Polymorphs of ar-degraders

Abstract

Disclosed, inter alia, are crystalline forms of the compound of formula (I).

Description

POLYMORPHS OF AR-DEGRADERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to PCT application No. PCT / CN24 / 81306, filed March 13, 2024; and U.S. Provisional Application No. 63 / 572,782, filed April 1, 2024; each of which is incorporated by reference herein in its entirety for all purposes.TECHNICAL FIELD

[0002] The present disclosure relates, for example, to crystalline forms of N-(trans-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)- 1 -oxo- 1 ,2-dihydrophthalazin-6-yl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)benzamide, referred to herein as Compound 1; methods of preparing the crystalline forms; pharmaceutical compositions comprising the crystalline forms; and uses thereof.BACKGROUND

[0003] N-(trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2- ((S)-2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6-yl)piperazin-l- yl)methyl)piperidin-l-yl)benzamide, referred to herein as Compound 1, is a small molecule proteolysis targeting chimeras (PROTAC) and is an androgen receptor degrader. Compound 1 is useful for medical treatment of, for example, prostate cancer. Compound 1 is described in, for example, U.S. Patent No. 11,767,312 (see, e.g., Embodiment 28), as well as International Patent Application Publication No. WO / 2021 / 249534, both of which are incorporated by reference herein for all purposes.

[0004] More effective cancer treatments are needed due to the high prevalence of cancer worldwide. Provided herein are crystalline forms of Compound 1, including form BA, that address this and other needs in the art.SUMMARY

[0005] The present disclosure provides crystalline forms of Compound 1(Compound 1), including crystalline form BA of Compound 1; methods of preparing the crystalline forms; pharmaceutical compositions comprising the crystalline forms; and uses thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of anhydrate Form BA of Compound 1.

[0007] FIG. 2 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of anhydrate Form BA of Compound 1.

[0008] FIG. 3 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type A of Compound 1.

[0009] FIG. 4 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type A of Compound 1.

[0010] FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type B of Compound 1.

[0011] FIG. 6 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type B of Compound 1.

[0012] FIG. 7 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type C of Compound 1.

[0013] FIG. 8 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type C of Compound 1.

[0014] FIG. 9 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type D of Compound 1.

[0015] FIG. 10 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type D of Compound 1.

[0016] FIG. 11 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type E of Compound 1 of Compound 1.

[0017] FIG. 12 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type E of Compound 1.

[0018] FIG. 13 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type F of Compound 1 overlaid with tosylate Type I.

[0019] FIG. 14 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type G of Compound 1 overlaid with tosylate Type K.

[0020] FIG. 15 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type H of Compound 1.

[0021] FIG. 16 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type H of Compound 1.

[0022] FIG. 17 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type I of Compound 1 overlaid with tosylate Type F.

[0023] FIG. 18 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type J of Compound 1 overlaid with tosylate Type O.

[0024] FIG. 19 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type K of Compound 1 overlaid with tosylate Type O.

[0025] FIG. 20 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type L of Compound 1.

[0026] FIG. 21 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type L of Compound 1.

[0027] FIG. 22 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type M of Compound 1.

[0028] FIG. 23 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type N of Compound 1.

[0029] FIG. 24 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type O of Compound 1 overlaid with tosylate Type J.

[0030] FIG. 25 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of tosylate Type O of Compound 1.

[0031] FIG. 26 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type P of Compound 1.

[0032] FIG. 27 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type Q of Compound 1.

[0033] FIG. 28 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type R of Compound 1.

[0034] FIG. 29 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type S of Compound 1.

[0035] FIG. 30 shows the X-ray powder diffraction (XRPD) pattern of tosylate Type T of Compound 1 overlaid with tosylate Type A and Type O.

[0036] FIG. 31 shows a phase diagram of tosylate forms of Compound 1.

[0037] FIG. 32 shows the X-ray powder diffraction (XRPD) pattern of freeform Type A of Compound 1.

[0038] FIG. 33 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type A of Compound 1.

[0039] FIG. 34 shows the X-ray powder diffraction (XRPD) pattern of freeform Type B of Compound 1.

[0040] FIG. 35 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type B of Compound 1.

[0041] FIG. 36 shows the X-ray powder diffraction (XRPD) pattern of freeform Type C of Compound 1.

[0042] FIG. 37 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type C of Compound 1.

[0043] FIG. 38 shows the X-ray powder diffraction (XRPD) pattern of freeform Type D of Compound 1.

[0044] FIG. 39 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type D of Compound 1.

[0045] FIG. 40 shows the X-ray powder diffraction (XRPD) pattern of freeform Type E of Compound 1.

[0046] FIG. 41 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type E of Compound 1.

[0047] FIG. 42 shows the X-ray powder diffraction (XRPD) pattern of freeform Type F of Compound 1.

[0048] FIG. 43 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type F of Compound 1.

[0049] FIG. 44 shows the X-ray powder diffraction (XRPD) pattern of freeform Type G of Compound 1.

[0050] FIG. 45 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type G of Compound 1.

[0051] FIG. 46 shows the X-ray powder diffraction (XRPD) pattern of freeform Type H of Compound 1 overalid with freeform Type A.

[0052] FIG. 47 shows the X-ray powder diffraction (XRPD) pattern of freeform Type I of Compound 1 overlaid with freeform Type J.

[0053] FIG. 48 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type I of Compound 1.

[0054] FIG. 49 shows the X-ray powder diffraction (XRPD) pattern of freeform Type J of Compound 1 overlaid with freeform Type I.

[0055] FIG. 50 shows the X-ray powder diffraction (XRPD) pattern of freeform Type K of Compound 1 overlaid with freeform Type A.

[0056] FIG. 51 shows the X-ray powder diffraction (XRPD) pattern of freeform Type L of Compound 1.

[0057] FIG. 52 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type L of Compound 1.

[0058] FIG. 53 shows the X-ray powder diffraction (XRPD) pattern of freeform Type M of Compound 1 overalid with freeform Type A.

[0059] FIG. 54 shows the X-ray powder diffraction (XRPD) pattern of freeform Type N of Compound 1.

[0060] FIG. 55 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type N of Compound 1.

[0061] FIG. 56 shows the X-ray powder diffraction (XRPD) pattern of freeform Type O of Compound 1 overlaid with freeform Type A.

[0062] FIG. 57 shows the X-ray powder diffraction (XRPD) pattern of freeform Type P of Compound 1.

[0063] FIG. 58 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type P of Compound 1.

[0064] FIG. 59 shows the X-ray powder diffraction (XRPD) pattern of freeform racemate Type Q of Compound 1.

[0065] FIG. 60 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform racemate Type Q of Compound 1.

[0066] FIG. 61 shows the X-ray powder diffraction (XRPD) pattern of freeform Type R of Compound 1.

[0067] FIG. 62 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type R of Compound 1.

[0068] FIG. 63 shows the X-ray powder diffraction (XRPD) pattern of freeform Type S of Compound 1.

[0069] FIG. 64 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type S of Compound 1.

[0070] FIG. 65 shows the X-ray powder diffraction (XRPD) pattern of freeform Type T of Compound 1.

[0071] FIG. 66 shows the X-ray powder diffraction (XRPD) pattern of freeform Type U of Compound 1.

[0072] FIG. 67 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type U of Compound 1.

[0073] FIG. 68 shows the X-ray powder diffraction (XRPD) pattern of freeform Type V of Compound 1.

[0074] FIG. 69 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type V of Compound 1.

[0075] FIG. 70 shows the X-ray powder diffraction (XRPD) pattern of freeform Type W of Compound 1.

[0076] FIG. 71 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type W of Compound 1.

[0077] FIG. 72 shows the X-ray powder diffraction (XRPD) pattern of freeform Type X of Compound 1.

[0078] FIG. 73 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type X of Compound 1.

[0079] FIG. 74 shows the X-ray powder diffraction (XRPD) pattern of freeform Type Y of Compound 1.

[0080] FIG. 75 shows the X-ray powder diffraction (XRPD) pattern of freeform Type Z of Compound 1 overlaid with freeform Type AA.

[0081] FIG. 76 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AA of Compound 1.

[0082] FIG. 77 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AA of Compound 1.

[0083] FIG. 78 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AB of Compound 1.

[0084] FIG. 79 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AB of Compound 1.

[0085] FIG. 80 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AC of Compound 1.

[0086] FIG. 81 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AC of Compound 1.

[0087] FIG. 82 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AD of Compound 1.

[0088] FIG. 83 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AD of Compound 1.

[0089] FIG. 84 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AE of Compound 1.

[0090] FIG. 85 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AE of Compound 1.

[0091] FIG. 86 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AF of Compound 1.

[0092] FIG. 87 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AG of Compound 1.

[0093] FIG. 88 shows a phase diagram of freeforms of Compound 1 of different form (Eli).

[0094] FIG. 89 shows a phase diagram of freeforms of Compound lof different form (II / II).

[0095] FIG. 90 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type A of Compound 1.

[0096] FIG. 91 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HBr salt Type A of Compound 1.

[0097] FIG. 92 shows the dynamic vapor sorption (DVS) plot of HBr salt Type A of Compound 1.

[0098] FIG. 93 shows the X-ray powder diffraction (XRPD) pattern of 1,5- naphthalenedisulfonate Type A of Compound 1.

[0099] FIG. 94 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of 1,5-naphthalenedisulfonate Type A of Compound 1.

[0100] FIG. 95 shows the dynamic vapor sorption (DVS) plot of 1,5-naphthalenedisulfonate Type A of Compound 1.

[0101] FIG. 96 shows the X-ray powder diffraction (XRPD) pattern of HC1 salt Type A of Compound 1.

[0102] FIG. 97 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HC1 salt Type A of Compound 1.

[0103] FIG. 98 shows the dynamic vapor sorption (DVS) plot of HC1 salt Type A of Compound 1.

[0104] FIG. 99 shows the X-ray powder diffraction (XRPD) pattern of esylate Type A of Compound 1.

[0105] FIG. 100 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of esylate Type A of Compound 1.

[0106] FIG. 101 shows the X-ray powder diffraction (XRPD) pattern of Hippurate Type A of Compound 1.

[0107] FIG. 102 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of Hippurate Type A of Compound 1.

[0108] FIG. 103 shows the X-ray powder diffraction (XRPD) pattern of besylate Types A, B, and C of Compound 1.

[0109] FIG. 104 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of besylate Type A of Compound 1.

[0110] FIG. 105 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of besylate Type B of Compound 1.

[0111] FIG. 106 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of besylate Type C of Compound 1.

[0112] FIG. 107 shows the X-ray powder diffraction (XRPD) pattern of mesylate Type A of Compound 1.

[0113] FIG. 108 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of mesylate Type A of Compound 1.

[0114] FIG. 109 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type A of Compound 1.

[0115] FIG. 110 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HBr salt Type A of Compound 1.

[0116] FIG. Ill shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type B of Compound 1.

[0117] FIG. 112 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HBr salt Type B of Compound 1.

[0118] FIG. 113 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type C of Compound 1.

[0119] FIG. 114 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HBr salt Type C of Compound 1.

[0120] FIG. 115 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type D of Compound 1.

[0121] FIG. 116 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type E of Compound 1.

[0122] FIG. 117 shows the X-ray powder diffraction (XRPD) pattern of HBr salt Type F of Compound 1 overlaid with HBr salt Type C.

[0123] FIG. 118 shows the the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of HBr salt Type F of Compound 1.

[0124] FIG. 119 shows the X-ray powder diffraction (XRPD) pattern of freeform Type Y of Compound 1.

[0125] FIG. 120 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type Y of Compound 1.

[0126] FIG. 121 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AH of Compound 1 overlaid with freeform Type N.

[0127] FIG. 122 shows the X-ray powder diffraction (XRPD) pattern of freeform Type Al of Compound 1 overlaid with freeform Type B.

[0128] FIG. 123 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type Al of Compound 1.

[0129] FIG. 124 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AJ of Compound 1 overlaid with freeform Type AA.

[0130] FIG. 125 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AJ of Compound 1.

[0131] FIG. 126 shows the dynamic vapor sorption (DVS) plot of freeform Type AJ of Compound 1.

[0132] FIG. 127 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AK of Compound 1 overlaid with freeform Type BA.

[0133] FIG. 128 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AK of Compound 1.

[0134] FIG. 129 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AL of Compound 1 overlaid with freeform Type BA.

[0135] FIG. 130 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AL of Compound 1.

[0136] FIG. 131 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AM of Compound 1, overlaid with freeform Type AN.

[0137] FIG. 132 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AM of Compound 1, overlaid with freeform Type AN and freeform Type BA.

[0138] FIG. 133 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AM of Compound 1.

[0139] FIG. 134 shows the X-ray powder diffraction (XRPD) pattern of freeform Type AN of Compound 1 overalid with freeform Type AM and freeform Type BA.

[0140] FIG. 135 shows the differential scanning calorimetry (DSC) thermogram as well as the thermal gravimetric analysis (TGA) of freeform Type AN of Compound 1.DETAILED DESCRIPTION OF EMBODIMENTS

[0141] The present application will be described in detail below with reference to embodiments, but it does not mean that there is any unfavorable limitation to the present application. The present application has been described in detail herein, and the specific embodiments thereof are also disclosed. For those skilled in the art, it would be obvious to make various changes and improvements to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0142] The present disclosure provides crystalline forms of Compound 1. These forms are characterized by an X-ray powder diffraction (XRPD) pattern. Selected crystalline forms are further characterized by a differential scanning calorimetry (DSC), a thermal gravimetric analysis (TGA), and / or a dynamic vapor sorption analysis (DVS). The present disclosure further provides pharmaceutical compositions of the crystalline forms of Compound 1 described herein.Definitions

[0143] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered to be indeterminate or unclear without specific definitions, but should be understood in its ordinarymeaning. When a trade name appears herein, it is intended to refer to a corresponding commercial product or an active ingredient thereof.

[0144] ‘ ‘About” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, “about” means a range extending to + / - 10% of the specified value.

[0145] In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “ includes,” “including,” and the like. “Consisting essentially of or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0146] As used herein, it should be appreciated that the phrase "at least one", when referring to a list of one or more elements, is intended to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of the elements in the list of elements. This definition further allows that elements, other than those specifically determined within the list of elements to which the phrase "at least one" refers, may be optionally present, no matter whether they are related or unrelated to those specifically determined elements.

[0147] Unless otherwise stated, a wedged solid bond and a wedged dotted bond are used to represent an absolute configuration of a stereocenter.

[0148] The compounds disclosed herein may exist in a specific form. Unless otherwise specified, the term "tautomers" or "tautomeric forms" means that isomers of different functional groups are in a dynamic equilibrium and can be rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (such as in a solution). For example, a proton tautomer (also referred to as a prototropic tautomer) comprises an interconversion via migration of a proton, such as keto-enol and imineenamine isomerizations.

[0149] The solvents used in the present invention are commercially available.

[0150] “Substantially free” refers to that an amount of 10% or less of another form is present in a particular desired form, such as 9%, 8.5%, 8%, 7.55, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, or less of another form.

[0151] Certain forms of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. “Hydrate” refers to a compound that is complexed to a stoichiometric or non-stoichiometric amount of water.

[0152] “Crystalline form” refers to a solid form of a compound wherein the constituent molecules are packed in a regularly ordered, repeating pattern. A crystalline form can include triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, and cubic crystal geometries. A crystalline form can include one or more regions, i.e., grains, with distinct crystal boundaries. A crystalline solid can include two or more crystal geometries. A crystalline form can comprise a compound in a salt form, or a compound in a freeform (i.e., non- salt form).

[0153] “Amorphous form” refers to a solid form of a compound having no definite crystal structure, i.e., lacking a regularly ordered, repeating pattern of constituent molecules.

[0154] As disclosed herein, an X-ray powder diffraction (XRPD) pattern may comprise peaks at particular values in degrees 29. In each instance, the recited peaks may vary, e.g., by ± 0.2 degrees 29,. ± 0.1 degrees 29, or ± 0.05 degrees 29.

[0155] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.Form BA of Compound 1

[0156] In embodiments, the crystalline form of Compound 1 is a freeform Type BA (“Form BA”). In embodiments, form BA of Compound 1 is an anhydrate. In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three, at least four, at least five, at least 6, at least 7, at least 8, at least 9, or at least 10 peaks selected from: 4.36, 7.93, 8.80, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.70, 17.91, 18.31, 18.95, 19.68, 20.04, 20.64, 21.09, and 24.11 degrees 29 (± 0.2 degrees 29).

[0157] In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 15.92, and 20.04 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 15.92, and 16.67 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 15.92, 16.67, and 20.04 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 11.98, 15.92, and 16.67 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 11.98, 12.57, 15.92, 16.67, and 20.04 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.98, 12.57, 15.92, 16.67, 17.91, and 20.04 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.98, 12.57, 15.46, 15.92, 16.67, and 17.91 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.91, 20.04, and 21.09 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 8.80, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.70, 17.91, 18.31, 18.95, 19.68, 20.04, 20.64, 21.09, and 24.11 degrees 29 (± 0.2 degrees 29). In embodiments, form BA of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.

[0158] In embodiments, form BA of Compound 1 is characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 185.4 °C and an exotherm peak at about 196.3 °C In embodiments, form BA of Compound 1 is characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 2.

[0159] In embodiments, form BA of Compound 1 is characterized by a weight loss of 1.64% upon heating from about 15 °C to about 200 °C, as measured by thermal gravimetric analysis (TGA). In embodiments, form BA of Compound 1 is characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 2.

[0160] In embodiments, form BA of Compound 1 is prepared by anti-solvent addition to a solution of Compound 1 in dichloromethane (DCM), followed by filtration and drying for isolation. In embodiments, the anti-solvent is acetone, MIBK, THF, ethyl acetate, isopropylacetate, or 2-MeTHF. In embodiments, the anti-solvent is ethyl acetate. In embodiments, form BA of Compound 1 is prepared by anti-solvent addition to a solution of Compound 1 in DCM and methanol, followed by filtration and drying for isolation. In embodiments, form BA of Compound 1 is prepared by anti-solvent addition to a solution of Compound 1 in DCM and methanol wherein methanol comprises less than about 10% by volume of the combined DCM and methanol solvent volume, e.g., less than 10%, less than 5%, or less than 2% by volume. In embodiments, the anti-solvent is acetone, MIBK, THF, ethyl acetate, isopropyl acetate, or 2- MeTHF. In embodiments, the anti-solvent is ethyl acetate.

[0161] In embodiments form BA of Compound 1 is reliably prepared and isolated at large scale, and exhibits sufficient stability and solubility for preparing formulations of Compound 1.

[0162] In embodiments, provided is a pharmaceutical composition comprising a crystalline form of Compound 1 and at least one pharmaceutically acceptable excipient. In embodiments, the crystalline form of Compound 1 is form BA.Other Crystalline Forms of Compound 1

[0163] In embodiments, the crystalline form of Compound 1 is any form as disclosed herein, including the forms disclosed in the Examples provided herein. In embodiments, the crystalline form is a freeform. In embodiments, the crystalline form is a tosylate salt form. In embodiments, the crystalline form is an HBr salt form. In embodiments, the crystalline form is a 1,5-naphthalenedisulfonate salt form. In embodiments, the crystalline form is an HC1 salt form. In embodiments, the crystalline form is an esylate salt form. In embodiments, the crystalline form is a hippurate salt form. In embodiments, the crystalline form is a besylate salt form. In embodiments, the crystalline form is a mesylate salt form. In embodiments, the crystalline form is a hydrate. In embodiments, the crystalline form is a solvate. In embodiments, the crystalline form is an anhydrate.EXAMPLESExample 1: Synthesis of Compound 1Compound 1

[0164] Step 1: Into a mixture of DI, D2, 2 hydroxypyridine N oxide (HOPO), and DMF was added N-(3-dimethylaminopropyl)-N’ -ethylcarbodiimide hydrochloride (EDCI) in portions. After the reaction was deemed complete (consumption of DI confirmed by HPLC analysis), water was added. The crude product was collected by filtration, washed with water, and dried under reduced pressure (residual solvent levels monitored by GC and residual water level monitored by KF). Crude D3 was dissolved in THF containing a small amount of water at elevated temperature, followed by the addition of n heptane to induce precipitation and cooling. The solids were collected by filtration, washed with a mixture of THF and n heptane,and dried under reduced pressure to provide the product D3 (residual solvent levels monitored by GC).

[0165] Step 2: Into a mixture of D3 and MeCN was added a H2SO4 solution. After the reaction was deemed complete (consumption of D3 confirmed by HPLC analysis), an NaOH solution was added. The crude product was collected by filtration, washed with water, and dried under reduced pressure (residual solvent levels monitored by GC and residual water level monitored by KF). Crude D4 was dissolved in DCM at elevated temperature. The solution was concentrated and solvent switched to a mixture of DCM and n heptane. The solids were collected by filtration, washed with a mixture of DCM and n heptane, and dried under reduced pressure to provide the product D4 (residual solvent levels monitored by GC).

[0166] Step 3: Into a mixture of D4, D5, NaOAc, DCM, and MeOH was added NaBH(OAc)3 in portions. After the reaction was deemed complete (consumption of D4 confirmed by HPLC analysis), DCM and MeOH were added, followed by aqueous NaHCOa solution. The layers were separated. (Optionally, the lower organic layer can be subject to additional aqueous washes.) The lower organic layer was polish filtered to obtain a solution of Compound 1 in the resulting filtrate.Example 1A - Preparation of Form BA

[0167] The solution of Compound 1 from Example 1 was concentrated under reduced pressure, optionally seeded with Compound 1, and diluted with EtOAc. The solids were collected by filtration, washed with a mixture of DCM and EtOAc, and dried under reduced pressure to provide the crystalline (form BA) Compound 1 product (residual solvent levels monitored by GC).

[0168] Alternatively, Compound 1 may be prepared as disclosed herein or by methods known in the art, for instance, as disclosed in U.S. Patent No. 11,767,312 and International Patent Application Publication No. WO / 2021 / 249534, and form BA may be prepared by anti-solvent addition of acetone, MIBK, THF, ethyl acetate, isopropyl acetate, or 2-MeTHF to a solution of Compound 1 in DCM, followed by filtration and drying for isolation.Example 2: Tosylate Polymorph ScreeningSummary

[0169] Salt screening on amorphous Compound 1 was performed using p-toluenesulfonic acid as salt co-former. A total of 4 salt screening experiments were performed starting with Compound 1 freeform. Tosylate was selected for further polymorph screening. A total of 100 polymorph screening experiments were performed on tosylate. Due to the complicated polymorphic landscape of the tosylate (FIG. 31), tosylate salts were not selected for further development.Experimental Methods

[0170] Compound 1 starting material was received and used for salt screening experiments. Baseline characterization, including approximate solubility, X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and proton nuclear magnetic resonance (*H NMR) was conducted. The starting material was amorphous. A total of 4 salt screening experiments were conducted in 4 solvent systems using p-toluenesulfonic acid.

[0171] Two crystalline salt hits, tosylate Type A and tosylate Type B, were obtained and characterized. Tosylate Type B showed high residual solvent, which was not selected for evaluation.

[0172] Tosylate was received for polymorph screening experiments. Baseline characterization was performed, which included approximate solubility, XRPD, TGA, DSC and!H NMR. XRPD result showed the sample was crystalline but different with tosylate Type A and B, which assigned tosylate Type C. 100 polymorph screening experiments were performed. 20 crystalline forms were obtained and assigned as tosylate Type A~T. Characterization and identification of the forms were performed, tosylate Type A / B / C / D / H / L / O were speculated to be hydrate, tosylate Type M / N / P / R / S were speculated to be anhydrate, and the other forms were speculated to be solvate and unidentified forms (form changed after exposed to ambient or failed to re-prepare). Characterization results of the polymorphs were summarized in Table1. Inter-conversion diagram of the crystal forms was shown in FIG. 31.Table 1Tosylate Type A

[0173] Tosylate Type A was obtained during salt screening and polymorph screening. As shown in FIG. 3, starting with tosylate Type C, tosylate Type A was obtained via solid vapor diffusion in IP Ac for 14 days followed by vacuum drying at RT for 1 day. TGA / DSC results were shown in FIG. 4. TGA result showed a weight loss of 6.9% up to 160 °C. DSC result showed three endotherms at 69.0 °C, 141.3 °C and 217.8 °C (peak).NMR result shows the molar ratio of acid / freeform was 1.0, and no obvious residual solvent was observed in tosylate Type A. VT-XRPD results showed tosylate Type A converted to tosylate Type P under N2 bleeding for 20 min, possibly due to dehydration. No form change was observed after heating tosylate Type A to 100 °C orl50 °C and then cooling to 30 °C under N2 protection. Tosylate Type P converted to tosylate Type A after exposed to ambient condition. Therefore, tosylate Type A was speculated to be hydrate and tosylate Type P was speculated to be metastable anhydrate form.Tosylate Type B

[0174] As shown in FIG. 5, tosylate Type B was obtained via slow evaporation in I. TGA / DSC results were shown in FIG. 6. TGA result showed a weight loss of 8.6% up to 150 °C. DSC result showed three endotherms at 77.7 °C, 162.5 °C and 193.9 °C (peak).NMR result showed the molar ratio of acid / freeform was 1.0, and no obvious residual solvent was observed in tosylate Type B. Tosylate Type B was speculated to be hydrate according to the characterization results.

[0175] The starting material freeform amorphous and 1 equivalent of p-toluenesulfonic acid were mixed in THF / H2O (19:1, v / v), and then stirred at RT for 4 days to re -prepared tosylate Type B. A mixture of tosylate Type B and tosylate Type D was obtained in the three repreparation experiments.Tosylate Type C

[0176] Tosylate Type C was received for polymorph screening experiments. Baseline characterization was performed, which included approximate solubility, XRPD, TGA, DSC NMR. XRPD pattern of tosylate Type C was displayed in FIG. 7. TGA / DSC results were shown in FIG. 8. TGA result showed a weight loss of 2.9% up to 150 °C. DSC result showed three endotherms at 69.5 °C, 193.2 °C and 219.2 °C (peak).NMR spectrum, the molar ratio of acid / freeform was 1.0 and no obvious residual solvent was observed. Tosylate Type C converted to tosylate Type A after heated to 100 °C and cooled to ambient. Based on the characterization result, tosylate Type C is speculated to be a hydrate.Tosylate Type D

[0177] As shown in FIG. 9, tosylate Type D was obtained via temperature cycling slurry of tosylate Type C in EtOH / H2O (1:4, v / v). TGA / DSC results were shown in FIG. 10. TGA result showed a weight loss of 6.6% up to 150 °C. DSC result showed one endotherms at104.4 °C (peak).NMR result showed the molar ratio of acid / freeform was 1.0, and no obvious residual solvent was observed in tosylate Type D. Tosylate Type D converted to amorphous after heated to 150 °C and cooled to ambient. VT-XRPD results showed tosylate Type D converted to tosylate Type M under N2 bleeding for 20 min, possibly due to dehydration. No form change was observed after heating tosylate Type M to 70 °C and cooling to 30 °C under N2 protection. Tosylate Type M converted back to tosylate Type D after exposed to ambient condition. Therefore, tosylate Type D was speculated to be hydrate. Tosylate Type M was speculated to be metastable anhydrate form.Tosylate Type H

[0178] As shown in FIG. 15 (bottom trace, “dry cake”), tosylate Type H was obtained via slurry tosylate Type C at 50 °C in I / H2O (aw~0.2) for 3 days. TGA / DSC results were shown in FIG. 16. TGA result showed a weight loss of 5.8% up to 150 °C. DSC result showed three endotherms at 80.7 °C, 95.5 °C and 193.9 °C (peak).NMR result showed the molar ratio of acid / freeform was 1.0, and no obvious residual solvent was observed in tosylate Type H. VT- XRPD results showed tosylate Type H converted to tosylate Type N after under N2 bleeding for 20 min, possibly due to dehydration. No form change was observed after heating tosylate Type N to 140 °C and cooling the sample to 30 °C under N2 protection. Tosylate Type N converted back to tosylate Type H after exposed to ambient condition. Tosylate Type H was speculated to be hydrate. Tosylate Type N was speculated to be metastable anhydrate form.Tosylate Type L

[0179] Tosylate Type L was obtained via slurry tosylate Type C in acetone at 50 °C followed by air drying. XRPD pattern of tosylate Type L was displayed in FIG. 20 (bottom trace, tosylate Type L ref). TGA / DSC results were shown in FIG. 21. TGA result showed a weight loss of 3.9% up to 110 °C. DSC result showed four endotherms at 72.7 °C, 159.9 °C, 183.2 °C and 197.8 °C (peak).NMR spectrum, the molar ratio of acid / freeform was 1.0 and no obvious residual solvent was observed in tosylate Type L.

[0180] VT-XRPD results of tosylate Type L showed no form change under N2 bleeding for 20 min, and tosylate Type L converted to tosylate Type S after heating to 100 / 160 / 185 °C and then cooling to 30 °C under N2 protection. Tosylate Type S converted back to tosylate Type L after exposed to condition for Ih. Tosylate Type L was speculated to be hydrate. Tosylate Type S was speculated to be metastable anhydrate form. Tosylate Type L was re-prepared for interconversion relationship study via slurry tosylate Type C in acetone for 2 days followed by air drying for 1 day. XRPD pattern of re-prepared tosylate Type L was displayed in FIG. 20 (top trace, “re -prepared sample”).Tosylate Type O

[0181] Tosylate Type J was only observed in wet cake and converted to tosylate Type O after air drying. XRPD pattern of tosylate Type O was displayed in FIG. 24. TGA / DSC results were shown in FIG. 25. TGA result showed a weight loss of 5.6% up to 150 °C. DSC result showed one endotherm at 204.0 °C (peak).NMR spectrum, the molar ratio of acid / freeform was 1.0 and no obvious residual solvent was observed in tosylate Type O.

[0182] VT-XRPD results showed no form change was observed under N2 bleeding for 20 min, and tosylate Type O converted to tosylate Type R after heated to 150 °C and cooled to 30 °C under N2 protection. Tosylate Type R converted to tosylate Type O after exposed to ambient condition for 20 min. Tosylate Type O was speculated to be hydrate according to the characterization results. Tosylate Type R was speculated to be metastable anhydrate. Form Tosylate Type O was re-prepared for inter-conversion relationship study via slurry tosylate Type C in acetone. Tosylate Type O was selected for evaluation and re-prepared on 500 mg scale. About 500 mg tosylate Type C was stirred in acetone for 2 days and tosylate Type L was obtained. After transferred to 50 °C slurry for 2 h, tosylate Type O was obtained. TGA result showed a weight loss of 2.6% up to 150 °C. DSC result showed two endotherms at 77.5 °C and 198.4 °C (peak).NMR spectrum, the molar ratio of acid / freeform was 1.2 and no residual solvent was observed in re-prepared tosylate Type O.AnhydrateTosylate Type M

[0183] In VT XRPD test, tosylate Type D converted to tosylate Type M FIG. 22 after N2 bleeding for 20 min, and tosylate Type M converted back to tosylate Type D after exposed to ambient condition for 30 min. Tosylate Type M was speculated to be metastable anhydrate form.Tosylate Type N

[0184] Tosylate Type N was observed by heating tosylate Type H to 140 °C and cooled to 30 °C under N2 protection in VT XRPD test. XRPD pattern of tosylate Type N was displayed in FIG. 23. Tosylate Type N converted back to tosylate Type H after exposed under ambient condition for 30 min. Tosylate Type N was speculated to be anhydrate according to the results. Tosylate Type P

[0185] In VT XRPD test, tosylate Type A converted to tosylate Type P after N2 bleeding for 20 min. XRPD pattern of tosylate Type P was displayed in FIG. 26. Tosylate Type P converted back to tosylate Type A after exposed to ambient condition for 30 min. Tosylate Type P was speculated to be anhydrate.Tosylate Type R

[0186] Tosylate Type R was obtained by heating tosylate Type O to 150 °C and cooled to 30 °C under N2 protection. Tosylate Type R converted to tosylate Type O after exposed underambient condition for 20 min. Tosylate Type R was speculated to be anhydrate according to the results. XRPD pattern of tosylate Type R was displayed in FIG. 28.Tosylate Type S

[0187] Tosylate Type S was obtained by heating tosylate Type L to 100 °C and cooled to 30 °C under N2 protection. Tosylate Type S converted to tosylate Type L after exposed to ambient condition for 60 min. Tosylate Type S was speculated to be anhydrate according to the results. XRPD pattern of tosylate Type S was displayed in FIG. 29.SolvateTosylate Type E

[0188] Tosylate Type E was obtained via slurry tosylate Type C in 1,4-dioxane at 50 °C. XRPD pattern was shown in FIG. 11. Low crystallinity sample was obtained after drying. TGA / DSC results were shown in FIG. 12. TGA result showed a weight loss of 6.2% up to 110 °C. DSC result showed one endotherm at 84.1 °C (peak) and one exothermic peak at 167.0 °C (peak).NMR result showed the molar ratio of 1,4- dioxane to tosylate was 0.6 (~4.8 wt%). To investigate the form origin, heating experiment was conducted. After heating tosylate Type E to 120 °C and cooling to ambient, no form change was observed.NMR result of heated sample showed the molar ratio of 1,4-dioxane to tosylate was 0.5 (~4.0 wt%). Therefore, tosylate Type E was speculated to be 1,4- dioxane solvate.Unidentified Crystal FormTosylate Type F

[0189] Tosylate Type I converted to tosylate Type F after air drying. XRPD pattern of tosylate Type I and Type F were displayed in FIG. 13 (top trace, “wet sample” tosylate Type I; middle trace, “dry sample” tosylate Type F formed after air-drying Tosylate Type I; bottom trace, tosylate Type F reference). Three batches of tosylate Type F was re-prepared via antisolvent experiments in DMSO / IPAc system (two batches) or DMSO / Toluene (one batch), while the samples converted to tosylate Type O after vacuum drying for 1 day. No further characterization was performed.Tosylate Type G

[0190] Tosylate Type G was obtained via slurry tosylate Type C in NMP / IPA (1:2, v / v) system for 3 days at 50 °C. Tosylate Type G converted to tosylate Type K after air drying. XRPD pattern of tosylate Type G was displayed in FIG. 14 (top trace, “wet sample” tosylate Type G; middle trace, “dry sample” tosylate Type K; bottom trace, tosylate Type K reference). Tosylate Type G was attempted to re-prepare for three times via anti-solvent experiments or slurry tosylate Type C in NMP / IPA (1:2, v / v). However, amorphous was obtained. No further characterization was performed.Tosylate Type I

[0191] Tosylate Type I was obtained via anti-solvent addition in DMSO / l,4-dioxane system. Tosylate Type I converted to tosylate Type F after air drying. XRPD pattern of tosylate Type I was displayed in FIG. 17 (top trace, “wet sample”, tosylate Type I; middle trace, “dry sample”, tosylate Type F; bottom trace, tosylate Type F reference.). No further characterization was performed.Tosylate Type J

[0192] Tosylate Type J was obtained via anti-solvent addition in DMSO / IPAc system.Tosylate Type J converted to tosylate Type O after air drying. XRPD pattern of tosylate Type J was displayed in FIG. 18. No further characterization was performed.Tosylate Type K

[0193] Tosylate Type K was obtained via anti-solvent addition in DMSO / acetone system. Tosylate Type K converted to tosylate Type O after air drying. XRPD pattern of tosylate Type K was displayed in FIG. 19. No further characterization was performed.Tosylate Type Q

[0194] Tosylate Type Q was obtained via slow cooling in THF followed by slow evaporation. Tosylate Type K converted to tosylate Type O after air drying. XRPD pattern of tosylate Type Q was displayed in FIG. 27. Tosylate Type Q was attempted to re-prepare for two times via slurry tosylate Type C in THF system in presence of seed, while tosylate Type A with additional peaks was obtained. No further characterization was performed.Tosylate Type T

[0195] Tosylate Type T was obtained via slurry tosylate Type C in acetone for 3 days. The sample was observed in wet cake (covered with film), and the sample converted to a mixture of tosylate Type A and Type O after exposed in air, and the wet sample converted to tosylate Type O after drying. XRPD pattern was displayed in FIG. 30 (top trace, tosylate Type T observed in wet cake (covered with film); second trace, tosylate Types A and O; third trace, tosylate Type O after drying; fourth trace, tosylate Type O ref; bottom trace, tosylate Type A reference). The form was speculated to be metastable form, and no further investigation was performed.Example 3: Freeform Polymorph Screening

[0196] Compound 1 as received was characterized by X-ray powder diffraction (XRPD), Thermo-gravimetric analysis (TGA) and modulated differential scanning calorimetry (DSC). The material showed low crystallinity.

[0197] Starting with Compound 1 freeform low crystallinity sample, polymorph screening experiments were conducted under 85 conditions, using methods of anti-solvent addition, slow evaporation, slurry at RT / 50 °C, temperature cycling, solid vapor diffusion and liquid vapordiffusion. Additionally, polymorph screening experiments were conducted under 15 conditions starting with freeform Type G, including slurry at RT / 5 °C / 50 °C. Based on the XRPD comparison 33 forms, Type A~AG were observed, in which Type Q was confirmed as racemate via chiral HPLC.

[0198] The characterization results are summarized in Table 2.Table 2Freeform Type A

[0199] Freeform Type A was obtained via slurry starting material in EtOAc at RT, as XRPD displayed in FIG. 32. As shown in FIG. 33, TGA result showed a weight loss of 1.25% up to 150 °C, and DSC result showed two endothermic peaks at 227.6 and 292.0 °C (peak temperature) and one exothermic peak at 230.3 °C (peak temperature). Based on!H NMR results, no EtOAc was detected. Combined the limited TGA weight loss and no endotherm before form transition in DSC, freeform Type A is speculated to be anhydrate.

[0200] To investigate DSC signals, heating experiment was conducted. After heating to 250 °C and cooling to ambient, form change to Type Q was observed. Freeform Type Q is speculated to be racemate by chiral HPLC test.Freeform Type G

[0201] Freeform Type G was obtained via heating-cooling in butyl acetate starting with material, as XRPD displayed in FIG. 44. As shown in FIG. 45, TGA result showed a weight loss of 1.40% up to 150 °C, and DSC result showed two endothermic peaks at 258.1 and 292.4 °C (peak temperature) and one exothermic peak at 261.0 °C (peak temperature). Based on!H NMR results, the molar ratio of butyl acetate to freeform was 0.02 (0.2 wt%). Combined the limited TGA weight loss and no endotherm before form transition in DSC, freeform Type G is speculated to be anhydrate.

[0202] To investigate DSC signals, heating experiment was conducted. After heating to 270 °C and cooling to ambient, form change to Type Q was observed. Type Q is confirmed as racemate by chiral HPLC test.Freeform Racemate Type Q

[0203] Freeform Type Q was obtained via heating Type A to 250 °C, as XRPD displayed in FIG. 59. As shown in FIG. 60, TGA result showed a weight loss of 2.73% up to 150 °C, and DSC result showed one endothermic peak at 292.1 °C (peak temperature). Based on ’ H NMR results, no residual solvent was detected. Combined the limited TGA weight loss and neat DSC, freeform Type Q is speculated to be anhydrate. Freeform Type Q is confirmed as racemate by chiral HPLC test.Freeform Type R

[0204] Freeform Type R was obtained via heating Type B to 180 °C, as XRPD displayed in FIG. 61. As shown in FIG. 62, TGA result showed a weight loss of 2.29% up to 150 °C, and DSC result showed two endothermic peaks at 253.1 and 291.5 °C (peak temperature) and two exothermic peaks at 188.9 and 255.0 °C (peak temperature). Based on1H NMR results, the molar ratio of 1,4-dioxane to freeform was 0.1 (1.3 wt%).

[0205] To investigate form origin, VT XRPD experiment was conducted for freeform Type R. VT XRPD results showed, no form change was observed after heating to 150 °C, 200 °C and cool to 30 °C under N2 protection.1H NMR results showed no residual 1,4-dioxane was observed. Combined characterization and VT results, freeform Type R is speculated to be anhydrate.Freeform Type S

[0206] Freeform Type S was obtained via heating Type E to 200 °C, as XRPD displayed in FIG. 63. As shown in FIG. 64, TGA result showed a weight loss of 5.60% up to 150 °C, and DSC result showed two endothermic peaks at 290.3 and 291.8 °C (peak temperature). Based onNMR results, no residual solvent was detected. Combined sample preparation method and characterization results, freeform Type S is speculated to be anhydrate.Freeform Type T

[0207] Freeform Type T was obtained via heating Type E to 150 °C, as XRPD displayed in FIG. 65. VT XRPD experiment was conducted for freeform Type E. VT XRPD results showed, form change to Type T was observed after heating to 150 °C and cool to 30 °C under N2 protection. Considering freeform Type T could be obtained via in-situ heating under low humidity, freeform Type T is speculated to be anhydrate.Freeform Type U

[0208] Freeform Type U was obtained via heating Type N to 150 °C, as XRPD displayed in FIG. 66. As shown in FIG. 67, TGA result showed a weight loss of 4.03% up to 150 °C, and DSC result showed two endothermic peaks at 252.6 and 291.4 °C (peak temperature). Based on NMR results, no residual solvent was observed.To investigate form origin, heating experiments were conducted. After heating to 260 °C and cooling to ambient, form change to Type Q was observed. VT XRPD experiment was conducted for freeform Type N. VT XRPD results showed, form change to Type U was observed after heating to 150 °C and cool to 30 °C under N2 protection. Considering freeform Type T could be obtained via in-situ heating under low humidity, freeform Type U is speculated to be anhydrate.Freeform Type V

[0209] Freeform Type V was obtained via heating Type P to 150 °C, as XRPD displayed in FIG. 68. As shown in FIG. 69, TGA result showed a weight loss of 1.75% up to 150 °C, and DSC result showed one endothermic peak at 291.6 °C (peak temperature) and one exothermic peak at 247.3 °C (peak temperature). Based onNMR results, no residual solvent was observed.

[0210] To investigate form origin, heating experiments were conducted. After heating to 260 °C and cooling to ambient, form change to Type Q was observed. VT XRPD experiment was conducted for freeform Type P. VT XRPD results showed, form change to Type V was observed after heating to 150 °C and cool to 30 °C under N2 protection. Considering freeform Type V could be obtained via in-situ heating under low humidity, freeform Type V is speculated to be anhydrate.Freeform Type X

[0211] Freeform Type X was obtained via heating Type W to 200 °C, as XRPD displayed in FIG. 72. As shown in FIG. 73FIG. 74, TGA result showed a weight loss of 2.83% up to 150 °C, and DSC result showed one endothermic peak at 292.0 °C (peak temperature) and oneexothermic peak at 248.4 °C (peak temperature). Based on!H NMR results, no residual solvent was observed.

[0212] To investigate form origin, VT XRPD experiment was conducted for freeform Type W. VT XRPD results showed form change to Type X was observed after heating to 200 °C and cool to 30 °C under N2 protection. Considering freeform Type X could be obtained via in-situ heating under low humidity, freeform Type X is speculated to be anhydrate.HydratesFreeform Type E

[0213] Freeform Type E was obtained via slurry starting material in EtOH / H2O (0.925 / 0.075, aw~0.4) at RT, as XRPD displayed in FIG. 41. As shown in FIG. 42, TGA result showed a weight loss of 4.97% up to 150 °C, and DSC result showed three endothermic peaks at 89.9, 175.3 and 291.6 °C (peak temperature) and one exothermic peak at 189.8 °C (peak temperature). Based onNMR results, no residual EtOH was observed.

[0214] To investigate form origin, heating experiments were conducted. After heating to 150 °C and cooling to ambient, form change to Type T was observed. After heating to 200 °C and cooling to ambient, form change to Type S was observed. Combined with characterization results and heating experiments, freeform Type E is speculated to be a hydrate.Freeform Type P

[0215] Freeform Type P was obtained via slurry starting material in H2O at 50 °C, as XRPD displayed in FIG. 57. As shown in FIG. 58, TGA result showed a weight loss of 3.08% up to 150 °C, and DSC result showed two endothermic peaks at 67.2 and 290.9 °C (peak temperature) and one exothermic peak at 245.9 °C (peak temperature). Based onNMR results, no residual EtOH was observed.

[0216] To investigate form origin, heating experiments were conducted. After heating to 150 °C and cooling to ambient, form change to Type V was observed. Combined with characterization results and heating experiments, freeform Type P is speculated to be a hydrate.Anhydrate or HydrateFreeform Type D

[0217] Freeform Type D was obtained via slurry starting material in acetone at RT, as XRPD displayed in FIG. 38. As shown in FIG. 39, TGA result showed a weight loss of 3.75% up to 180 °C, and DSC result showed three endothermic peaks at 180.0, 222.2 and 292.4 °C (peak temperature) and two exothermic peaks at 192.1 and 249.1 °C (peak temperature). Based on ’ H NMR results, the molar ratio of acetone to freeform was 0.3 (2.2 wt%).

[0218] To investigate form origin, heating experiments were conducted. After heating to 200 °C and cooling to ambient, form change to Type S was observed. After heating to 260 °C and cooling to ambient, form change to Type Q was observed. After N2 bleeding, no form changewas observed andresults showed the molar ratio of acetone to freeform was 0.03 (0.2 wt%) Combined with characterization results and heating experiments, freeform Type D is speculated to be anhydrate or hydrate.Freeform Type W

[0219] Freeform Type W was obtained via slurry starting material in acetone at RT, as XRPD displayed in FIG. 70. As shown in FIG. 71, TGA result showed a weight loss of 4.37% up to 150 °C, and DSC result showed three endothermic peaks at 105.0, 158.8 and 292.3 °C (peak temperature) and two exothermic peaks at 177.5 and 248.8 °C (peak temperature). Based on NMR results, the molar ratio of acetone to freeform was 0.04 (0.3 wt%).

[0220] To investigate form origin, heating experiments were conducted. After heating to 200 °C and cooling to ambient, form change to Type X was observed. After heating to 260 °C and cooling to ambient, form change to Type Q was observed. Combined with characterization results and heating experiments, freeform Type W is speculated to be anhydrate or hydrate.SolvateFreeform Type B

[0221] Freeform Type B was obtained via slurry starting material in 1,4-dioxane at RT, as XRPD displayed in FIG. 34. As shown in FIG. 35, TGA result showed a weight loss of 20.99% up to 180 °C, and DSC result showed four endothermic peaks at 115.6, 163.6, 253.3 and 292.2 °C (peak temperature) and two exothermic peaks at 199.1 and 255.4 (peak temperature). Based onNMR results, the molar ratio of 1,4-dioxane to freeform was 2.4 (20.8 wt%).

[0222] To investigate form origin, heating experiments were conducted. After heating to 180 °C and cooling to ambient, form change to Type R was observed. After heating to 220 °C and cooling to ambient, form change to Type Y was observed. Combined with characterization results and heating experiments, freeform Type B is speculated to be 1,4-dioxane solvate.Freeform Type F

[0223] Freeform Type F was obtained via slurry starting material in DMF / MEK (1:3, v / v) at RT, as XRPD displayed in FIG. 42. As shown in FIG. 43, TGA result showed a weight loss of 8.25% up to 180 °C, and DSC result showed three endothermic peaks at 153.2, 228.0 and 292.4 °C (peak temperature) and one exothermic peak at 251.2 (peak temperature). Based onNMR results, the molar ratio of DMF to freeform was 0.8 (6.7 wt%).

[0224] To investigate form origin, heating experiments were conducted. After heating to 180 °C and cooling to ambient, form change to Type A was observed. Combined with characterization results and heating experiments, freeform Type F is speculated to be DMF solvate.Freeform Type I

[0225] Freeform Type I was obtained via anti-solvent addition in DMAc / MTBE at RT followed by air drying, as XRPD displayed in FIG. 47. The wet sample was freeform Type J. As shown in FIG. 48, TGA result showed a weight loss of 10.83% up to 200 °C, and DSC result showed four endothermic peaks at 159.7, 226.4, 253.3 and 292.2 °C (peak temperature) and one exothermic peak at 254.2 (peak temperature). Based on!H NMR results, the molar ratio of DMAc to freeform was 1.2 (11.0 wt%) and the molar ratio of MTBE to freeform was 0.02 (0.2%).

[0226] To investigate form origin, heating experiments were conducted. After heating to 200 °C and cooling to ambient, form change to Type Q was observed. Combined with characterization results and heating experiments, freeform Type I is speculated to be DMAc solvate.Freeform Type AA

[0227] Freeform Type AA was obtained via slurry competition in THF starting with from G / S / Q at RT and 50 °C followed by air drying, as XRPD displayed in FIG. 76. As shown in FIG. 77, TGA result showed a weight loss of 6.43% up to 180 °C, and DSC result showed one endothermic peak at 291.9 °C (peak temperature). Based on!H NMR results, the molar ratio of THF to freeform was 0.6 (5.1 wt%).

[0228] To investigate form origin, heating experiment was conducted. After heating to 180 °C and cooling to ambient, form change to Type U was observed.1H NMR results showed no THF was observed. Combined with characterization results and heating experiments, freeform Type AA is speculated to be THF solvate.Freeform Type AB

[0229] Freeform Type AB was obtained via liquid vapor in DMSO / IPA at RT, as XRPD displayed in FIG. 78. As shown in FIG. 79, TGA result showed a weight loss of 9.83% up to 200 °C, and DSC result showed three endothermic peaks at 178.7, 253.6 and 292.0 °C (peak temperature) and one exothermic peak at 216.9 °C (peak temperature). Based on1H NMR results, the molar ratio of DMSO to freeform was 0.8 (7.1 wt%).

[0230] To investigate form origin, VT XRPD was conducted. After heating to 200 °C under N2 protection, form change to Type AF was observed.1H NMR results showed no DMSO was observed. Combined with characterization results and heating experiments, freeform Type AB is speculated to be DMSO solvate.Freeform Type AC

[0231] Freeform Type AC was obtained via liquid vapor in 1 ,4-dioxane / IPA at RT, as XRPD displayed in FIG. 80. As shown in FIG. 81, TGA result showed a weight loss of 11.06% up to 200 °C, and DSC result showed three endothermic peaks at 163.3, 229.8 and 292.7 °C (peaktemperature) and one exothermic peak at 234.4 °C (peak temperature). Based onNMR results, the molar ratio of 1,4-dioxane to freeform was 0.9 (9.2 wt%).

[0232] To investigate form origin, heating experiment was conducted. After heating to 200 °C and cooling to ambient, form change to Type A was observed.NMR results showed no 1,4- dioxane was observed. Combined with characterization results and heating experiments, freeform Type AC is speculated to be 1,4-dioxane solvate.Freeform Type AD

[0233] Freeform Type AD was obtained via solid vapor in DMSO at RT, as XRPD displayed in FIG. 82. As shown in FIG. 83, TGA result showed a weight loss of 17.38% up to 180 °C, and DSC result showed five endothermic peaks at 94.2, 141.3, 217.9, 256.9 and 292.3 °C (peak temperature) and one exothermic peak at 259.9 °C (peak temperature). Based onNMR results, the molar ratio of DMSO to freeform was 2.1 (16.7 wt%).

[0234] To investigate form origin, heating experiments were conducted. After heating to 130 °C and cooling to ambient, form change to Type G+peaks was observed. After heating to 180 °C and cooling to ambient, form change to Type G was observed. Combined with characterization results and heating experiments, freeform Type AD is speculated to be DMSO solvate.Solvate or HydrateFreeform Type C

[0235] Freeform Type C was obtained via slurry in MTBE at RT, as XRPD displayed in FIG. 36. As shown in FIG. 37, TGA result showed a weight loss of 5.64% up to 180 °C, and DSC result showed three endothermic peaks at 139.2, 226.8 and 292.0 °C (peak temperature) and one exothermic peak at 229.3 °C (peak temperature). Based onNMR results, the molar ratio of MTBE to freeform was 0.3 (2.9 wt%).

[0236] To investigate form origin, heating experiments were conducted. After heating to 180 °C and cooling to ambient, form change to Type A was observed. After N2 bleeding for 30 mins, no form change was observed andNMR results showed the molar ratio of MTBE to freeform was 0.2 (2.2 wt%). Combined with characterization results and heating experiments, freeform Type C is speculated to be MTBE solvate or hydrate.Freeform Type L

[0237] Freeform Type L was obtained via slurry in ACN at 50 °C, as XRPD displayed in FIG. 51. As shown in FIG. 52, TGA result showed a weight loss of 4.40% up to 150 °C, and DSC result showed three endothermic peaks at 89.7, 165.2 and 292.3 °C (peak temperature) and two exothermic peaks at 205.7 and 249.2 °C (peak temperature). Based on NMR results, the molar ratio of ACN to freeform was 0.4 (2.1 wt%).

[0238] To investigate form origin, heating experiments were conducted. After heating to 130 °C and cooling to ambient, no form change but with peak shift was observed, After heating to 220 °C and cooling to ambient, form change to Type Y was observed. After heating to 260 °C and cooling to ambient, form change to Type Q was observed. After N2 bleeding for 30 mins, no form change but with peak shift was observed andNMR results showed no ACN was observed. Combined with characterization results and heating experiments, freeform Type L is speculated to be ACN solvate or hydrate.Freeform Type N

[0239] Freeform Type N was obtained via slurry in toluene at 50 °C, as XRPD displayed in FIG. 54. As shown in FIG. 55, TGA result showed a weight loss of 21.42% up to 150 °C, and DSC result showed two endothermic peaks at 130.8 and 291.4 °C (peak temperature) and two exothermic peaks at 175.5 and 225.0 °C (peak temperature). Based onNMR results, the molar ratio of toluene to freeform was 1.4 (13.8 wt%).

[0240] To investigate form origin, heating experiment was conducted. After heating to 150 °C and cooling to ambient, form change to Type U was observed. Combined with characterization results and heating experiments, freeform Type N is speculated to be toluene solvate or hydrate.Freeform Type AE

[0241] Freeform Type AE was obtained via liquid vapor in NMP / EtOH at RT, as XRPD displayed in FIG. 84. As shown in FIG. 85, TGA result showed a weight loss of 23.64% up to 200 °C, and DSC result showed two endothermic peaks at 116.5 and 186.7 °C (peak temperature) and two exothermic peaks at 116.5 and 186.7 °C (peak temperature). Based on NMR results, the molar ratio of toluene to freeform was 1.0 (10.5 wt%).

[0242] To investigate form origin, VT XRPD was conducted. After heating to 200 °C and cooling to 30 °C under N2 protection and then exposing at ambient, form change to Type AG was observed and no NMP was observed. Combined with characterization results and heating experiments, freeform Type AE is speculated to be NMP solvate or hydrate.Metastable FormFreeform Type H

[0243] Freeform Type H was obtained via anti-solvent addition in DMSO / IPA at RT, as XRPD displayed in FIG. 46. Freeform Type H was only observed in wet sample and converted to freeform Type A after air drying. Therefore, freeform Type H was metastable form.Freeform Type J

[0244] Freeform Type J was obtained via anti-solvent addition in DMAc / MTBE at RT, as XRPD displayed in FIG. 49. Freeform Type J was only observed in wet sample and converted to freeform Type I after air drying. Therefore, freeform Type J was metastable form.Freeform Type K

[0245] Freeform Type K was obtained via anti- solvent addition in THF / H2O at RT, as XRPD displayed in FIG. 50. Freeform Type K was only observed in wet sample and converted to freeform Type A after air drying. Therefore, freeform Type K was metastable form.Freeform Type M

[0246] Freeform Type M was obtained via slurry in CPME at 50 °C, as XRPD displayed in FIG. 53. Freeform Type M was only observed in wet sample and converted to freeform Type A after air drying. Therefore, freeform Type M was metastable form.Freeform Type O

[0247] Freeform Type O was obtained via slurry in IPA at 50 °C, as XRPD displayed in FIG. 56. Freeform Type O was only observed in wet sample and converted to freeform Type A after air drying. Therefore, freeform Type O was metastable form.Freeform Type Z

[0248] Freeform Type Z was obtained via slurry competition of freeform Type G / S / Q in THF at RT and 50 °C, as XRPD displayed in FIG. 75. Freeform Type Z was only observed in wet sample and converted to freeform Type AA after air drying. Therefore, freeform Type Z was metastable form.Unidentified FormsFreeform Type Y

[0249] Freeform Type Y could be obtained via heating freeform Type B / L to 220 °C and cooling to ambient, as XRPD displayed in FIG. 74. Freeform Type L was attempted to reprepared for 11 times, while pure freeform Type L was not obtained.Freeform Type AF

[0250] Freeform Type AF was obtained via heating freeform Type AB to 200 °C under N2 protection, as XRPD displayed in FIG. 86. Freeform Type AB was attempted to re-prepared for 3 times, while only clear solution obtained.Freeform Type AG

[0251] Freeform Type AG was obtained via heating freeform Type AE to 200 °C under N2 protection, as XRPD displayed in FIG. 87. Freeform Type AE was attempted to re-prepared for 3 times, while only clear solution obtained (Table 2 3).Example 4: Further Salt and Polymorph Screening

[0252] Summary: Using Compound 1 amorphous as the starting material, salt screening was performed under 176 different conditions using 44 acids in 4 solvent systems. The results were summarized in Table 3. A total of 10 crystalline salt hits were obtained during screening and identification, which were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The salt stoichiometry was determined using high performance liquid chromatography (HPLC) combined with ion chromatography (IC) or 1H solution nuclear magnetic resonance (*H NMR).Using HBr salt Type A as the starting material, 101 polymorph screening experiments were performed, using methods of anti-solvent addition, slow evaporation, slow cooling, slurry at RT / 50 °C, temperature cycling, solid vapor diffusion, liquid vapor diffusion, and grinding. Based on the XRPD characterization results, a total of six HBr salt polymorphs were obtained, including two anhydrates (HBr salt Type F and D), two hydrates (HBr salt Type A and C), one to-be-identified form (HBr salt Type E) and a disproportionated product (“HBr salt Type B”).

[0253] Besides salt screening studies, investigation was also performed on freeform to determine the inter-conversion relationship among the freeform anhydrates discovered in previous studies (Type A / G / Q / R / S / T / U / V / X). To set slurry competition experiments, repreparation of the anhydrates were firstly performed. As a result, freeform Type A / G / Q / S / T / U / V / X were successfully re-prepared. For freeform anhydrate Type R, only a mixture of freeform Type R+G was obtained. Meanwhile, two new freeform anhydrates (Type BA and AN) were obtained from follow-up studies. Also, the unidentified freeform Type Y in previous studies (Example 3) was successfully re-prepared and identified to be anhydrous.Salt Screening

[0254] Around 20 mg of starting material and corresponding salt former were added in 0.5 mL solvent followed by slurry at RT for 2 days. The solids obtained were characterized byXRPD. The results were summarized in Table 3Table 3a: Clear solution was transferred to slurry at 5 °C / -20 °C and evaporation; b: Gel was transferred to slurry at 5 °C and temperature cycling.HBr salt

[0255] HBr salt Type A was obtained via slurry the mixture of freeform and HBr (molar ratio of 1:1, acid / FB) in EtOH at RT for 1 day. The XRPD overlay displayed in FIG. 90 showed that no form change was observed before and after drying. The TGA / DSC curves of HBr salt Type A were displayed in FIG. 91, which showed a weight loss of 2.05% up to 200 °C and two endotherms at 67.1 °C and 293.3 °C (peak temperature). The ’ H NMR result showed the molar ratio of EtOH / freeform was 0.03 (0.2 wt%). HPLC / IC results showed the molar ratio of acid / FB was 0.9. Achiral HPLC purity of HBr salt Type A was determined to be 99.61 area% . Chiral purity of HBr salt Type A was determined to be 99.33 area%. DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH, as shown in FIG. 92. Three re-prepared salt samples were equilibrated at ambient humidity (30%RH) to prevent form change before testing. XRPD characterization was performed to check any solid form change for the samples after DVS test. No form change was observed after DVS test.1,5-Naphthalenedisulfonate

[0256] 1,5-Naphthalenedisulfonate Type A was obtained via slurry the mixture of freeform and 1,5-naphthalenedisulfonic acid (molar ratio of 1:1, acid / FB) in EtOH at RT for 4 days. The XRPD overlay was displayed in FIG. 93. No form change was observed before and after drying. The TGA / DSC curves of 1,5-naphthalenedisulfonate Type A were displayed in FIG. 94, which showed a weight loss of 1.81% up to 200 °C and three endotherms at 92.6 °C, 233.3 °C and 295.1 °C (peak temperature). The1H NMR result showed the molar ratio of acid / FB was 1.0 and the molar ratio of EtOH / freeform was 0.1 (0.6 wt%). Achiral HPLC purity of 1,5- naphthalenedisulfonate Type A was determined to be 98.87 area%. Chiral purity of 1,5- naphthalenedisulfonate Type A was determined to be 99.16 area%. DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH, as shown in FIG. 95. Three re-prepared salt samples were equilibrated at ambient humidity (30%RH) to prevent form change before testing. XRPD characterization was performed to check any solid form change for the samples after DVS test. No form change was observed after DVS test.HC1 Salt

[0257] HC1 salt Type A was obtained via slurry the mixture of freeform and HC1 (molar ratio of 1:1, acid / FB) in ACN / H2O (19:1, v / v) at RT for 1 day. XRPD overlay was displayed in FIG. 96. No form change was observed before and after drying. The TGA / DSC curves of HC1 salt Type A were displayed in FIG. 97, which showed a weight loss of 4.46% up to 200 °C and multiple endotherms at 83.4 °C, 134.5 °C, 247.9 °C and 300.7 °C (peak temperature). The1HNMR result showed the molar ratio of ACN / freeform was 0.1 (0.5 wt%). HPLC / IC results showed the molar ratio of acid / FB was 0.8. Achiral HPLC purity of HC1 salt Type A was determined to be 99.47 area% . Chiral purity of HC1 salt Type A was determined to be 99.19 area% . DVS isotherm plots were collected at 25 °C between 0%RH and 95%RH, as shown in FIG. 98. Three re-prepared salt samples were equilibrated at ambient humidity (30%RH) to prevent form change before testing. XRPD characterization was performed to check any solid form change for the samples after DVS test. No form change was observed after DVS test.Esylate

[0258] Esylate Type A was obtained via slurry freeform and ethanesulfonic acid (molar ratio of 1:1, acid / FB) in Acetone at RT for 2 days. The XRPD overlay was displayed in FIG. 99. No form change was observed after drying via vacuum at RT. The TGA / DSC curves of esylate Type A were displayed in FIG. 100, which showed a weight loss of 1.84% up to 200 °C and two endotherms at 76.8 °C and 241.9 °C (peak temperature). The!H NMR result showed the molar ratio of acid / FB was 1.2 and the molar ratio of Acetone / freeform was 0.03 (0.2 wt%). Achiral HPLC purity of esylate Type A was determined to be 99.78 area%. Chiral purity of esylate Type A was determined to be 99.16 area%.Hippurate

[0259] Hippurate Type A was obtained via slurry freeform and hippuric acid (molar ratio of 1:1, acid / FB) in EtOH at RT for 2 days. The XRPD overlay was displayed in FIG. 101. No form change was observed after drying via vacuum at RT. The TGA / DSC curves of hippurate Type A were displayed in FIG. 102, which showed a weight loss of 3.95% up to 170 °C and 10.19% from 170 °C to 260 °C. DSC result showed multiple signals at 76.7 °C, 149.2 °C, 181.4 °C and 279.6 °C and one exotherm at 186.3 °C (peak temperature). The1H NMR result showed the molar ratio of acid / FB was 0.6 and the molar ratio of EtOH / freeform was 0.12 (0.5 wt%). Achiral HPLC purity of hippurate Type A was determined to be 99.65 area%. Chiral purity of hippurate Type A was determined to be 99.17 area%.Besylate

[0260] Besylate Type A / B / C were obtained via slurry freeform and benzenesulfonic acid (molar ratio of 1:2 and 1: 1, acid / FB) at RT for 2 days in EtOAc, ACN / H2O (19:1, v:v) and Acetone, respectively. After drying via vacuum at RT, no form change was observed for three salt hits. The XRPD overlay were displayed in FIG. 103.

[0261] The TGA / DSC curves of besylate Type A were displayed in FIG. 104, which showed a weight loss of 3.06% up to 200 °C and three endotherms at 87.1 °C, 201.9 °C and 217.5 °C (peak temperature). The1H NMR result showed the molar ratio of acid / FB was 0.9 and the molar ratio of EtOH / freeform was 0.4 (2.3 wt%). Achiral HPLC purity of besylate Type A wasdetermined to be 99.59 area%. Chiral purity of besylate Type A was determined to be 99.17 area%.

[0262] The TGA / DSC curves of besylate Type B were displayed in FIG. 105, which showed a weight loss of 4.04% up to 200 °C and three endotherms at 85.8 °C, 183.8 °C and 264.9 °C (peak temperature). The!H NMR result showed the molar ratio of acid / FB was 1.0 and the molar ratio of ACN / freeform was 0.02 (0.08 wt%). Achiral HPLC purity of besylate Type B was determined to be 99.95 area%. Chiral purity of besylate Type B was determined to be 99.13 area%.

[0263] The TGA / DSC curves of besylate Type C were displayed in FIG. 106, which showed a weight loss of 7.08% up to 200 °C and three endotherms at 97.9 °C, 162.7 °C and 175.3 °C (peak temperature). The!H NMR result showed the molar ratio of acid / FB was 1.4 and the molar ratio of Acetone / freeform was 0.03 (0.2 wt%). Achiral HPLC purity of besylate Type C was determined to be 99.54 area%. Chiral purity of besylate Type C was determined to be 99.20 area%.Mesylate

[0264] Mesylate Type A was obtained via slurry freeform and methanesulfonic acid (molar ratio of 1:1, acid / FB) in EtOH at RT for 2 days. After drying via vacuum at RT, no form change was observed. The XRPD overlay was displayed in FIG. 107. The TGA / DSC curves of mesylate Type A were displayed in FIG. 108, which showed a weight loss of 4.81% up to 200 °C and two endotherms at 91.8 °C and 256.7 °C (peak temperature) and an exotherm at 212.3 °C (peak temperature). The ’ H NMR result showed the molar ratio of acid / FB was 1.1 and the molar ratio of EtOH / freeform was 0.2 (1.0 wt%). Achiral HPLC purity of mesylate Type A was determined to be 99.36 area%. Chiral purity of mesylate Type A was determined to be 99.18 area%.Polymorph Screening for HBr Salt

[0265] HBr salt Type A was successfully scaled up to 3 g scale. Using the re-prepared HBr salt Type A as the starting material, a total of 101 polymorph screening experiments were performed, including anti-solvent addition, slow cooling, slurry (RT and 50 °C), slow evaporation, liquid vapor diffusion, temperature cycling (50 to 5 °C), solid vapor diffusion and grinding. A total of 6 crystalline forms were obtained during screening and identification, including two anhydrates (HBr salt Type F and D), two hydrates (HBr salt Type A and C), one to-be-identified form (HBr salt Type E) and one disproportionated product (“HBr salt Type B”).AnhydratesHBr Salt Type F

[0266] HBr salt Type F was obtained via heating hydrate HBr salt Type C to 200 °C and cooling to 30 °C under N2 purge during VT-XRPD test. The XRPD pattern was displayed in FIG. 117. Since HBr salt Type F was obtained after heating and cooling under N2 purge, it was postulated to be an anhydrate.

[0267] To obtain more HBr salt Type F solids for further characterization, the re -preparation experiment was conducted via heating the HBr salt Type C to 200 °C, cooling to 30 °C under N2 protection, and then exposing to the air. The XRPD result FIG. 117 showed HBr salt Type F was successfully obtained. TGA / DSC results FIG. 118 showed a weight loss of 1.71% up to 200 °C and an endotherm at 299.4 °C (peak temperature). The1H NMR spectrum showed the signal of acetone was overlapped with that of freeform at ~2.1 ppm. HPLC / IC results showed the molar ratio of acid / FB was 1.0. Achiral HPLC purity of HBr salt Type F was determined to be 99.89 area%. Chiral purity of HBr salt Type F was determined to be 93.89 area%.HBr Salt Type D

[0268] HBr salt Type D was obtained via N2 purging the HBr salt Type A for 20 minutes during VT-XRPD. The XRPD pattern was displayed in FIG. 115. Since HBr salt Type D was obtained under N2 purge and no form conversion was observed after heating to 200 °C and cooling back to 30 °C under N2 protection, Type D was postulated to be an anhydrate. HBr salt Type D re-converted to HBr salt Type A after exposure to air, so further investigation was not performed on HBr salt Type D.HydratesHBr Salt Type A

[0269] HBr salt Type A was obtained via slurry the mixture of amorphous and equimolar HBr in EtOH at RT on 3-g scale. The XRPD overlay was displayed in FIG. 109. No form change was observed after vacuum drying at RT for -3 days. The TGA / DSC results were displayed in FIG. 110, which showed a weight loss of 1.44% up to 200 °C and two endotherms at 73.0 °C and 297.6 °C (peak temperature). The1H NMR result showed around 0.05 molar (~0.3 wt%) of EtOH was detected. HPLC / IC results showed the molar ratio of acid / FB was 0.9. Achiral HPLC purity of HBr salt Type A was determined to be 99.82 area%. Chiral purity of HBr salt Type A was determined to be 97.82 area%.

[0270] In order to identify HBr salt Type A, VT-XRPD test was performed. The results showed that: 1) Peak shift was observed after purging with N2 for 20 minutes, indicating one new form of HBr salt Type D was obtained; 2) After heating to 100 °C / 200 °C under N2 protection, certain diffraction peaks shifted slightly, which might be caused by expansion of crystal lattice at high temperature (100 °C / 200 °C); 3) After cooling down to 30 °C under N2 protection, peak shift disappeared; 4) After exposure to ambient conditions for 30 minutes,HBr salt Type A was observed again. Therefore, HBr salt Type A was postulated to be a hydrate.HBr Salt Type C

[0271] HBr salt Type C was obtained via temperature cycling of HBr salt Type A in THF / H2O (1:9, v / v) for 2 cycles (50 °C~5 °C). The XRPD overlay was displayed in FIG. 113. No form change was observed after drying in the air. The TGA / DSC results were displayed in FIG. 114, which showed a weight loss of 3.20% up to 200 °C and three endotherms at 119.8 °C, 281.5 and 299.7 °C (peak temperature). The ’ H NMR result showed around 0.03 molar (~0.2 wt%) of THF was detected. HPLC / IC results showed the molar ratio of Br- / FB was 0.9. Achiral HPLC purity of HBr salt Type C was determined to be 99.80 area%. Chiral purity of HBr salt Type C was determined to be 97.80 area%.

[0272] In order to identify HBr salt Type C, VT-XRPD test was performed. The results showed that: 1) No form change was observed after purging with N2 for 20 minutes; 2) After heating to 130 °C under N2 protection, a new form was obtained and named as HBr salt Type E; 3) After heating to 200 °C, a second new form was obtained and named as HBr salt Type F; 4) After cooling to 30 °C under N2 protection, certain diffraction peaks shifted slightly, which might be caused by expansion of crystal lattice at high temperature (200 °C); 5) After exposure to ambient conditions, no form change was observed. Therefore, HBr salt Type C was postulated to be a hydrate.To-be-Identified FormsHBr Salt Type E

[0273] HBr salt Type E was obtained via heating HBr salt Type C to 130 °C under N2 purge during VT-XRPD (section 5.2.2). The XRPD pattern was displayed in FIG. 116.

[0274] To identify HBr salt Type E, re-preparation of HBr salt Type E was performed via VT-XRPD of HBr salt Type C. The results showed that: 1) No form change was observed after purging with N2 for 20 minutes; 2) After heating to 130 °C under N2 protection, HBr salt Type E was observed; 3) After cooling to 25 °C under N2 protection, certain diffraction peaks shifted slightly, which might be caused by expansion of crystal lattice at high temperature. Type E at 25 °C under N2 protection was used as reference; 4) After exposure to ambient conditions, HBr salt Type C was observed. Therefore, HBr salt Type E was speculated to be a metastable form and could be observed under nitrogen protection. Therefore, no further investigation was performed on HBr salt Type E.Possible Disproportionated ProductHBr Salt Type B

[0275] HBr salt Type B was obtained via anti-solvent addition in NMP / MTBE using HBr salt Type A as the starting material. The XRPD overlay was displayed in FIG. 111. After air-drying at RT for 4 days, peak shift (marked by box within FIG. Ill) was observed. The TGA / DSC results were displayed in FIG. 112, which showed a weight loss of 25.45% up to 200 °C and multiple signals at 64.0 °C, 136.1 °C, 212.0 °C and 290.8 °C (peak temperature). The!H NMR result showed around 2.09 molar (-19.1 wt%) of NMP was detected. HPLC / IC results showed the molar ratio of acid / FB was 0.7, indicating that HBr salt Type B was partially disproportionated. Achiral HPLC purity of HBr salt Type A was determined to be 98.07 area%. Chiral purity of HBr salt Type B was determined to be 98.01 area%. Due to the low stoichiometry, low crystallinity and high organic solvent residue, further studies were not performed on HBr salt Type B.Characterization of Freeform Crystal Forms

[0276] In previous polymorph screening studies (Example 3), totally 33 forms were obtained, including nine anhydrates (freeform Type A / G / Q / R / S / T / U / V / X). To further identify the relationship among anhydrates, re-preparation and slurry competition were performed. Based on the XRPD results, a total of eight new forms were obtained from re-preparation and slurry competition, including two anhydrates (freeform Type BA and AN), one hydrate (freeform Type AM), three solvates (freeform Type AH, Al and AJ) and two to-be-determined forms (freeform Type AK and AL).Freeform Type BA

[0277] Freeform Type BA was prepared as described in Example 1. The XRPD pattern was displayed in FIG. 1. The XRPD peaks for type BA are shown in the table below.

[0278] As shown in FIG. 2, TGA result showed a weight loss of 1.64% up to 200 °C, and DSC result showed multiple thermal signals at 185.4 °C, 196.3 °C, 251.0 °C, 258.8 °C, 260.3 °C and 292.8 °C (peak temperature).

[0279] To identify freeform Type BA, heating experiment was conducted. Freeform Type BA was heated to 185 °C / 220 °C and cooled down under N2 protection, followed by being exposedto ambient conditions. XRPD results showed freeform Type G+weak peak (possibly attributed to freeform Type Q) was observed. Freeform Type BA was further heated to 280 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. As a result, freeform Type Q was observed. Combined the limited TGA weight loss and no endotherm before form transition in DSC, freeform Type BA was speculated to be an anhydrate.

[0280] Form BA is a primitive orthorhombic form confirmed by solution and refinement of the Powder X-ray Diffraction pattern. Form BA is crystalline by PXRD and shows a meltrecrystallization event in the DSC thermogram. The endotherm has an onset temperature of 175 °C and delta Hf of 27 J / g, associated with melting of Compound 1 Form BA and recrystallization to Form G, with eventual racemization to Form Q. Form BA is slightly hygroscopic, with 2% (w / w) water uptake when exposed to 0-95% RH at 25 °C in a DVS experiment. Water solubility of Form BA is below 1 mg / mL, but it is soluble in a variety of organic solvents and mixtures. All solubility data were obtained at 25 °C.Freeform Type AN

[0281] Freeform Type AM was observed via slurry the mixture of freeform Type G and Type BA in EtOAc at RT for 25 days during slurry competition with the protection of kapton film. After removal of the kapton film and exposure to the air, one new XRPD pattern was obtained and named as freeform Type AN, which was similar to that of freeform Type BA. The XRPD overlay was displayed in FIG. 134. The differences of freeform Type AN and Type BA were marked by stars. After drying via vacuum at RT for 4 hours, no form change was observed. As shown in FIG. 135, TGA result showed a weight loss of 4.38% up to 150 °C, and DSC result showed multiple thermal signals at 164.4 °C, 166.3 °C, 256.1 °C, 257.9 °C and 291.8 °C (peak temperature). TheNMR result showed the molar ratio of EtOAc / freeform was 0.01 (0.07 wt%).

[0282] In order to identify freeform Type AN, re-preparation was performed via slurry amorphous and freeform Type AN in EtOAc at RT for 4 days. As a result, freeform Type AN was obtained. After drying, no form change was observed. The TGA / DSC results showed a weight loss of 1.83% up to 150 °C and multiple signals at 174.8 °C, 183.5 °C, 218.1 °C, 258.3 °C, 260.3 °C and 292.0 °C (peak temperature). TheNMR result showed the molar ratio of EtOAc / freeform was 0.01 (0.07 wt%). VT-XRPD was performed on the re-prepared freeform Type AN. The results showed that: 1) No form change was observed after purging with N2 for 20 minutes; 2) After heating to 150 °C under N2 protection, certain diffraction peaks shifted slightly, which might be caused by expansion of crystal lattice at high temperature (150 °C); 3) After cooling down to 25 °C under N2 protection, peaks shift disappeared, indicating that freeform Type AN was anhydrous.Freeform Type Y

[0283] Freeform Type Y was obtained by heating freeform Type B / L to 220 °C, cooling and exposing to ambient conditions, while characterization data were not collected in previous studies due to challenges in re-preparation. Based on the VT-XRPD results of amorphous, Freeform Type Y could be obtained via heating amorphous to 210 °C and cooling down to the air under N2 during VT-XRPD. Thus re-preparation was performed via heating amorphous to 210 °C, cooling and exposing to ambient conditions. The XRPD pattern was displayed in FIG. 119. As shown in FIG. 120, TGA result showed a weight loss of 0.31% up to 200 °C, and DSC result showed multiple thermal signals at 248.8 °C, 252.5 °C and 291.2 °C (peak temperature). Considering that freeform Type Y showed limited TGA weight loss and that Type Y was obtained at 210 °C under N2 protection, freeform Type Y was speculated to be an anhydrate. Achiral HPLC purity of freeform Type Y was determined to be 99.62 area%. The chiral HPLC test showed its chiral purity was 76.95 area%.HydrateFreeform Type AM

[0284] Freeform Type AM was observed via slurry the mixture of freeform Type G and Type BA in EtOAc at RT for 25 days during slurry competition with the protection of kapton film. After removal of kapton film and exposure to the air, the new form of freeform Type AN was obtained. XRPD overlay was displayed in FIG. 131. The re-preparation experiment of freeform Type AM was conducted via slurry amorphous and Type AN in EtOAc at RT for 1 day. The XRPD result FIG. 132 showed Type AN (slight peak shift was marked by the red star) was observed. After drying via vacuum at RT for ~7 hours, Type AM was observed, (top trace, Type BA reference; second trace, Type AN reference; third trace, type AN before drying; fourth trace, type AM reference; bottom trace, type AM after drying of type AN). TGA / DSC results FIG. 133 showed a weight loss of 8.42% up to 150 °C, and DSC result showed multiple thermal signals at 149.6 °C, 165.1 °C, 220.8 °C, 258.4 °C, 260.3 °C and 291.7 °C (peak temperature). TheNMR result showed the molar ratio of EtOAc / freeform was 0.01 (0.14 wt%).

[0285] In order to identify freeform Type AM, heating experiment was performed on freeform Type AM. The results showed that Type AN + a weak peak (which might be assigned to freeform Type S or Type AM) was obtained after freeform Type AM was heated to 140 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. When the sample was further heated to 150 °C by the same method, a mixture of freeform Type AN+S was observed. Combined with the TGA / 1!! NMR, freeform Type AM was speculated to be a hydrate.SolvatesFreeform Type Al

[0286] Freeform Type Al was obtained via slurry amorphous in 1,4- dioxane at RT for three days during re-preparation of freeform Type B. XRPD overlay was displayed in FIG. 122. No form change was observed after drying. The TGA / DSC results were displayed in FIG. 123, which showed a weight loss of 5.99% up to 165 °C and 4.22% from 165 °C to 220 °C. DSC result showed multiple signals at 168.1 °C, 184.8 °C, 209.4 °C, 249.3 °C, 251.6 °C and 291.8 °C (peak temperature). The!H NMR result showed the molar ratio of 1,4- Dioxane / freeform was 0.9 (9.1 wt%).

[0287] Heating experiment was performed on re-prepared freeform Type Al. Freeform Type Al was heated to 165 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. XRPD results showed that the crystallinity of the sample decreased slightly. After the sample was further heated to 185 °C by the same method, a mixture of freeform Type G and Type R was obtained. Combined with TGA / DSC / 1H NMR results, freeform Type Al was speculated to be a 1,4-dioxane solvate.Freeform Type A J

[0288] Freeform anhydrate Type R was obtained by heating Type AA to 200 °C, and Type AA was obtained via slurry competition in THF starting with from G / S / Q at RT and 50 °C followed by air drying. (Freeform AA was speculated to be a THF solvate.) Then freeform Type AJ was obtained via slurry amorphous in THF at 50 °C for one day during re-preparation of freeform Type AA. After drying in the air for 1 day, no form change was observed. The XRPD overlay was displayed in FIG. 124. The TGA / DSC results were displayed in FIG. 125, which showed a weight loss of 9.36% up to 220 °C and multiple signals at 176.7 °C, 202.4 °C, 246.3 °C and 290.4 °C (peak temperature). The1H NMR result showed the molar ratio of THF / freeform was 1.0 (8.1 wt%). Combined with TGA / ' H NMR results, freeform Type AJ might be a THF solvate. The DVS result in FIG. 126 showed water uptake of 0.162% was observed at 25 °C / 80%RH. XRPD result showed that no form change was observed after DVS test.

[0289] To further study freeform Type AJ, heating experiment was performed on freeform Type AJ. The results showed that amorphous was obtained after Type AJ was heated to 175 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. When the sample was further heated to 210 °C by the same method, a mixture of freeform Type S+AJ+an extra peak was observed. Combined with the form change after heating to 175 °C, freeform Type A J was speculated to be a THF solvate.

[0290] In order to investigate the TGA weight loss and DSC signals before melting, VT- XRPD was performed on re-prepared freeform Type AJ. The results showed that: 1) No form change was observed after purging with N2 for 20 minutes; 2) After heating to 175 °C under N2 protection, the peak intensity decreased obviously; 3) After further heating to 210 °C / 250 °C,freeform Type AF was observed; 4) After cooling down to 30 °C under N2 protection, freeform Type Q was observed. The results of VT-XRPD suggested that the DSC signals at 176.7 °C might be related to desolvent and the signal at 202.4 °C might be related to re-crystallization.To-be-identified FormsFreeform Type AH

[0291] Freeform Type AH was obtained via slurry amorphous in Toluene at RT for 1 day during re-preparation of freeform Type U (refer to 9.6.6). After drying in the air for two days, freeform Type N was observed.10 The XRPD overlay was shown in FIG. 121. Since freeform Type AH was not stable under ambient conditions, no further investigation was performed on freeform Type AH.Freeform Type AK

[0292] Freeform Type AK was obtained via slurry a mixture of freeform Type BA and freeform Type G in Acetone at RT for 1 day. Since the amount was limited, re-preparation was performed via slurry amorphous and freeform Type BA in Acetone for 2 days. After drying via vacuum at RT for 6 hours, no form change was observed. The XRPD overlay was displayed in FIG. 127 (top trace: freeform Type BA reference; second trace: freeform Type AK reference; third trace: freeform Type AK before drying; bottom trace, freeform Type AK after drying). The TGA / DSC results were displayed in FIG. 128, which showed a weight loss of 7.59% up to 150 °C and multiple signals at 173.7 °C, 179.0 °C, 182.9 °C, 220.6 °C, 258.4 °C, 259.7 °C and 292.1 °C (peak temperature). The1H NMR result showed the molar ratio of Acetone / freeform was 0.3 (2.2 wt%).

[0293] Heating experiment was further performed on re-prepared freeform Type AK. Freeform Type AK was heated to 150 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. XRPD results showed freeform Type BA was observed. Combined with TGA / 1H NMR results, freeform Type AK from Acetone system was speculated to be a solvate or hydrate.Freeform Type AL

[0294] Freeform Type AL was obtained via slurry a mixture of freeform Type BA and Type G in THF at RT for 1 day. Since the amount was limited, re-preparation was performed via slurry amorphous and freeform Type BA in THF for 1 day. After drying via vacuum at RT for 2 hours, no form change was observed. The XRPD overlay was displayed in FIG. 129 (top trace: freeform Type BA reference; second trace: freeform Type AL reference; third trace: freeform Type AL before drying; bottom trace: freeform Type AL after drying; differences of freeform Type AL and Type BA marked by stars). The TGA / DSC results were displayed in FIG. 130, which showed a weight loss of 9.92% up to 150 °C and multiple signals at 166.6 °C, 171.7 °C, 175.3 °C, 200.1 °C, 252.7 °C, 256.4 °C, 260.4 °C and 293.8 °C (peak temperature).The NMR result showed the molar ratio of THF / freeform was 0.6 (5.1 wt%). Heating experiment was performed on re-prepared freeform Type AL. Freeform Type AL was heated to 145 °C and cooled down under N2 protection, followed by being exposed to ambient conditions. XRPD results showed freeform Type BA was observed. Combined with TGA / 1H NMR results, freeform Type AL was speculated to be a solvate or hydrate.

Claims

CLAIMS1. A crystalline form of Compound 1characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from: 4.36, 7.93, 8.80, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.70, 17.91, 18.31, 18.95, 19.68, 20.04, 20.64, 21.09, and 24.11 degrees 29 (± 0.2 degrees 29), Form BA.

2. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 15.92, and 20.04 degrees 29 (± 0.2 degrees 29).

3. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 15.92, and 16.67 degrees 29 (± 0.2 degrees 29).

4. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 15.92, 16.67, and 20.04 degrees 29 (± 0.2 degrees 29).

5. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 11.98, 15.92, and 16.67 degrees 29 (± 0.2 degrees 29).

6. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 10.07, 11.98, 12.57, 15.92, 16.67, and 20.04 degrees 29 (± 0.2 degrees 29).

7. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.98, 12.57, 15.92, 16.67, 17.91, and 20.04 degrees 29 (± 0.2 degrees 29).

8. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.98, 12.57, 15.46, 15.92, 16.67, and 17.91 degrees 29 (± 0.2 degrees 29).

9. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.91, 20.04, and 21.09 degrees 29 (± 0.2 degrees 29).

10. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 4.36, 7.93, 8.80, 9.20, 10.07, 11.77, 11.98, 12.57, 15.46, 15.92, 16.67, 17.70, 17.91, 18.31, 18.95, 19.68, 20.04, 20.64, 21.09, and 24.11 degrees 29 (± 0.2 degrees 29).

11. The crystalline form of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.

12. The crystalline form of any one of claims 1-11, characterized by a differential scanning calorimetry thermogram (DSC) comprising an endotherm peak at about 185.4 °C and an exotherm peak at about 196.3 °C.

13. The crystalline form of any one of claims 1-11, characterized by a differential scanning calorimetry thermogram (DSC) substantially in accordance with FIG. 2.

14. The crystalline form of any one of claims 1-13, characterized by a weight loss of 1.64% upon heating from about 15 °C to about 200 °C, as measured by thermal gravimetric analysis (TGA).

15. The crystalline form of any one of claims 1-13, characterized by a thermal gravimetric analysis (TGA) thermogram substantially in accordance with FIG. 2.

16. The crystalline form of any one of claims 1-15, wherein the crystalline form is a single crystalline form substantially free of other crystalline or amorphous forms.

17. A pharmaceutical composition comprising a crystalline form of any one of claims 1-16 and at least one pharmaceutically acceptable excipient.

18. Use of a crystalline form of any one of claims 1-16 or a pharmaceutical composition of claim 17 for treatment of cancer.

19. Use of a crystalline form of any one of claims 1-16 or a pharmaceutical composition of claim 17 for the manufacture of a medicament for treating cancer.

20. The use of claim 18 or 19, wherein the cancer is prostate cancer.

21. A crystalline form of any one of claims 1-16 or a pharmaceutical composition of claim 17 for treatment of cancer.

22. A crystalline form of any one of claims 1-16 or a pharmaceutical composition of claim 17 for the manufacture of a medicament for treating cancer.

23. The crystalline form of claim22 or 23, wherein the cancer is prostate cancer.

24. A method of treating a cancer in a subject in need thereof, comprising administering to the subject a crystalline form of any one of claims 1-16 or a pharmaceutical composition of claim 17.

25. The method of claim 24, wherein the cancer is prostate cancer.

26. A crystalline form of Compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 44, freeform Type G.

27. A crystalline form of Compound 1, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 24, tosylate Type O.