in a sample stored at 60°C/75% relative humidity, but remained unchanged in a sample stored at 60°C after 2 weeks of accelerated storage. conditions.

Evaluation of Form C of the free base of compound 1.

Form C can be isolated from a limited number of solvents. In particular, it can be prepared by resuspending in IPA or by hot dissolving in acetone. Form C was found to be physically and chemically stable under enhanced stability conditions. While scaling this shape, a new shape was obtained (shape K). Comparison of the DSC heat of fusion and PXRD peak sharpness values for Form C and Form K showed that the latter was relatively more crystalline.

Competitive suspension experiments between Form C, Form B and Form A showed that in both binary and ternary mixtures containing Form C, Form B and Form A were rapidly converted to Form C within 24 hours in aqueous suspension at room temperature . In the absence of Form C, a mixture of Forms A and B remained unchanged in aqueous suspension for 24 hours. These data clearly show that of the three forms, Form C is the relatively more thermodynamically stable form.

Like Form C, Form K also showed chemical and physical stability in accelerated stability studies. Competitive suspension experiments in water were performed with mixtures of both forms, and gradual conversion of form C to form K occurred with prolonged stirring, suggesting that form K was the more thermodynamically stable form.

Estimating the K form of the free base of compound 1

Form K was first discovered in IPA-water mixtures. Seed-to-suspension conversions of solvent-mediated IPA-water (90:10) conversions starting with form C sequentially generated form K. Subsequent preliminary protocols included dissolution in acetone followed by addition of water, seeding, and loading of additional water to reduce the concentration. This process also consistently produced the K form.

To explore the space in which Form K is the most stable form in acetone/water, competitive suspension studies were conducted, starting with a mixture of Form B, Form C, and Form K in acetone/water under different conditions. Form K was found to be the most stable form at water content (vol%) of 5% and above at both room temperature and 45°C. Form B was prepared at room temperature and Form C was prepared at 45°C in acetone only.

Based on the results, the following process for obtaining Form K was developed: loading compound 1 into reactor R-1; loading acetone (15x) and starting stirring at room temperature; heating the batch to 40°C; holding the mixture for at least 1 hour at 40°C; cooling the charge to 22.5°C for at least 50 minutes; loading of acetone (15 copies); kneading time 2 hours; transfer of batch from R-1 to R-2 through a polishing filter; concentration of the charge in R-2 to a total volume of ~ 15 volumes. with partial va

- 131 044284 kuume; heating the batch to 42.5°C; loading water (2 volumes) into the batch; inoculation with 5% form K of compound 1; performing PSA grinding through a recirculation loop at a speed of 23 m/s for 8 hours; cooling to 22.5°C for at least 4 hours; exposure for 3 hours; charging water (6 times) for 8 hours; exposure for 4 hours; transfer of batch to filter F-1; washing the filter cake three times with a mixture of acetone:water (66:34 v/v); dry sediment on the filter with nitrogen purging at a temperature not exceeding 45°C; carrying out wet aging of the cake for at least 12 hours at a humidity of 70%; and product analysis and packaging.

It was observed that after form K was dried, the XRD peaks of form K shifted to a higher value and the resulting XRD pattern was termed form K'. To better understand the relationship between the two forms, Form K and Form K' of the free base were placed on XRPD sample holders and stored in closed containers with saturated salt solutions to control relative humidity at ambient temperature, respectively. Samples were analyzed after 2 days and 6 days of storage, for the following relative humidity at ambient temperature. Salts used: lithium chloride for 11% relative humidity, potassium acetate for 22% relative humidity, magnesium chloride for 33% relative humidity and potassium carbonate for 43% relative humidity. XRPD diffraction patterns of samples after 2 days of storage are presented in Fig. 132 and 133 respectively. The results show that the K form is converted to K' at a relative humidity of less than 11%, and the K' form is converted to a K at a relative humidity of 22% or higher. Because the peaks of form K shift to higher 2-theta as form K loses water molecules to form K', form K and form K' are in a continuous state.

To assess whether it is likely that form K and form K' have different bioavailability, comparative solubility measurements were performed in physiologically relevant media. Samples of Form K and Form K' were individually equilibrated with pure water, pH 2.0 buffer, and pH 6.8 buffer for fifteen minutes, and then the solids were separated from the solvents. The concentration of the compound in the filtrate (i.e., solubility) was assessed in each case, and solid residues were also monitored by powder X-ray diffraction. All six solid residues correspond to form K, confirming that form K' rapidly incorporates water into its lattice when suspended in an aqueous medium, even when solubility is low. Although the solubility in pure water and at pH 6.8 was below the limit of quantitation of 0.0001 mg/mL, the solubility at pH 2.0 could be measured. Both were found to be essentially the same, namely 0.93 mg/ml for Form K' and 0.96 mg/ml for Form K, and no evidence of increased solubility was found for Form K'. Thus, the bioavailability of the two forms is expected to be similar, and precise control of water content (and therefore solid form) does not appear to be scientifically necessary. Given that the critical activity of water is in the range a _H2O = 0.11-0.17, the hydrated form of K is likely to be more easily stabilized of the two forms under laboratory environmental conditions.

Hygroscopic: Form K absorbs water at very low humidity. Water sorption continues to occur at any humidity, gradually reaching an absorption plateau of ~3.2% by weight, corresponding to ~1 mol of water. The adsorbed water was released in the desorption phase without hysteresis in the drying phase.

Physical Stability: Visually, all Form K samples appeared as a white powder with no visible color change in samples stored under accelerated conditions (40°C, 40°C/75% RH, 60°C, 60°C/75%). RH and sample are stored in a light chamber in clear vials exposed to light and covered with aluminum foil for 14 days relative to the sample stored under refrigerated and ambient conditions. No visual color change was observed in any of the samples stored under enhanced stability conditions. Based on DSC, PXRD and TGA data, no major changes in crystal shape and water content are observed for Form K under conditions of elevated temperature, humidity and light exposure.

Solid State Chemical Stability: HPLC analysis was performed on Form K samples stored under enhanced stability conditions. Overall, no significant degradation of the pure drug was observed under accelerated storage conditions. Minor degradation was seen in the sample exposed to light (1.2 million lux). Based on HPLC analysis data, there is a measurable but small change in the chemical stability of Form K under conditions of elevated temperature, humidity, and light exposure over a 14-day period. Form K is considered physically and chemically stable.

Chiral stability in solid state: The chiral stability of Form K samples stored under accelerated stability conditions was tested. The initial sample contained ~2.9% of the R enantiomer (97.1% of the area of the active S-isomer). After storage under accelerated conditions, there was no change in the chiral stability of the compound under accelerated conditions, and the results were within the limits of analytical variability.

Shear Sensitivity: Form K was compressed at 2000 psi for 1 min and analyzed

- 132 044284 lysed using XRPD. The solid form remained as the K form.

Evaluation of Form A of the hydrobromide salt of compound 1.

Form C of the hydrobromide salt of compound 1 was prepared on a salt screen from MeCN only. Because Form C had favorable thermal properties, it was chosen for scale-up. The HBr salt was prepared using the same method as for the salt screen, but with all scales increased to obtain the salt from 500 mg of the free base: 500 mg of the free base of compound 1 was dissolved in 60 ml of 1,4-dioxane before adding 1. 05 equivalent of 1 M hydrobromic acid in water. Another 5 mL of water was added to facilitate dissolution for freeze drying. The material was then freeze-dried. After removal from the freeze dryer, 12.5 mL of acetonitrile was added to prepare a suspension. The suspension was then subjected to thermal cycling for ~72 h (with stirring). The thermal cycle was 4 hours at room temperature followed by 40°C for 4 hours. Form C was not successfully produced on the 500 mg scale. Form A was produced instead.

In an attempt to reproduce Form C, the material was re-lyophilized to obtain an amorphous starting point, and then 12.5 ml of acetonitrile was added to form a suspension, and the resulting suspension was again thermally cycled for ~72 hours. Form A was produced again. It is likely that Form A is a more stable HBr salt form than Form C. Form A was used in the following analysis.

The material did not have a clear morphology, consisted of aggregates of different sizes and was birefringent (PLM). The material had an average purity of 98.8%. The chemical structure was confirmed by 1H NMR - unsolvated salt.

Thermal analysis showed an initial mass loss (TGA) of ~1.8%, likely due to loss of unbound solvent, and both TG/DTA and DSC showed onset of melting at ~277 and 280°C, respectively. DVS found the material to be slightly hygroscopic, with a mass increase of ~0.69 up to 90% RH - minimal hysteresis observed. No volumetric changes in crystal shape were observed by XRPD after DVS. The material was found to be both physically and chemically stable when stored at 40°C/75% RH, 80°C and ambient light/temperature for 1 week - with no change in XRPD volume or chemical purity (HPLC).

The HBr salt was largely insoluble in the various buffers when 1 mg/mL suspensions were prepared and the stock solution concentration determined (by HPLC) was <0.05 mg/mL in all buffers tested. When suspended in acetone/water mixtures of varying water activities, the HBr salt showed no volumetric changes in the diffraction pattern obtained from the isolated solids—no hydrate formation was observed. The HBr salt did not appear to disproportionate back to the free base when suspended in water for ~24 h.

Evaluation of form B of the besylate salt of compound 1.

The salt filter yielded only one besylate salt of Compound 1 (Form A) when isopropyl acetate was added as an antisolvent to acetone/water (50:50 v/v) and THF/water (50:50 v/v).

Form B of the besylate salt of Compound 1 (the form not obtained on the salt screen) was scaled up for a 10 g batch of the free base, Compound 1, according to the following procedure: 10 g of the free base of Compound 1 was weighed into a sample bottle and 220 ml of acetonitrile was added to form suspensions. The suspension was stirred at moderate speed at room temperature. Benzenesulfonic acid (6.14 g) was added to the suspension to form a homogeneous solution. ~20 to 30 mg of seeds were added (with stirring) and after ~30 min a large amount of sediment was visible. The suspension was left to stir overnight before the solid was isolated by Buchner filtration. XRPD was collected of the filtered solid and remaining seeds to check if the desired salt form was obtained. The material was then dried in a vacuum oven at 40°C for ~72 h before any other analysis was performed.

Form B of the besylate salt was successfully prepared in an amount of 10 g. The material did not have a clear morphology, consisted of aggregates of different sizes and was birefringent (PLM). The yield of the resulting salt was ~82.4%. The material had an average purity of 99.2%. The chemical structure was confirmed by 1H NMR - unsolvated salt (compound 1: besylate - monosalt, 1:1).

Thermal analysis showed a steady mass loss of ~1.5% above ~120°C (TGA), likely due to loss of bound solvent or possibly slow degradation, and both TG/DTA and DSC showed onset of melting/ decomposition at ~ 251 and 252°C, respectively.

The material was found to be physically stable under accelerated stability conditions (40°C, 40°C/75% RH, 60°C, 60°C/75% RH and exposure to light for 14 days) - with no volume change in diffraction pattern (XRPD). Chemical purity (HPLC) showed a degradation peak (probably hydrolysis of the -CN group) with an increasing trend with temperature and humidity. Chiral purity (area % of the S isomer) remained above 99% under enhanced stability conditions.

Solubility data for several polymorphic forms of compound 1 in physiologically relevant

- 133 044284 media and the final pH of these solutions are summarized in the following tables.

Table 12

Solubility of different forms at different pH

Wednesday Solubility (mg/ml) Close to Form A Form WITH Form A Form IN Form TO HCl salt NVg salt buffer pH 1 HCl/NaCl) 0.107 0.108 0.088 0.085 0.133 0.071 0.018 buffer pH 3 (phosphate) 0.212 0.277 0.280 0.125 0.090 0.149 0.032 buffer pH 4 (acetate) 0.120 0.065 0.159 0.115 0.011 0.124 0.038 buffer pH 5 (acetate) 0.004 0.003 0.008 0.007 0.001 0.017 0.004 SGF with pepsin 0.391 0.427 0.429 0.406 0.420 0.295 0.077 FaSSIF 0.001 0.001 0.001 0.001 0.001 0.001 <LOQ FeSSiF 0.064 0.031 0.086 0.077 0.005 0.094 0.111 Water - <LOQ <LOQ <LOQ <LOQ - 0.3 01 (to), 0.212(t24)

Table 13 pHs for corresponding samples in the above table

Wednesday Final pH Close to Form A Form WITH Form A Form IN Form K NS1 salt NVg salt buffer pH 1 HCl/NaCl) 1.29 1.07 1D4 1.09 1.20 1.05 0.95 buffer pH 3 (phosphate) 3.96 3.31 3.70 4.05 3.09 3.05 z, p buffer pH 4(acetate) 4.13 4.14 4,P 4,P 3.98 4.00 4.18 buffer pH 5(acetate) 5.04 5,P 5.03 5.05 5.01 4.83 5.08 SGF with pepsin 1.49 1.29 1.34 1.29 1.47 1.28 1.15 FaSSIF 6.40 6.44 6.44 6.43 6.33 5.96 6.40 FeSSiF 5.05 5.05 5.05 5.03 5.02 4.99 5.16 Water - 6.86 6.77 6.46 6.71 - 4.53

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6.11. Screening of polymorphism No. 2 of the hydrochloride salt of compound 1.

Additional studies of the polymorphic forms of the hydrochloride salt of compound 1 were carried out considering that the anhydrous form or hydrated form of the hydrochloride salt of compound 1 was not found in the screen for polymorphism No. 1 of the hydrochloride salt of compound 1. Ultimately, the anhydrous form L was identified through many reactive experiments crystallization. A wide range of factors were studied, including 1) solvents, 2) HCl sources (organic and aqueous), 3) temperature (0°C, room temperature and 80°C), and 4) HCl stoichiometry, and the results are listed in the following table .

Table 14

Polymorph Screening for Compound 1 Hydrochloride Salt Form L

Experiments with the addition of 1.1 eq. HC1 in an organic solvent. No water added.

Solvents HC1 (mol eq.) Solvent Solid state KF (%) XRPD SRME BUT »2 Crystal X Form A option MeOH Salt is not oof ) called X 1,4-Dioxane 0.64 0.27 Low crystallinity 3 CPME after heating/cooling cycle 1 0.59 Low crystallinity 2.5 Heptane 0.89 0.02 Partially crystalline 4

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Toluene 0.9 0.49 Partially crystalline 1.7 Acetone BUT 0.03 Partially crystalline 1.1 Acetonitrile 0.91 0.08 Crystal 0.2 Shape L 2.2Dimethoxypropan BUT 0.01 Partially crystalline 1.5 MTBE 0.6 0.84 Crystal 1 Form A option Secondary solutions containing water Solid CPME particles re-suspended in water CPME solids are recycled 1 BUT Crystal X Shape L suspended But 0.01 Crystal 0.4 Shape L nye in the mixture 20% acetone/water Experiments with the addition of 1.2 eq. NS1 1 n. aq. NS1 DMSO:water (1: 7.5-34Х) 0.93 0.04 Crystal 0.4 Shape L 2-MeTHF BUT 0.69 Partially crystalline 1.8 THF 0.88 0.47 Partially crystalline 1.6 Acetone solution ND EtOH BUT 0.01 Crystal 3.2 Form B

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MeCN solution nd IP Ac 0.85 <0.01 Crystal 0.4 Shape L DMAc solution ND EtOAc BUT 0.01 Crystal 0.1 Shape L NMP/water (3 : 7) 0.89 0.03 Crystal 0.3 Shape L DMF/water (3 : 7) 0.93 0.04 Crystal 0.4 Shape L DMAc/water (3 : 6) 0.93 0.03 Crystal 0.2 Shape L Experiments with 2 eq. and 4 ek! V. Vodn. NS1 20% acetone in water+2 eq. 0.94 0.01 Crystal 0.3 Shape L NS1 20% acetone in water+4 eq. 0.87 0.01 Crystal 0.2 Shape L NS1 CPME+2 or 4 eq. NS1 Obrazova resin ND Experiment with 2.5 eq. NS1. No water added. SRME 0.85 0.44 Partially crystalline 1.4 Experiments at 0 °C SRME Weakly crystalline Form cue L+other DMSO: water (1:4) Weakly crystalline Shape L Experiments at 80 °C SRME 0.81 BUT. Crystal Shape L DMSO: water (1:4) Crystal Shape L

Alcohol solvents + 2 eq. aq. NS1

IPA 1-propanol 1-butanol — Crystal Crystal Crystal Form B as an isomorphic solvate Shape L Shape L 2-methyl-2butanol Crystal Form B as an isomorphic solvate

Screening for stress polymorph using Form L as starting form: Form L was suspended in various solvents at different temperatures for a week. XRPD plots were collected for both wet and room temperature dried cakes. The results are presented in the following table.

Table 15

Tension polymorph suspension sieve - Compound 1 HCl form L as starting form

Solvent Temperature (°C) XRPD wet XRPD dry EtOAc 50°C Shape L Shape L IPA 50°C Shape L nd Acetone CT Shape L Shape L DCM 4 °C slightly crystalline slightly crystalline MeCN 50°C Shape L ND THF CT Form O Form O* Water 50°C Form N ND H ₂ O/MeOH 1:3 v/v (Aw=0.5) CT Form B Form B* H ₂ O/MeCN 1:3 v/v (Aw=0.9) 4 °C Form N Form N Ethanol 50°C Shape L ND MTBE CT slightly crystalline slightly crystalline anisole 50°C Shape L+other Shape L+other Toluene 50°C Shape L ND DMAc From room temperatures up to 80°C to 4°C Form P Form P* DMSO to water (grinding sediments) CT Form N Form N

*Peak shifts and differences were observed during drying.

Polymorph Screening by Crush Precipitation: 200 mg of compound 1 hydrochloride salt form L was dissolved in 1 ml of DMSO. 200 μL of DMSO solution was added to each antisolvent (EtOAc, MTBE, toluene, MeCN, and acetone). The results are presented in the following table.

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Table 16

Polymorphic network of compound 1 HCl by crushing precipitation

Solvent Temperature (°C) XRPD wet XRPD dry DMSO/EtOAc (1:5 v/v) CT Form Q Form Q DMSO/MTBE (1:5 v/v) CT Form R Form R DMSO/toluene (1:5 v/v) CT Shape S Shape S DMSO/MeCN (1:5 v/v) CT Shape S Shape S DMSO/acetone (1:5 v/v) CT Form N+other Form N

Polymorph screening using the amorphous hydrochloride salt of compound 1:. approximately 50-100 mg of the amorphous hydrochloride salt of compound 1 was suspended in 15 different organic solvents for 1 week. Five of them were inoculated with 5 mg of form L, kept at 50°C for a week and tested using XRPD. The results are presented in the following table.

Table 17

Polymorphic network of compound 1 HCl with amorphous material

Solvent Temperature (°C) XRPD wet XRPD dry XRPD wet (seeded with form L) iPAc CT Shape T Form T* nd AcOH CT U shape Shape U* nd NMP CT Form H Form V Form H anisole 50°C Shape W Form W* Shape W SRME 50°C Shape X Shape X* Shape L MTBE 50°C Y shape Y shape nd nBuOH 50°C Z shape Z shape Shape L acetone 50°C Low crystal personal Low crystalline Shape L MeCN 50°C Shape L Shape L nd EtOAc 50°C AB form Form AB* ND EtOH 50°C Shape L Shape L ND Toluene 50°C AC form AC form ND Nitromethane 50°C Shape L Shape L ND MeOH 50°C Shape L Shape L ND water 50°C Form N Form N ND

*Dry XRPD chart is slightly different from wet XRPD chart.

Scaling up Form M: 150 mg of Form L was heated to 160°C, held at this temperature for 10 minutes and cooled to room temperature. XRPD and DSC confirmed that the thermally annealed material was converted to the M form.

Determination of the phase transition temperature for Form L and Form M: 4 suspensions of a 1:1 mixture of Form M/L in different solvents were stirred at different temperatures (60, 80, 100 and 120°C). The results (as shown in the following table) indicate that the transition temperature between the M/L form is 60-100°C and is likely to be in the range of 60-80°C. The L form and the M form are enantiotropically related (the L form is more stable at room temperature, and the M form is more stable at high temperature).

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Table 18

Study of phase transition for form L and form M

Solvent Temperature (°C) XRPD result MeCN 60°C L MeCN 80°C M/L* Toluene 100 °C Shape M i-xylene 120 °C Shape M

*suspension remained an M/L mixture after 2 weeks. The peak of the M form has increased overtime.

Determination of critical water activity for Form L and Form N: 50 mg of Form L was suspended in 0.5-1 ml of water/acetone solution with the specific activity of water. The solutions were stirred at room temperature or 60°C. Shape conversion was monitored using XRPD over a 2-week period. The results (as shown in the following table) show that 1) the critical activity of water at room temperature is 0.2-0.4; and 2) the critical value of water at 60°C is 0.4-0.5. Under conditions of high water activity, the L form is converted to the N form. The N form is stable under ambient conditions, while after drying in a vacuum oven at 40°C, the N form is easily converted to the L form.

Table 19

Study of phase transition for form L and form M

Aw OD 0.2 0.3 0.4 0.5 Pace CT Shape L Shape L Form AA Form N Form N 60°C - Shape L Shape L Shape L Form N

The shape conversion diagram for L shape, M shape and N shape is shown in FIG. 170.

The detection conditions for form L to form AC are summarized in the following table.

Table 20

Detection conditions for Form L to Form AC hydrochloride salt of Compound 1

Polymorph Detection conditions Shape L suspend Form K free base in 20% acetone/water, then load 4 eq. 1 n. aqueous H O solution and performing several cycles of heating (40 °C) and cooling (RT) Shape M 150 mg of Form L was heated to 160 °C, isothermally for 10 min and cooled to room temperature.

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Form N Form L was suspended in 20% acetone in water (v/v) at 60°C overnight. Form O 50 mg of Form L was suspended in 1 ml of THF at room temperature for a week. Form P 50 mg of Form L was suspended in 1 ml of DMAc for a week with temperature cycling from RT to 80°C to 4°C. Form Q 50 mg of Form L was dissolved in 200 μl of DMSO, which was added dropwise to a solution of 1 ml of EtOAc and suspended at room temperature overnight. Form R 50 mg of Form L was dissolved in 200 μl of DMSO, which was added dropwise to a solution of 1 ml of MTBE and suspended at room temperature overnight. Shape S 50 mg of Form L was dissolved in 200 μl of DMSO, which was added dropwise to a solution of 1 ml of toluene and suspended at room temperature overnight. Shape T 50-100 mg of amorphous HC1 salt was suspended in iPAc at room temperature for a week. U shape 50-100 mg of amorphous HC1 salt was suspended in AcOH at room temperature for a week. Form V 50-100 mg of amorphous HC1 salt was suspended in NMP at room temperature for a week. Shape W 50-100 mg of amorphous HC1 salt was suspended in anisole at 50°C for a week. Shape X 50-100 mg of amorphous HC1 salt was suspended in CPME at 50°C for a week. Y shape 50-100 mg of amorphous HC1 salt was suspended in MTBE at 50°C for a week. Z shape 50-100 mg of amorphous HC1 salt was suspended in nBuOH at 50°C for a week. Form AA 50 mg of Form L was suspended in 1 ml of acetone/water (97:3 v/v) at room temperature for 2 weeks. AB form 50-100 mg of amorphous H O salt was suspended in EtOAc at 50°C for a week. AC form 50-100 mg of amorphous HO salt was suspended in toluene at 50°C for a week.

The following table shows the solid forms of the hydrochloride salt of compound 1 (form L to form AC).

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Table 21

Summary of solid forms of the hydrochloride salt of compound 1

Name Description Shape L anhydrous form. DSC: 1st endo at 124°C to solidify and 2nd endo at 262°C to melt. Shape M anhydrous form. Form M and form L are enantiotropic. Form M is more stable at high temperature, and form L is more stable at low temperature. DSC: Form M melts at ~259 °C. Form N probable hydrate form. DSC: 1st endo at 44°C for dehydration, 2nd endo at 127°C for solidification and 3rd endo at 256°C for melting. Form O probable THF solvate Form P probable DMAc solvate Form Q obtained from a suspension of DMSOZEtOAc (1:5); possibly mixed solvate Form R prepared from a DMSO/MTBE (1:5) suspension; possibly mixed solvate Shape S obtained from a DMSO/toluene (1:5) suspension; possibly mixed solvate Shape T probable solvate IP Ac U shape probable AcOH solvate Form V probable NMP solvate Shape W probable anisole solvate Shape X probable solvate of CPME Y shape probable MTBE solvate Z shape probable pViON solvate Form AA prepared from a 97:3 acetone:water suspension; possibly acetone/aqueous solvate AB form probable EtOAc solvate AC form probable toluene solvate

6.12. Preparation of Form A of the hydrobromide salt of compound 1.

(S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin1-yl)-3- fluorobenzonitrile (compound 1) free base (2 g) was loaded into acetone (70 ml) at 25°C and the solution was heated to 40°C. The hydrobromide salt of compound 1 (0.1 g) was loaded as a seed. A hydrobromic acid solution was prepared by mixing 48 wt.% hydrobromic acid (0.440 ml) and water (7.6 ml). The hydrobromic acid solution was loaded into the acetone mixture for 9 hours, maintaining 40°C, to crystallize the HBr salt of compound 1. The suspension was cooled to 20°C. The suspension was filtered and washed with three washes of acetone (6 ml each). The wet solids were dried in a vacuum oven to obtain the hydrobromide salt of compound 1, a white to off-white solid (2 g, 88% yield). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 1.93-2.06 (m, 1H), 2.39-2.48 (m, 1H), 2.55-2.66 (m, 1H), 2.93 (ddd, J=17.51, 13.62, 5.49 Hz, 1H), 3.14-3.29 (m, 3H), 3.40-3.49 (m, 2H), 3.73 (br d, J=12.05 Hz, 2 H), 4.19-4.54 (m, 4H), 5.13 (dd, J=13.28, 5.19 Hz , 1H), 5.32 (s, 2H), 7.23 (t, J=8.77 Hz, 1H), 7.35 (dd, J=7.86, 5.11 Hz, 2H), 7 .46-7.53 (m, 1H), 7.55-7.68 (m, 5H), 7.79 (dd, J=13.12, 1.68 Hz, 1H), 9.92 (s , 1H), 10.98 (s, 1H), melting point 283°C.

6.13. Screening for polymorphism of the hydrobromide salt of compound 1.

Screening for stress polymorph using Form A as starting form: 50 to 60 mg of Compound 1 HBr salt Form A was suspended in a solvent at room temperature or 50°C for several days, and the results are shown in the following table.

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Table 22

Tension Polymorph Suspension Sieve - Compound 1 HBr Form A as the starting form

Solvent Temperature Time Experiment XRPD result Ethyl acetate 50°C 10 days Suspension Form A ^a Isopropanol 50°C 10 days Suspension Form A Acetone Room 10 days Suspension Form A Dichloromethane 4 °C 10 days Suspension Form A Acetonitrile 50°C 10 days Suspension Form A T ethrahydrofuran Room 10 days Suspension Form A Water 50°C 10 days Suspension Form A ^a H ₂ O/Methanol (1/3 by volume) Room 10 days Suspension Form A H ₂ O/Acetonitrile (1/3 by volume) 4 °C 10 days Suspension Form A Ethanol 50°C 10 days Suspension Form A ^a MTBE Room 10 days Suspension Form A ^a Anisole 50°C 10 days Suspension Form A Toluene 50°C 10 days Suspension Form A DMAc Room 10 days Suspension Form A DMSO Room 10 days Drops into the water Form A 1,4-Dioxane 50°C 2 days Suspension Form A MeOH 50°C 2 days Suspension Form A DMF 50°C 2 days Suspension Form A NMP 50°C 2 days Suspension Form A

with a very small peak at 18°.

Additional studies confirmed that the small peak was attributed to the free base of compound 1.

Slow evaporation using a centrifuge overnight: the results are shown in the following table.

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Table 23

Slow evaporation

Solvent for crystallization results 1,4 dioxane no solid particles observed DMAc Form E as DMAc solvate; turned into form A after drying out l:2MeCN:H ₂ O Highly crystalline form A MeOH Weakly crystalline form A DMF form E in the form of DMF solvate - isomorphic to DMAc solvate; turned into form A after drying DMSO Film only NMP Form F as NMP solvate; 3-day drying at room temperature temperature while maintaining the same pattern Anisole Film only

Amorphous form: Three batches of amorphous HBr salt of compound 1 were prepared by lyophilization (apparatus: DSD Labconco FreeZone 2.5 L -84°C) and confirmed by XRPD. DSC of the material showed an amorphous glass transition temperature with an onset of ~ 162°C (inflection temperature 165.9°C with ΔСр=0.39 J/(g°C)). No new shape was observed in the DSC temperature cycle experiment starting with an amorphous material.

Polymorph screening using amorphous HBr salt as starting form: About 50 mg of amorphous HBr salt of compound 1 was added to a vial with ~1.0-2.0 ml of each solvent to be stored as a suspension. The mixture was suspended at room temperature for 2 hours, at 50°C for 0.5 hours, at room temperature for 6 days and then at 50°C for 4 hours. Solids were isolated and analyzed by XRPD. The results are presented in the following table.

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Table 24

Filter a polymorphic suspension using amorphous HBr compound 1 as the starting form

Solvent Experiment XRPD result Ethyl acetate Suspension Form A Toluene Suspension Form G - probably hydrated toluene solvate SNS1z Suspension Wet (form I) is different from dry; dry phase in the form of a hydrate, form H - hydrate with traces of CH3 Methanol Suspension Form A Acetonitrile Suspension Form A T ethrahydrofuran Suspension Form A Water Suspension Form A nitromethane Suspension Form A 1,4-dioxane Suspension Form J as 1,4-dioxane solvate (wet); loss of crystallinity on drying MEK Suspension Form A SRME Suspension Form A Acetone/H ₂ O (96.2/3.8 v/v) Suspension Form A DMSO:H ₂ O (2:9) Form A

Hydrated form H and anhydrous form A study: A suspension experiment was carried out in water at room temperature overnight (20 mg form H in 0.5 ml water). Anhydrous form A was the final form observed by XRPD.

In another experiment, 25 mg of amorphous HBr salt was seeded with 5 mg of form H hydrate in 1.0 ml of water, and the mixture was suspended at 4 and 50°C, respectively. Anhydrous Form A was the final form observed by XRPD, suggesting that Form A is the most stable form in water under the conditions studied.

The following table shows the solid forms of the hydrobromide salt of compound 1.

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Table 25

Summary of solid forms of the hydrobromide salt of Compound 1

Name Description Form A The most stable form among the identified forms; anhydrous with onset of melting at approximately 283 °C Form B isomorphic solvates with acetone, EA Ac, MEK, THF, THF/H ₂ O, toluene, water, 1,4-dioxane Form C probable anhydrous phase Form D derived from MeOH; possibly methanol solvate Form E derived from DMAc and DMF; drying at room temperature overnight converted to form A; isomorphic solvates Form F derived from NMP; probable NMP solvate Shape G derived from toluene; probably hydrated toluene solvate Form H obtained by desolvation of form I; probably hydrate; Converts to form A when dissolved in water Form I derived from SHC13; probably SHC13 solvate Form J obtained from 1,4-dioxane; probably 1,4-dioxane solvate; turned amorphous when dried

The embodiments presented herein are not intended to be limited in scope to the specific embodiments presented in the examples, which are intended to illustrate several aspects of the embodiments provided, and any embodiments that are functionally equivalent are covered by the present description. Indeed, various modifications to the embodiments presented herein, in addition to those shown and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited, the descriptions of which are incorporated herein by reference in their entirety.

Claims (74)

CLAIM 1. Solid free base form of compound 1: characterized by an XRPD diagram containing peaks at 14.6, 18.2 and 18.3°±0.2° 2θ. 2. The solid form of claim 1, wherein the XRPD diagram further contains peaks at 22.3 and 23.1°±0.2° 2θ. 3. The solid form of claim 2, wherein the XRPD diagram further contains peaks at 20.5 and 20.9°±0.2° 2θ. 4. The solid form of claim 1, wherein the XRPD diagram further contains peaks at 8.6, 14.3, 14.6, 16.6, 18.2, 18.3, 20.5, 20.9, 22 .3 and 23.1°±0.2° 2θ. 5. The solid form of claim 1, which is characterized by an XRPD diagram that corresponds to the XRPD diagram shown in FIG. 35 or 36. 6. Solid form of the hydrobromide salt of compound 1: characterized by an XRPD diagram containing peaks at 10.3, 19.3 and 24.0° 2Θ ±0.2° 2θ. 7. The solid form of claim 6, wherein the XRPD diagram additionally contains peaks at 17.1 and 20.7' - 146 044284 2Θ ±0.2° 2Θ. 8. Solid form according to claim 7, wherein the XRPD diagram additionally contains peaks at 12.8 and 15.6° 2θ ±0.2° 2θ. 9. The solid form of claim 6, which is characterized by an XRPD diagram that corresponds to the XRPD diagram shown in FIG. 76. 10. Solid form of free base of compound 1: 1. which is: free base form A of compound 1, characterized by an XRPD diagram containing peaks at 11.3, 14.1 and 17.4° 2Θ ±0.2° 2Θ; free base form B of compound 1, characterized by an XRPD diagram containing peaks at 6.6, 16.3 and 17.1° 2Θ ±0.2° 2Θ; free base form C of compound 1, characterized by an XRPD diagram containing peaks at 14.2, 15.9 and 21.5° 2Θ ±0.2° 2Θ; free base form D of compound 1, characterized by an XRPD diagram containing peaks at 6.1, 11.1 and 18.5° 2Θ ±0.2° 2Θ; free base form E of compound 1, characterized by an XRPD diagram containing peaks at 6.2, 14.3 and 18.8° 2Θ ±0.2° 2Θ; free base form F of compound 1, characterized by an XRPD diagram containing peaks at 5.0, 14.3 and 26.3° 2Θ ±0.2° 2Θ; free base form G of compound 1, characterized by an XRPD diagram containing peaks at 6.4, 19.1 and 19.6° 2Θ ±0.2° 2Θ; Form H of the free base of compound 1, characterized by an XRPD diagram containing peaks at 5.4, 7.5 and 10.7° 2Θ ±0.2° 2Θ; free base form I of compound 1, characterized by an XRPD diagram containing peaks at 14.9, 15.6 and 21.3° 2Θ ±0.2° 2Θ; the free base form J of compound 1, characterized by an XRPD diagram containing peaks at 13.8, 15.2 and 22.0° 2Θ ±0.2° 2Θ; the free base form L of compound 1, characterized by an XRPD diagram containing peaks at 15.9, 17.9 and 26.2° 2Θ ±0.2° 2Θ; form M of the free base of compound 1, characterized by an XRPD diagram containing peaks at 14.1, 17.0 and 18.4° 2Θ ±0.2° 2Θ; the N form of the free base of compound 1, characterized by an XRPD diagram containing peaks at 13.0, 25.0 and 25.7° 2Θ ±0.2° 2Θ; Form O of the free base of compound 1, characterized by an XRPD diagram containing peaks at 6.5, 16.5 and 20.6° 2Θ ±0.2° 2Θ; free base form P of compound 1, characterized by an XRPD diagram containing peaks at 14.3, 16.3 and 21.0° 2Θ ±0.2° 2Θ; free base form Q of compound 1, characterized by an XRPD diagram containing peaks at 5.7, 15.5 and 20.7° 2Θ ±0.2° 2Θ; the free base form R of compound 1, characterized by an XRPD diagram containing peaks at 14.9, 25.4 and 26.7° 2Θ ±0.2° 2Θ; or the S form of the free base of compound 1, characterized by an XRPD diagram containing peaks at 6.6, 16.5 and 20.8° 2Θ±0.2° 2Θ. 11. The solid form of claim 10, which is Compound 1 free base Form A characterized by an XRPD diagram containing peaks at 11.3, 14.1 and 17.4° 2Θ ±0.2° 2Θ. 12. The solid form of claim 10, which is the free base form B of compound 1 characterized by an XRPD diagram containing peaks at 6.6, 16.3 and 17.1° 2Θ ±0.2° 2Θ. 13. The solid form of claim 10, which is the free base form C of compound 1 characterized by an XRPD diagram containing peaks at 14.2, 15.9 and 21.5° 2Θ ±0.2° 2Θ. 14. The solid form of claim 10, which is the free base form D of compound 1 characterized by an XRPD diagram containing peaks at 6.1, 11.1 and 18.5° 2Θ ±0.2° 2Θ. 15. The solid form of claim 10, which is the free base form E of compound 1 characterized by an XRPD diagram containing peaks at 6.2, 14.3 and 18.8° 2Θ ±0.2° 2Θ. - 147 044284 16. The solid form of claim 10, which is Form F of the free base of the compound 1, characterized by an XRPD diagram containing peaks at 5.0, 14.3 and 26.3° 2Θ ±0.2° 2θ. 17. The solid form of claim 10, which is Form G of the free base of the compound 1, characterized by an XRPD diagram containing peaks at 6.4, 19.1 and 19.6° 2Θ ±0.2° 2θ. 18. The solid form of claim 10, which is the free base form H of compound 1 characterized by an XRPD diagram containing peaks at 5.4, 7.5 and 10.7° 2Θ ±0.2° 2Θ. 19. The solid form of claim 10, which is Form I of the free base of compound 1 characterized by an XRPD diagram containing peaks at 14.9, 15.6 and 21.3° 2Θ ±0.2° 2Θ. 20. The solid form of claim 10, which is the free base form J of compound 1 characterized by an XRPD diagram containing peaks at 13.8, 15.2 and 22.0° 2Θ ±0.2° 2Θ. 21. The solid form of claim 10, which is the free base form L of compound 1 characterized by an XRPD diagram containing peaks at 15.9, 17.9 and 26.2° 2Θ ±0.2° 2Θ. 22. The solid form of claim 10, which is the free base form M of compound 1 characterized by an XRPD diagram containing peaks at 14.1, 17.0 and 18.4° 2Θ ±0.2° 2Θ. 23. The solid form of claim 10, which is the free base form N of compound 1 characterized by an XRPD diagram containing peaks at 13.0, 25.0 and 25.7° 2Θ ±0.2° 2Θ. 24. The solid form of claim 10, which is the free base form O of compound 1 characterized by an XRPD diagram containing peaks at 6.5, 16.5 and 20.6° 2Θ ±0.2° 2Θ. 25. The solid form of claim 10, which is the free base form P of compound 1 characterized by an XRPD diagram containing peaks at 14.3, 16.3 and 21.0° 2Θ ±0.2° 2Θ. 26. The solid form of claim 10, which is the free base form Q of compound 1 characterized by an XRPD diagram containing peaks at 5.7, 15.5 and 20.7° 2Θ ±0.2° 2Θ. 27. The solid form of claim 10, which is the free base form R of compound 1 characterized by an XRPD diagram containing peaks at 14.9, 25.4 and 26.7° 2Θ ±0.2° 2Θ. 28. The solid form of claim 10, which is the free base form S of compound 1 characterized by an XRPD diagram containing peaks at 6.6, 16.5 and 20.8° 2Θ ±0.2° 2Θ. 29. Solid form of the hydrochloride salt of compound 1: 1, which is: form A of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 14.1, 16.6 and 26.0° 2Θ ±0.2° 2Θ; form B of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 6.1, 13.4 and 24.6° 2Θ ±0.2° 2Θ; form C of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.2, 8.2 and 15.0° 2Θ ±0.2° 2Θ; form D of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 14.6, 25.1 and 25.6° 2Θ ±0.2° 2Θ; form E of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 5.5, 19.4 and 25.7° 2Θ ±0.2° 2Θ; form F of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.4, 9.6 and 24.9° 2Θ ±0.2° 2Θ; form G of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 13.9 and 25.1° 2Θ ±0.2° 2Θ; form H of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.3, 16.3 and 26.7° 2Θ ±0.2° 2Θ; Form I of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 4.9, 16.1 and 21.5° 2Θ ±0.2° 2Θ; form L of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 10.1, 19.1 and 24.6° 2Θ ±0.2° 2Θ; form M of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 10.3, 19.3 and 24.6° 2Θ ±0.2° 2Θ; form N of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.9, 15.4 and 18.3° 2Θ ±0.2° 2Θ; - 148 044284 form O of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 16.9 and 18.1° 2θ ±0.2° 2θ; form P of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 16.6 and 18.9° 2θ ±0.2° 2θ; form Q of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 15.5 and 17.7° 2θ ±0.2° 2θ; form R of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 17.7, 20.1 and 21.6° 2θ ±0.2° 2θ; form S of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 16.6, 18.6 and 22.4° 2θ ±0.2° 2θ; form T of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.7, 16.9 and 17.8° 2θ ±0.2° 2θ; form U of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.1, 19.2 and 24.4° 2θ ±0.2° 2θ; form V of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.2, 9.5 and 14.3° 2θ ±0.2° 2θ; form W of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.6, 16.8 and 17.6° 2θ ±0.2° 2θ; form X of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 16.8 and 17.6° 2θ ±0.2° 2θ; form Y of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 16.7 and 18.2° 2θ ±0.2° 2θ; form Z of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 17.3, 18.8 and 20.4° 2θ ±0.2° 2θ; form AA of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 8.3, 15.5 and 18.2° 2θ ±0.2° 2θ; form AB of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.7, 18.2 and 20.9° 2θ ±0.2° 2θ; or the AC form of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 14.1, 18.2 and 25.8° 2θ ±0.2° 2θ. 30. The solid form according to claim 29, which is Form A of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 14.1, 16.6 and 26.0° 2θ ±0.2° 2θ. 31. The solid form according to claim 29, which is Form B of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 6.1, 13.4 and 24.6° 2θ ±0.2° 2θ. 32. The solid form of claim 29, which is Form C of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.2, 8.2 and 15.0° 2θ ±0.2° 2θ. 33. The solid form according to claim 29, which is Form D of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 14.6, 25.1 and 25.6° 2θ ±0.2° 2θ. 34. The solid form of claim 29, which is Form E of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 5.5, 19.4 and 25.7° 2θ ±0.2° 2θ. 35. The solid form according to claim 29, which is Form F of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.4, 9.6 and 24.9° 2θ ±0.2° 2θ. 36. The solid form of claim 29, which is Form G of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 13.9 and 25.1° 2θ ±0.2° 2θ. 37. The solid form according to claim 29, which is the hydrochloride salt form H of compound 1 characterized by an XRPD diagram containing peaks at 7.3, 16.3 and 26.7° 2θ ±0.2° 2θ. 38. The solid form according to claim 29, which is Form I of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 4.9, 16.1 and 21.5° 2θ ±0.2° 2θ. 39. The solid form of claim 29, which is Form L of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 10.1, 19.1 and 24.6° 2θ ±0.2° 2θ. 40. The solid form according to claim 29, which is Form M of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 10.3, 19.3 and 24.6° 2θ ±0.2° 2θ. 41. The solid form according to claim 29, which is the N form of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.9, 15.4 and 18.3° 2θ ±0.2° 2θ. 42. The solid form according to claim 29, which is Form O of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 16.9 and 18.1° 2θ ±0.2° 2θ. 43. The solid form according to claim 29, which is Form P of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 16.6 and 18.9° 2θ ±0.2° 2θ. 44. The solid form of claim 29, which is Form Q of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 15.5 and 17.7° 2θ ±0.2° 2θ. - 149 044284 45. The solid form of claim 29, which is Form R of the hydrochloride salt of the compound 1, characterized by an XRPD diagram containing peaks at 17.7, 20.1 and 21.6° 2Θ ±0.2° 2θ. 46. The solid form of claim 29, which is Form S of the hydrochloride salt of the compound 1, characterized by an XRPD diagram containing peaks at 16.6, 18.6 and 22.4° 2Θ ±0.2° 2θ. 47. The solid form of claim 29, which is Form T of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.7, 16.9 and 17.8° 2Θ ±0.2° 2θ. 48. The solid form according to claim 29, which is the U form of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.1, 19.2 and 24.4° 2θ ±0.2° 2θ. 49. The solid form according to claim 29, which is Form V of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.2, 9.5 and 14.3° 2Θ ±0.2° 2θ. 50. The solid form of claim 29, which is Form W of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.6, 16.8 and 17.6° 2Θ ±0.2° 2θ. 51. The solid form according to claim 29, which is Form X of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 9.5, 16.8 and 17.6° 2Θ ±0.2° 2θ. 52. The solid form according to claim 29, which is Form Y of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.6, 16.7 and 18.2° 2Θ ±0.2° 2θ. 53. The solid form according to claim 29, which is Form Z of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 17.3, 18.8 and 20.4° 2Θ ±0.2° 2θ. 54. The solid form of claim 29, which is Form AA of the hydrochloride salt of compound 1 characterized by an XRPD diagram containing peaks at 8.3, 15.5 and 18.2° 2θ ±0.2° 2θ. 55. The solid form according to claim 29, which is the AB form of the hydrochloride salt of compound 1, characterized by an XRPD diagram containing peaks at 7.7, 18.2 and 20.9° 2Θ ±0.2° 2θ. 56. The solid form of claim 29, which is the AC hydrochloride salt form of compound 1 characterized by an XRPD diagram including peaks at 14.1, 18.2 and 25.8° 2Θ ±0.2° 2θ. 57. Solid form of mesylate salt, hydrobromide salt, besylate salt, glycolate salt or L-malate salt of compound 1: O 1, which is: form A of the mesylate salt of compound 1, characterized by an XRPD diagram containing peaks at 16.9, 17.7 and 22.7° 2Θ ±0.2° 2Θ; form B of the mesylate salt of compound 1, characterized by an XRPD diagram containing peaks at 5.7, 9.1 and 26.1° 2Θ ±0.2° 2Θ; form B of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 5.8, 13.9 and 25.3° 2Θ ±0.2° 2Θ; form C of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 9.7, 10.1 and 12.1° 2Θ ±0.2° 2Θ; form D of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 12.2, 12.4 and 24.5° 2Θ ±0.2° 2Θ; form E of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 8.1, 13.5 and 24.4° 2Θ ±0.2° 2Θ; form F of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 18.4, 23.6 and 24.5° 2Θ ±0.2° 2Θ; form G of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 10.6, 18.1 and 25.1° 2Θ ±0.2° 2Θ; form H of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 7.5, 15.1 and 18.0° 2Θ ±0.2° 2Θ; Form I of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 18.8, 21.4 and 25.4° 2Θ ±0.2° 2Θ; form J of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 19.4, 25.2 and 25.9° 2Θ ±0.2° 2Θ; form A of the besylate salt of compound 1, characterized by an XRPD diagram containing peaks at 13.2, 21.1 and 24.3° 2Θ ±0.2° 2Θ; form B of the besylate salt of compound 1, characterized by an XRPD diagram containing peaks at 16.9, 17.7 and 21.9° 2Θ ±0.2° 2Θ; - 150 044284 form A of the glycolate salt of compound 1, characterized by an XRPD diagram containing peaks at 13.6, 17.6 and 22.2° 2Θ ±0.2° 2Θ; or Form A of the L-malate salt of compound 1, characterized by an XRPD diagram containing peaks at 8.1, 14.7 and 25.3° 2Θ ±0.2° 2Θ. 58. The solid form according to claim 57, which is Form A of the mesylate salt of compound 1, characterized by an XRPD diagram containing peaks at 16.9, 17.7 and 22.7° 2Θ ±0.2° 2θ. 59. The solid form according to claim 57, which is Form B of the mesylate salt of compound 1, characterized by an XRPD diagram containing peaks at 5.7, 9.1 and 26.1° 2θ ±0.2° 2θ. 60. The solid form according to claim 57, which is Form B of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 5.8, 13.9 and 25.3° 2Θ ±0.2° 2Θ. 61. The solid form according to claim 57, which is Form C of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 9.7, 10.1 and 12.1° 2Θ ±0.2° 2Θ. 62. The solid form according to claim 57, which is Form D of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 12.2, 12.4 and 24.5° 2Θ ±0.2° 2Θ. 63. The solid form of claim 57, which is Form E of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 8.1, 13.5 and 24.4° 2Θ ±0.2° 2Θ. 64. The solid form according to claim 57, which is Form F of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 18.4, 23.6 and 24.5° 2Θ ±0.2° 2Θ. 65. The solid form according to claim 57, which is Form G of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 10.6, 18.1 and 25.1° 2Θ ±0.2° 2Θ. 66. The solid form of claim 57, which is Form H of the hydrobromide salt of Compound 1, characterized by an XRPD diagram containing peaks at 7.5, 15.1 and 18.0° 2Θ ±0.2° 2Θ. 67. The solid form according to claim 57, which is Form I of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 18.8, 21.4 and 25.4° 2Θ ±0.2° 2Θ. 68. The solid form of claim 57, which is Form J of the hydrobromide salt of compound 1, characterized by an XRPD diagram containing peaks at 19.4, 25.2 and 25.9° 2Θ ±0.2° 2Θ. 69. The solid form of claim 57, which is Form A of the besylate salt of compound 1, characterized by an XRPD diagram including peaks at 13.2, 21.1 and 24.3° 2Θ ±0.2° 2Θ. 70. The solid form of claim 57, which is Form B of the besylate salt of Compound 1, characterized by an XRPD diagram containing peaks at 16.9, 17.7 and 21.9° 2Θ ±0.2° 2Θ. 71. The solid form according to claim 57, which is Form A of the glycolate salt of compound 1, characterized by an XRPD diagram containing peaks at 13.6, 17.6 and 22.2° 2Θ ±0.2° 2Θ. 72. The solid form of claim 57, which is Form A of the L-malate salt of compound 1, characterized by an XRPD diagram containing peaks at 8.1, 14.7 and 25.3° 2Θ ±0.2° 2Θ. 73. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 72, and a pharmaceutically acceptable excipient or carrier. 74. A method of treating multiple myeloma, comprising administering a therapeutically effective amount of a solid form according to any one of claims 1 to 72 to a patient in need thereof.