Salt forms and solvates of Mcl-1 antagonists

Abstract

As used herein, (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'[20]oxa[13]thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 Disclosed herein are salts and solvate forms, including crystalline salts and solvate forms thereof, of pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (AMG 176). Methods for making the salts and solvate forms, and methods for using the salts and solvate forms to treat diseases and disorders are also disclosed. TIFF2025513774000037.tif31170

Description

[Technical field]

[0001] The present disclosure relates to the use of (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0])-1,2'-dihydro-2H,15'H-pyridinyl ... 3,6 .0 19,24 ]pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (AMG176), including salts and solvates thereof. [Background technology]

[0002] The compound (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24 ]Pentacosa[8,16,18,24]tetraene]-15'-one 13',13'-dioxide (AMG176) is useful as an inhibitor of myeloid cell leukemia-1 (Mcl-1). [ka]

[0003] A common feature of human cancers is overexpression of Mcl-1, which prevents programmed cell death (apoptosis) in cancer cells and allows them to survive despite widespread genetic damage.

[0004] Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes proapoptotic members (e.g., BAX and BAK) that, when activated, form homocomplexes in the outer mitochondrial membrane, resulting in pore formation and release of mitochondrial contents, a step in the induction of apoptosis. Antiapoptotic members of the Bcl-2 family (e.g., Bcl-2, Bcl-XL, Mcl-1) inhibit the activity of BAX and BAK. Other proteins (e.g., BID, BIM, BIK, BAD) have further regulatory functions. Studies have shown that Mcl-1 inhibitors may be useful in cancer treatment. MCl-1 is overexpressed in many cancers. Summary of the Invention [Problem to be solved by the invention]

[0005] US Patent No. 9,562,061 discloses AMG176 as an Mcl-1 inhibitor and provides a method for its preparation, the entire specification of which is incorporated herein by reference. However, alternative forms of AMG176 with improved properties are desired, especially in the clinical use of AMG176. [Means for solving the problem]

[0006] Provided herein are crystalline salt and solvate forms of AMG176, wherein AMG176 has the structure: [ka] has.

[0007] Also provided is a crystalline form of AMG176 as the ammonium salt, the crystalline salt being characterized by peaks at 16.6, 17.6 and 18.4 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0008] Also provided is a crystalline form of AMG176 as a diethylamine salt ("diethylamine Form A"), characterized by an XRPD pattern substantially as shown in FIG.

[0009] Also provided is a crystalline form of AMG176 as a diethylamine salt ("diethylamine Form B"), characterized by an XRPD pattern substantially as shown in FIG.

[0010] Also provided is a crystalline form of AMG176 as the diethanolamine salt ("diethanolamine salt toluene solvate"), characterized by an XRPD pattern substantially as shown in FIG.

[0011] Also provided is a crystalline form of AMG176 as the diethanolamine salt ("diethanolamine salt anhydrous"), characterized by an XRPD pattern substantially as shown in FIG.

[0012] Also provided is a crystalline form of AMG176 as a 1,4-dioxane solvate, characterized by peaks at 12.4, 12.8, 15.8 and 17.7 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0013] Also provided is a crystalline form of AMG176 as an imidazole salt acetone solvate, characterized by peaks at 4.2, 8.1 and 20.7 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0014] Also provided is a crystalline form of AMG176 as a hemimagnesium salt dihydrate, characterized by peaks at 3.8, 5.8 and 7.5 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0015] Also provided is a crystalline form of AMG176 as a methyl tert-butyl ether solvate, characterized by peaks at 12.4, 15.6 and 20.1 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0016] Also provided is a crystalline form of AMG176 as a 2-methyltetrahydrofuran solvate, characterized by peaks at 12.4, 15.6 and 20.1 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0017] Also provided is a crystalline form of AMG176 as a potassium salt hydrate, characterized by peaks at 5.9, 7.6 and 23.5 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0018] Also provided is a crystalline form of AMG176 as a potassium salt isopropanol solvate, characterized by peaks at 5.8, 18.7, 22.5 and 23.5 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0019] Also provided is a crystalline form of AMG176 as a tetrahydrofuran solvate, characterized by peaks at 12.5, 15.8 and 17.8 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0020] Also provided is a crystalline form of AMG176 as the sodium salt acetonitrile solvate, characterized by peaks at 3.4, 3.7 and 16.7 (2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

[0021] Also provided are pharmaceutical formulations comprising a crystalline or amorphous form of AMG176 described herein and a pharma- ceutically acceptable excipient.

[0022] Also provided is a method for treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a crystalline or amorphous form of AMG176 described herein, or a pharmaceutical formulation comprising AMG176 described herein and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0023] [Figure 1]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline ammonium salt form of AMG176. [Diagram 2] 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline ammonium salt form of AMG176, showing a Tm of 156°C. [Diagram 3] 1 is a thermogravimetric analysis ("TGA") curve for the crystalline ammonium salt form of AMG176, showing a weight loss of 2.5%. [Figure 4] FIG. 1 shows the moisture sorption profile (DVS) of AMG176 crystalline ammonium salt form, showing a weight gain of approximately 1.2% at 95% relative humidity. [Diagram 5] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline diethylamine salt Form A of AMG176. [Figure 6] 1 is a differential scanning calorimetry ("DSC") thermogram and overlay of a thermogravimetric analysis ("TGA") curve for the crystalline diethylamine salt of AMG176, Form A, showing a Tm of 151°C and a weight loss of 19.0% from 37 to 177°C. [Figure 7] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline diethylamine salt Form B of AMG176. [Figure 8] 1 is a differential scanning calorimetry ("DSC") thermogram overlaid with a thermogravimetric analysis ("TGA") curve for the crystalline diethylamine salt of AMG176, Form B, showing a Tm of 140°C and a weight loss of 2% from 60 to 183°C. [Figure 9] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline diethanolamine salt toluene solvate of AMG176. [Figure 10] 1 is a differential scanning calorimetry ("DSC") thermogram overlaid with a thermogravimetric analysis ("TGA") curve for the crystalline diethanolamine salt toluene solvate of AMG176, showing a Tm of 134°C and a weight loss of 4.2% from 43 to 147°C. [Figure 11] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline diethanolamine salt anhydrous form of AMG176. [Figure 12] 1 is a differential scanning calorimetry ("DSC") thermogram overlaid with a thermogravimetric analysis ("TGA") curve for the crystalline diethanolamine salt anhydrous form of AMG176, showing a Tm of 126°C and a weight loss of 0.3% from 55 to 160°C. [Figure 13] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline 1,4-dioxane solvate of AMG176. [Figure 14] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline imidazole salt Form A of AMG176. [Figure 15] 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline imidazole salt Form A of AMG176 showing a Tm of 110°C. [Figure 16] 1 depicts a thermogravimetric analysis ("TGA") curve for the crystalline imidazole salt Form A of AMG176, showing a weight loss of 9%. [Figure 17] FIG. 17 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline hemimagnesium salt dihydrate form of AMG176. [Figure 18] 1 is a differential scanning calorimetry ("DSC") thermogram overlaid with a thermogravimetric analysis ("TGA") curve for the crystalline hemimagnesium salt dihydrate form of AMG176, showing endothermic transitions at 84°C and 115°C, with a weight loss of 5.4%. [Figure 19] FIG. 1 depicts a moisture sorption / desorption curve (DVS) for the crystalline hemimagnesium salt dihydrate form of AMG176, showing a weight gain of approximately 12% at 95% relative humidity. [Figure 20] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline methyl t-butyl ether solvate of AMG176. [Figure 21]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline 2-methyltetrahydrofuran solvate of AMG176. [Figure 22] 1 shows an X-ray powder diffraction ("XRPD") pattern of the crystalline potassium salt hydrate of AMG176. [Figure 23] 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline potassium salt hydrate of AMG176, showing endothermic events at 58 and 182°C. [Figure 24] 1 is a thermogravimetric analysis ("TGA") curve for the crystalline potassium salt hydrate form of AMG176, showing a weight loss of 3.6%. [Diagram 25] Figure 1 shows the moisture sorption / desorption curve (DVS) of the crystalline potassium salt hydrate form of AMG176, showing a weight gain of approximately 5% at 95% relative humidity, which is lost upon desorption. [Figure 26] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline potassium salt isopropanol solvate of AMG176. [Figure 27] 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline potassium salt isopropanol solvate of AMG176, showing endothermic events at 64 and 180° C. [Figure 28] 1 is a thermogravimetric analysis ("TGA") curve for the crystalline potassium salt isopropanol solvate form of AMG176, showing a weight loss of 12%. [Figure 29] FIG. 1 depicts the moisture sorption-desorption curve (DVS) of AMG176 crystalline potassium salt isopropanol solvate form, showing a weight gain of about 4.5% at 95% relative humidity, which is lost upon desorption. [Diagram 30] FIG. 1 is an overlay of proton nuclear magnetic resonance (H NMR) spectra of crystalline AMG176 free acid, sodium salt and potassium salt isopropanol solvate forms of AMG176 (top to bottom), showing the presence of isopropanol in the solvates. [Diagram 31]1 shows the X-ray powder diffraction ("XRPD") pattern of a crystalline tetrahydrofuran solvate of AMG176. [Diagram 32] 1 is a differential scanning calorimetry ("DSC") thermogram overlaid with a thermogravimetric analysis ("TGA") curve for the crystalline tetrahydrofuran solvate form of AMG176, showing an endothermic transition at 174°C and a weight loss of 10%. [Diagram 33] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline sodium salt acetonitrile solvate of AMG176. [Diagram 34] 1 is a differential scanning calorimetry ("DSC") thermogram of the crystalline sodium salt acetonitrile solvate form of AMG176, showing an endothermic transition at 58°C. [Diagram 35] 1 is a thermogravimetric analysis ("TGA") curve for the crystalline sodium salt acetonitrile solvate form of AMG176, showing a weight loss of 29% up to 150° C. [Diagram 36] FIG. 1 depicts a moisture sorption / desorption curve (DVS) for AMG176 crystalline sodium salt acetonitrile solvate form, showing a weight gain of approximately 14% at 95% relative humidity, which subsequently decreases by 13% upon desorption. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] As used herein, (1S,3'R,6'R,7'S,8'E,11'S,12'R)-6-chloro-7'-methoxy-11',12'-dimethyl-3,4-dihydro-2H,15'H-spiro[naphthalene-1,22'

[20] oxa

[13] thia[1,14]diazatetracyclo[14.7.2.0 3,6 .0 19,24

[0010] Disclosed herein are salts or solvates, including crystalline salts and solvates thereof, of pentacosa[8,16,18,24]tetraen]-15'-one 13',13'-dioxide (AMG176). [ka]

[0025] Form 1 of AMG176 is a stable crystalline form suitable for development, but has low solubility under neutral conditions (<0.1 μg / mL in water). Amorphous forms as well as salt and solvate forms of AMG176 may exhibit advantageous solubility for dosage form development. The crystalline forms described herein possess unique physical properties that may be advantageous for novel formulations of AMG176.

[0026] Also provided herein are pharmaceutical formulations of salt and solvate forms of AMG176 and methods of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of a salt or solvate form disclosed herein.

[0027] US Pat. No. 9,562,061 discloses synthetic procedures for synthesizing Mcl-1 inhibitors such as AMG176 and is incorporated herein by reference in its entirety.

[0028] Further provided herein are crystalline salt and solvate forms of AMG176, pharmaceutical formulations thereof, and methods of treating a subject suffering from cancer, comprising administering to the subject a pharmaceutical formulation of the crystalline salt or solvate form disclosed herein.

[0029] The compounds disclosed herein may be identified herein by either their chemical structure and / or chemical name. When the chemical structure and the chemical name conflict, the chemical structure is determinative of the compound's identity.

[0030] When ranges are used herein with respect to a physical property, such as molecular weight, or a chemical property, such as a chemical formula, it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein.

[0031] As used herein, dashed and bold bonds (i.e. [ka] Chemical structures containing one or more stereocenters, as represented using the symbols ( ) and ( b ), are meant to depict the absolute stereochemistry of the stereocenters present in the chemical structure. As used herein, bonds symbolized as simple lines do not depict a preferred configuration. Unless otherwise indicated, chemical structures containing one or more stereocenters illustrated herein without depicting absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers, enantiomers) and mixtures thereof. Structures having a single bold or dashed line and at least one additional simple line encompass a single enantiomeric series of all possible diastereomers.

[0032] The term "about" is meant to take into account variations due to experimental error. All measurements reported herein are understood to be modified by the term "about" unless otherwise indicated, whether or not this term is expressly stated. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0033] "Treatment" or "treating" refers to any treatment of a disease in a patient, including a) preventing the disease, i.e., not causing clinical symptoms of the disease to develop; b) inhibiting the disease; c) slowing or arresting the progression of clinical symptoms; and / or d) relieving the disease, i.e., causing regression of clinical symptoms. Treatment of diseases and disorders, as used herein, is also intended to include prophylactic administration of the pharmaceutical formulations described herein to a subject (i.e., an animal, preferably a mammal, most preferably a human) believed to be in need of treatment, such as, for example, cancer.

[0034] A "salt" is an ionic compound formed by treating AMG176 with an acid or base. Any salt whose overall stability and usefulness is consistent with the compound of AMG176 can be obtained by conventional methods. Suitable salts include, but are not limited to, salts of acidic or basic groups that may be present in the compounds provided herein. The compounds can form a wide variety of salts with various inorganic and organic acids under certain acidic conditions. Acids that can be used to prepare pharma- ceutically acceptable salts of such basic compounds include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrazone, tetrahydrofuran ... The compounds may form salts with pharmaceutically acceptable anions, such as, but not limited to, bamates, hydroxynaphthoates, isionates, lactates, lactobionates, malates, maleates, mandelates, mesylates (methylenesulfonates), methylsulfates, muscates, napsylates, nitrates, pantothenates, phosphates / diphosphates, polygalacturonates, salicylates, stearates, succinates, sulfates, tannates, tartrates, theoclates, triethiodides and pamoates. Under certain basic conditions, the compounds may form base salts with various pharmacologically acceptable cations. Non-limiting examples of this type of salt include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts, as well as tetraalkylammonium salts. General information regarding pharma- ceutically acceptable salts can be found in Stahl PH, and Wermuth CG, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2002, Wiley-VCH / VHCA Weinheim / Zuerich.

[0035] The term "therapeutically effective amount" means an amount effective when administered to a human or non-human patient to effectively treat a disease, e.g., a therapeutically effective amount can be an amount sufficient to treat a disease or disorder responsive to myosin activation. A therapeutically effective amount can be ascertained experimentally, e.g., by analyzing blood levels of a chemical, or theoretically, by calculating bioavailability.

[0036] The term "solvate" refers to a chemical compound formed by the interaction of a solvent with a compound. In particular, the solvate of AMG176 crystals used in the formulation herein is intended. Solvents that can form crystalline solvate forms of AMG176 include, but are not limited to, toluene, 1,4-dioxane, acetone, methyl tert-butyl ether, 2-methyltetrahydrofuran, isopropanol, tetrahydrofuran, and acetonitrile. The solvate optionally has 0.5 to 2 solvent molecules per AMG176 molecule.

[0037] Salts and solvate forms Ammonium Salt Form: The crystalline ammonium salt form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 16.6, 17.6, and 18.4 (2θ)±0.2°, and optionally further characterized by additional peaks at 19.2, 21.6, 22.4, and 23.8 (2θ)±0.2° using CuKα radiation, and / or additional peaks at 7.9, 10.1, 11.0, 12.7, 13.9, 20.2, 24.9, 27.7, and 29.8 (2θ)±0.2° using CuKα radiation. In some embodiments, the crystalline ammonium salt form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 1, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0038] A differential scanning calorimetry (DSC) thermogram of the crystalline ammonium salt form of AMG176 was obtained as described in the Examples. The DSC curve shows an endothermic transition occurring at 156° C.±3° C. For example, in some embodiments, the crystalline ammonium salt form of AMG176 is characterized by DSC as shown in FIG.

[0039] The crystalline ammonium salt form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline ammonium salt form of AMG176 can be characterized by exhibiting a weight loss in the range of about 2.5%. In some embodiments, the crystalline ammonium salt hydrate form of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 3, where "substantially" means that the reported TGA properties can vary by ±5° C.

[0040] The crystalline ammonium salt form of AMG 176 can be characterized by a moisture sorption-desorption curve, for example, in some embodiments, the crystalline ammonium salt form of AMG 176 is characterized by a moisture sorption-desorption curve showing a weight gain of about 1.2% at 95% relative humidity, as shown in FIG.

[0041] Diethylamine Salt Form A (Diethylamine Salt Toluene Solvate): Crystalline diethylamine salt Form A of AMG176 can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, for example, an X-ray powder diffraction pattern substantially as shown in Figure 5, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the art of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0042] A differential scanning calorimetry (DSC) thermogram of the crystalline diethylamine salt of AMG176, Form A, was obtained as described in the Examples. The DSC curve shows that an endothermic transition occurs at 151° C.±3° C. Thus, in some embodiments, the crystalline diethylamine salt of AMG176, Form A, can be characterized by a DSC thermogram that shows an endothermic transition with an onset between 148° C. and 154° C. For example, in some embodiments, the crystalline diethylamine salt of AMG176, Form A, is characterized by a DSC as shown in FIG. 6.

[0043] The crystalline diethylamine salt of AMG176, Form A, may be characterized by thermogravimetric analysis (TGA). That is, the crystalline diethylamine salt of AMG176, Form A, may be characterized by exhibiting a weight loss in the range of about 19.0% between 37-111° C. In some embodiments, the crystalline diethylamine salt of AMG176, Form A, exhibits a thermogravimetric analysis result substantially as shown in FIG. 6, where "substantially" means that the reported TGA properties may vary by ±5° C.

[0044] Diethylamine Salt Form B (Diethylamine Salt Anhydrous): Crystalline diethylamine salt Form B of AMG176 can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, for example, an X-ray powder diffraction pattern substantially as shown in Figure 7, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the art of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0045] A differential scanning calorimetry (DSC) thermogram of the crystalline diethylamine salt of AMG176, Form B, was obtained as described in the Examples. The DSC curve shows that an endothermic transition occurs at 140° C.±3° C. Thus, in some embodiments, the crystalline diethylamine salt of AMG176, Form B, can be characterized by a DSC thermogram that shows an endothermic transition beginning at 140° C. and extending to 260° C. For example, in some embodiments, the crystalline diethylamine salt of AMG176, Form B, is characterized by a DSC as shown in FIG. 8.

[0046] The crystalline diethylamine salt Form B of AMG176 may be characterized by thermogravimetric analysis (TGA). That is, the crystalline diethylamine salt Form B of AMG176 may be characterized by exhibiting a weight loss in the range of about 2% between 60-183° C. In some embodiments, the crystalline diethylamine salt Form B of AMG176 exhibits thermogravimetric analysis results substantially as shown in FIG. 8, where "substantially" means that the reported TGA properties may vary by ±5° C.

[0047] Diethanolamine salt toluene solvate: The crystalline diethanolamine salt toluene solvate of AMG176 can be characterized by an X-ray powder diffraction pattern, obtained as described in the Examples, for example, an X-ray powder diffraction pattern substantially as shown in Figure 9, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0048] A differential scanning calorimetry (DSC) thermogram of the crystalline diethanolamine salt toluene solvate of AMG176 was obtained as described in the Examples. The DSC curve shows that an endothermic transition occurs at 134° C.±3° C. Thus, in some embodiments, the crystalline diethanolamine salt toluene solvate of AMG176 can be characterized by a DSC thermogram that shows an endothermic transition beginning at 134° C. and extending to 230° C. For example, in some embodiments, the crystalline diethanolamine salt toluene solvate of AMG176 is characterized by a DSC as shown in FIG. 10.

[0049] The crystalline diethanolamine salt toluene solvate of AMG176 may be characterized by thermogravimetric analysis (TGA). That is, the crystalline diethanolamine salt toluene solvate of AMG176 may be characterized by exhibiting a weight loss in the range of about 4.2% at 43-147° C. In some embodiments, the crystalline diethanolamine salt toluene solvate of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 10, where "substantially" means that the reported TGA properties may vary by ±5° C.

[0050] Diethanolamine Salt Anhydrous Form: The crystalline diethanolamine salt anhydrous form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, for example, an X-ray powder diffraction pattern substantially as shown in Figure 11, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0051] A differential scanning calorimetry (DSC) thermogram of the crystalline diethanolamine salt anhydrous form of AMG176 was obtained as described in the Examples. The DSC curve shows that an endothermic transition occurs at 126° C.±3° C. Thus, in some embodiments, the crystalline diethanolamine salt anhydrous form of AMG176 can be characterized by a DSC differential thermogram that shows an endothermic transition beginning at 126° C. to 240° C. For example, in some embodiments, the crystalline diethylamine salt anhydrous form of AMG176 is characterized by DSC as shown in FIG. 12.

[0052] The crystalline diethanolamine salt anhydrous form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline diethanolamine salt toluene solvate of AMG176 can be characterized by exhibiting a weight loss in the range of about 0.3% at 55-160° C. In some embodiments, the crystalline diethanolamine salt anhydrous form of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 12, where "substantially" means that the reported TGA properties can vary by ±5° C.

[0053] 1,4-Dioxane Solvate Form: The crystalline 1,4-dioxane solvate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 12.4, 12.8, 15.8, and 17.7 (2θ)±0.2 degrees, and optionally further characterized by additional peaks at 18.0, 19.4, 20.2, and 22.3 (2θ)±0.2 degrees using CuKα radiation, and / or at 8.1, 10.1, 14.0, 16.2, 16.7, 17.4, 19.0, 20.3, 20.9, 21.5, 22.8, 23.5, 24.0, 25.0, 25.7, 26.7, and 27.1 (2θ)±0.2 degrees using CuKα radiation. In some embodiments, the crystalline 1,4-dioxane solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 13, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0054] Imidazole Salt Acetone Solvate Form: The crystalline imidazole salt acetone solvate form of AMG 176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 4.2, 8.1, and 20.7 (2θ)±0.2 degrees, and optionally further characterized by additional peaks at 8.7, 12.9, 16.4, and 17.4 (2θ)±0.2 degrees using CuKα radiation, and / or at 6.4, 7.0, 8.5, 9.1, 10.7, 13.8, 14.1, 15.1, 15.5, 16.7, 18.8, 19.7, 19.9, 21.0, 22.4, and 23.6 (2θ)±0.2 degrees using CuKα radiation. In some embodiments, the crystalline imidazole salt acetone solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 14, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0055] A differential scanning calorimetry (DSC) thermogram of the crystalline imidazole salt acetone solvate form of AMG176 was obtained as described in the Examples. The DSC curve shows an endothermic transition occurring at 110° C.±3° C. For example, in some embodiments, the crystalline imidazole salt acetone solvate form of AMG176 is characterized by DSC as shown in FIG.

[0056] The crystalline imidazole salt acetone solvate form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline imidazole salt acetone solvate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 9%. In some embodiments, the crystalline imidazole salt acetone solvate form of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 16, where "substantially" means that the reported TGA properties can vary by ±5°C.

[0057] Hemimagnesium Salt Dihydrate Form: The crystalline magnesium salt hydrate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 3.8, 5.8, and 7.5 (2θ)±0.2°, and optionally further characterized by the appearance of additional peaks at 10.3, 12.3, 13.7, 15.1, 16.7, 19.7, 20.7, and 23.5 (2θ)±0.2° using CuKα radiation. In some embodiments, the crystalline magnesium salt hydrate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in FIG. 17, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the art of XRPD that the relative heights of peaks in a spectrum depend on many factors, such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0058] A differential scanning calorimetry (DSC) thermogram of the crystalline hemimagnesium salt dihydrate form of AMG176 was obtained as described in the Examples. The DSC curve shows endothermic transitions occurring at 84° C.±3° C. and 115° C.±3° C. For example, in some embodiments, the crystalline hemimagnesium salt dihydrate form of AMG176 is characterized by DSC as shown in FIG.

[0059] The crystalline hemimagnesium salt dihydrate form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline hemimagnesium salt dihydrate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 5.4%. In some embodiments, the crystalline hemimagnesium salt dihydrate form of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 18, where "substantially" means that the reported TGA properties can vary by ±5° C.

[0060] The crystalline hemimagnesium salt dihydrate form of AMG 176 can be characterized by a moisture sorption-desorption curve, for example, in some embodiments, the crystalline hemimagnesium salt dihydrate form of AMG 176 is characterized by a moisture sorption-desorption curve showing a weight gain of about 12% at 95% relative humidity, as shown in FIG.

[0061] Methyl tert-butyl ether solvate form: The crystalline methyl tert-butyl ether solvate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 12.4, 15.6, and 20.1 (2θ) ± 0.2 degrees, and optionally further characterized by additional peaks at 8.0, 12.6, 17.7, 17.9, 19.3, and 22.0 (2θ) ± 0.2 degrees, using CuKα radiation, and / or at 10.8, 13.8, 16.1, 16.3, 16.6, 17.2, 18.7, 20.9, 21.4, 22.6, 23.2, 24.9, 25.3, 26.3, and 26.4 (2θ) ± 0.2 degrees, using CuKα radiation. In some embodiments, the crystalline methyl tert-butyl ether solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 20, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0062] 2-Methyltetrahydrofuran solvate form: The crystalline 2-methyltetrahydrofuran solvate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 12.4, 15.6, and 20.1 (2θ) ± 0.2 degrees, and optionally further characterized by additional peaks at 12.6, 17.8, 19.4, and 21.9 (2θ) ± 0.2 degrees, using CuKα radiation, and / or at 8.1, 13.7, 16.2, 16.7, 17.9, 18.7, 21.0, 21.4, 22.6, and 23.1 (2θ) ± 0.2 degrees, using CuKα radiation. In some embodiments, the crystalline 2-methyltetrahydrofuran solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 21, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0063] Potassium Salt Hydrate Form: The crystalline potassium salt hydrate form of AMG176 may be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 5.9, 7.6, and 23.5 (2θ)±0.2°, and optionally further characterized by the appearance of additional peaks at 11.2, 13.6, 15.3, 16.9, 18.5, and 22.5 (2θ)±0.2° using CuKα radiation. In some embodiments, the crystalline potassium salt hydrate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in FIG. 22, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the art of XRPD that the relative heights of peaks in a spectrum depend on many factors, such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0064] A differential scanning calorimetry (DSC) thermogram of the crystalline potassium salt hydrate form of AMG176 was obtained as described in the Examples. The DSC curve shows endothermic events occurring at 58° C.±3° C. and 182° C.±3° C. For example, in some embodiments, the crystalline potassium salt hydrate form of AMG176 is characterized by DSC as shown in FIG.

[0065] The crystalline potassium salt hydrate form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline potassium salt hydrate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 3.6%. In some embodiments, the crystalline potassium salt hydrate form of AMG176 exhibits thermogravimetric analysis results substantially as shown in FIG. 24, where "substantially" means that the reported TGA properties can vary by ±5° C.

[0066] The crystalline potassium salt hydrate form of AMG 176 can be characterized by a moisture sorption-desorption curve, for example, in some embodiments, the crystalline potassium salt hydrate form of AMG 176 is characterized by a moisture sorption-desorption curve showing a weight gain of about 5% at 95% relative humidity, as shown in FIG.

[0067] Potassium salt isopropanol solvate form: The crystalline potassium salt isopropanol solvate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 5.8, 18.7, 22.5, and 23.5 (2θ)±0.2°, and optionally further characterized by the appearance of additional peaks at 11.0, 12.0, 13.6, 14.7, 17.4, 19.4, 20.4, and 29.2 (2θ)±0.2° using CuKα radiation. In some embodiments, the crystalline potassium salt isopropanol solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 26, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0068] A differential scanning calorimetry (DSC) thermogram of the crystalline potassium salt isopropanol solvate form of AMG176 was obtained as described in the Examples. The DSC curve shows endothermic events occurring at 64° C.±3° C. and 180° C.±3° C. For example, in some embodiments, the crystalline potassium salt isopropanol solvate form of AMG176 is characterized by DSC as shown in FIG.

[0069] The crystalline potassium salt isopropanol solvate form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline potassium salt isopropanol solvate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 12%. In some embodiments, the crystalline potassium salt isopropanol solvate form of AMG176 exhibits thermogravimetric analysis results substantially as shown in FIG. 28, where "substantially" means that the reported TGA properties can vary by ±5°C.

[0070] The crystalline potassium salt isopropanol solvate form of AMG 176 can be characterized by a moisture sorption-desorption curve, for example, in some embodiments, the crystalline potassium salt hydrate form of AMG 176 is characterized by a moisture sorption-desorption curve showing a weight gain of about 4.5% at 95% relative humidity, as shown in FIG.

[0071] Tetrahydrofuran solvate form: The crystalline tetrahydrofuran solvate form of AMG176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 12.5, 15.8, and 17.8 (2θ)±0.2 degrees, and optionally further characterized by additional peaks at 12.8, 16.2, 18.0, 19.4, 20.3, 20.4, and 22.3 (2θ)±0.2 degrees using CuKα radiation, and / or at 8.1, 10.1, 14.0, 19.0, 21.0, 21.6, 22.9, 23.5, 25.7, and 26.8 (2θ)±0.2 degrees using CuKα radiation. In some embodiments, the crystalline tetrahydrofuran solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 31, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0072] A differential scanning calorimetry (DSC) thermogram of the crystalline tetrahydrofuran solvate form of AMG176 was obtained as described in the Examples. The DSC curve shows an endothermic event at 174° C.±3° C. For example, in some embodiments, the crystalline tetrahydrofuran solvate form of AMG176 is characterized by DSC as shown in FIG.

[0073] The crystalline tetrahydrofuran solvate form of AMG176 can be characterized by thermogravimetric analysis (TGA). That is, the crystalline tetrahydrofuran solvate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 10%. In some embodiments, the crystalline tetrahydrofuran solvate form of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 32, where "substantially" means that the reported TGA properties can vary by ±5°C.

[0074] Sodium Salt Acetonitrile Solvate Form: The crystalline sodium salt acetonitrile solvate form of AMG 176 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation as described in the Examples, having peaks at 3.4, 3.7, and 16.7 (2θ)±0.2 degrees, and optionally further characterized by additional peaks at 17.1, 17.9, 21.0, 21.4, and 21.7 (2θ)±0.2 degrees using CuKα radiation, and / or at 6.9, 7.4, 13.5, 14.4, 14.7, 16.4, 17.6, 18.7, 19.1, 19.3, 20.2, 22.4, 23.9, 24.2, and 24.7 (2θ)±0.2 degrees using CuKα radiation. In some embodiments, the crystalline sodium salt acetonitrile solvate form of AMG176 has an X-ray powder diffraction pattern substantially as shown in Figure 33, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative heights of peaks in a spectrum depend on many factors such as sample preparation and instrument configuration, while the peak positions are relatively insensitive to experimental details.

[0075] A differential scanning calorimetry (DSC) thermogram of the crystalline sodium salt acetonitrile solvate form of AMG176 was obtained as described in the Examples. The DSC curve shows endothermic transitions occurring at 58° C.±3° C. and 223° C.±3° C. For example, in some embodiments, the crystalline sodium salt acetonitrile solvate form of AMG176 is characterized by DSC as shown in FIG.

[0076] The crystalline sodium salt, acetonitrile solvate form of AMG176 can be characterized by thermogravimetric analysis (TGA), i.e., the crystalline sodium salt, acetonitrile solvate form of AMG176 can be characterized by exhibiting a weight loss in the range of about 29% by 150° C. In some embodiments, the crystalline sodium salt, acetonitrile solvate of AMG176 exhibits a thermogravimetric analysis result substantially as shown in FIG. 35, where "substantially" means that the reported TGA properties can vary by ±5° C.

[0077] The crystalline sodium salt acetonitrile solvate form of AMG176 can be characterized by a moisture sorption-desorption curve, for example, in some embodiments, the crystalline sodium salt acetonitrile solvate form of AMG176 is characterized by a moisture sorption-desorption curve showing a weight gain of about 14% at 95% relative humidity, followed by a loss of 13% by desorption, as shown in FIG.

[0078] Pharmaceutical preparations Provided herein is a pharmaceutical formulation comprising a salt or solvate of AMG176 disclosed herein and a pharma- ceutically acceptable excipient.

[0079] In some embodiments, the pharmaceutical formulation is in tablet form. In some embodiments, the pharmaceutical formulation is in immediate release tablet form. Solid oral drug compositions (e.g., tablets) or formulations have various release profiles, such as immediate release profiles as referred to by FDA guidelines ("Dissolution Testing of Immediate Release Solid Oral Dosage Forms", published August 1997, Section IV-A). In dissolution testing guidelines for immediate release profiles, a material that dissolves at least 80% in the first 30-60 minutes in solution is recognized as having an immediate release profile. Thus, an immediate release solid dosage form can release most or all of the active ingredient over a short period of time, such as 60 minutes or less, allowing the drug to be rapidly absorbed. In contrast, a sustained release solid oral dosage form can release the active ingredient over an extended period of time, with the aim of improving compliance by maintaining a therapeutically effective plasma concentration over a similarly long time interval and / or modifying other pharmacokinetic properties of the active ingredient.

[0080] "Pharmaceutically acceptable excipient" refers to a wide range of ingredients that can be combined with the compounds or salts of the present invention to prepare pharmaceutical compositions or formulations. Excipients are additives included in a formulation to either impart or enhance the stability, deliverability, and manufacturability of the formulation, and are physiologically harmless to the person ingesting it. Regardless of the reason for including an excipient, it is an essential component of the formulation and therefore needs to be safe and well tolerated by the patient. With the teachings and guidance provided herein, one of ordinary skill in the art would be able to easily vary the amount or range of excipients without increasing the viscosity to undesirable levels. Excipients may be selected to achieve the desired bioavailability, the desired stability, resistance to aggregation or degradation or precipitation, protection under freezing, lyophilization, or high temperature conditions, or other properties. In general, excipients include, but are not limited to, diluents, colorants, solvents, anti-adherents, glidants, disintegrants, flavorings, coatings, binders, sweeteners, lubricants, adsorbents, preservatives, and the like. Examples of suitable excipients will be well known to those skilled in the art of tablet formulation and are described, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0081] As used herein, the term "excipient" is intended to refer, inter alia, to basifying agents, solubilizing agents, glidants, fillers, binders, lubricants, diluents, preservatives, surfactants, dispersing agents, etc. The term also includes agents such as sweetening agents, flavoring agents, coloring agents, preservatives, etc. Such components will generally be present in the tablet as a mixture.

[0082] Examples of solubilizing agents include, but are not limited to, ionic surfactants (including both ionic and non-ionic surfactants), such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and macrogols.

[0083] Examples of lubricants, glidants and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, colloidal silicon dioxide and talc. The amount of lubricant in a tablet can generally be 0.1-5% by weight.

[0084] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, croscarmellose sodium, and the like.

[0085] Examples of fillers (also known as bulking agents or diluents) include, but are not limited to, starch, maltodextrin, polyols (such as lactose) and cellulose. The tablets provided herein may contain lactose and / or microcrystalline cellulose. Lactose can be used in anhydrous or hydrated forms (e.g., monohydrate) and is typically prepared by spray drying, fluidized bed granulation or roller drying.

[0086] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, starch, and the like.

[0087] In some embodiments, the pharma- ceutically acceptable excipients may include one or more diluents, binders, or disintegrants. In some embodiments, the pharma-ceutically acceptable excipients may include diluents including one or more of microcrystalline cellulose, starch, dicalcium phosphate, lactose, sorbitol, mannitol, sucrose, and methyldextrin, binders including one or more of povidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose, and disintegrants including one or more of crospovidone, sodium starch glycolate, and croscarmellose sodium.

[0088] The tablets provided herein may be uncoated or coated (in which case the tablet includes a coating). Although uncoated tablets can be used, it is more common to provide coated tablets, in which case a conventional non-enteric coating can be used. Film coatings are known in the art and may be composed of hydrophilic polymeric materials, including but not limited to hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), polysaccharide materials such as poly(vinyl alcohol-co-ethylene glycol), and other water-soluble polymers. The water-soluble material included in the film coating of the present invention may include a single type of polymeric material, but may also be formed using a mixture of multiple polymers. The coating may be white or colored, for example gray. Suitable coatings include, but are not limited to, polymeric film coatings, such as those comprising polyvinyl alcohol, e.g., "Opadry® II" (partially hydrolyzed PVA, titanium dioxide, macrogol 3350, and talc, with optional colorants such as iron oxide or indigo carmine or yellow iron oxide or FD&C Yellow No. 6). The amount of coating will generally be 2-4% of the core weight, with 3% being a particular specific embodiment. Unless otherwise specified, if the dosage form is coated, references to weight % of the tablet should be understood to mean weight % of the entire tablet, i.e., including the coating.

[0089] The pharmaceutical formulations disclosed herein may further comprise a surfactant. The surfactants used herein may be cationic, anionic or non-ionic. In some embodiments, the pharmaceutical formulations may comprise a non-ionic surfactant. In some embodiments, the surfactant may comprise a polysorbate, a poloxamer or a combination thereof. In some embodiments, the surfactant may comprise polysorbate 20, polysorbate 60, polysorbate 80 or a combination thereof.

[0090] Treatment method for the subject Further provided herein is a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a salt or solvate form of AMG176 disclosed herein, optionally in a pharmaceutical formulation, hi some embodiments, the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

[0091] Preparation of Salt and Solvate Forms The salt and solvate forms disclosed herein can be prepared by various methods known to those skilled in the art. For example, the salt and solvate forms can be prepared from amorphous, crude or crystalline forms of AMG176. In some embodiments, AMG176 is mixed with a solvent and / or salt former to form the desired salt or solvate form, for example, as described below in the Examples. In some embodiments, AMG176 is dissolved or mixed with a solvent to form a slurry. In some embodiments, AMG176 is dissolved or mixed with a solvent to form a slurry, and then a salt former is added to the slurry. In some embodiments, the salt former is added before forming the slurry. In some embodiments, AMG176 is mixed with a solvent and / or salt former, and the solution or slurry thus formed is aged to form the salt or solvate form. In some embodiments, heating is performed before aging the solution or slurry or forming crystals.

[0092] Other embodiments While the present disclosure is to be read in conjunction with its detailed description, it should be understood that the foregoing description is intended to be illustrative, and not limiting, of the scope of the disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. EXAMPLES

[0093] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0094] Materials and Methods Unless otherwise specified, commercially available reagents were used as received without further purification.

[0095] The starting material (AMG176) for the synthetic method set forth below is disclosed in U.S. Patent No. 9,562,061. The crystalline forms disclosed herein may be characterized using conventional means, including physical constants and spectral data.

[0096] X-ray powder diffraction: X-ray powder diffraction data were acquired using a PANalytical X-Pert Pro diffractometer. The radiation used was CuKα (1.542 Å), the voltage was 45 kV, and the current was 40 mA. Data were collected at ambient temperature with a scan range of 5.00 to 40.00° (2θ) and a step width of 0.0167°. A low background sample holder was used and the stage was rotated with a rotation time of 2.0 seconds. The incident beam path was equipped with a 0.02 rad Soller slit, a 15 mm mask, a 4° fixed anti-scatter slit, and a programmable divergence slit. The diffracted beam path was equipped with a 0.02 rad Soller slit, a programmable anti-scatter slit, and a 0.02 mm nickel filter.

[0097] Alternatively, XRPD patterns were collected in transmission using a PANalytical X'Pert PRO MPD diffractometer with Cu radiation generated using an Optix long, fine-focus source as the incident beam. An elliptically graded multilayer mirror was used to focus the CuKα X-rays through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to ensure that the observed position of the Si 111 peak was consistent with the NIST-certified position. The sample coupons were sandwiched between 3 μm thick films and analyzed in transmission geometry. To minimize background due to air, a beam stop was used, a short antiscatter extension to the detector, and a knife edge was used for antiscatter. Soller slits for the incident and diffracted beams were used to minimize the spread of the axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b. Data acquisition parameters for each pattern, including the divergence slit (DS) in front of the mirror, are displayed above the images in the data section of this report.

[0098] XRPD patterns were collected in reflection on a PANalytical X'Pert PRO MPD diffractometer using CuKα radiation generated using a far-focus microfocus source and nickel filter as the incident beam. The diffractometer was configured in a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to ensure that the observed position of the Si 111 peak was consistent with the NIST-certified position. Sample specimens were loaded into wells. Anti-scatter slits (SS) were used to minimize air background. Soller slits were used for the incident and diffracted beams to minimize the spread of axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b. Data acquisition parameters for each pattern, including divergence slit (DS) and incident beam SS, are displayed above the images in the data section of this report.

[0099] With reference to a given indexed XRPD pattern in the figures, the agreement of the observed peaks with the accepted peak positions marked with red lines indicates consistency with the determined unit cell. Unless otherwise specified, successful indexing of the pattern indicates that the sample is composed primarily of a single crystalline phase. The assigned annihilation symbols, unit cell parameters and space groups consistent with derived quantities are given in the table below the figures. To support the hypothetical indexing solution, the molecular packing motif within the crystallographic unit cell needs to be determined. Molecular packing was not attempted.

[0100] Single crystal structure: A colorless needle-like crystal (monohydrate) with dimensions 0.18 × 0.11 × 0.05 mm was mounted on a nylon loop using a trace of paraton oil. After mounting the crystal and confirming that the unit cell was a monohydrate, the temperature was raised to 400 K to dehydrate it. The crystal was held at 400 K for 4 hours, after which the temperature was lowered to 173 K and data were collected. Data were collected using a Bruker CCD (charge-coupled device) diffractometer with an Oxford Cryostream cryostat operating at 173 K. Data were collected using ω and φ scans with 0.5° between frames for 30 seconds per frame. The total number of images was based on the results of the program COSMO, with an expected multiplicity of 4.0 and 100% completeness to 0.83 Å. Lattice parameters were determined using APEX II software, and refinements were performed using SAINT for all observed reflections. Data were reduced using SAINT software. Scaling and absorption correction were performed using the SADABS multi-scan method. The structure was solved by direct methods using the SHELXS-97 program, and refined by least-squares methods using F2 (SHELXL-97) implemented in SHELXTL-PC V 6.10.

[0101] Differential Scanning Calorimetry: Differential scanning calorimetry (DSC) was performed using a TA Instruments Q100 instrument. Sample amounts of approximately 1 mg were weighed into standard DSC aluminum pans. The pans were not crimped. Samples were heated at 10°C / min from ambient to 300°C in 50 mL / min dry nitrogen. Modulated DSC analysis was performed using a TA Instruments Q100 instrument. Sample amounts of approximately 1 mg were used in aluminum pans, and the pans were not crimped. Samples were equilibrated at 20°C and held for 5 minutes before being heated to 300°C at a heating rate of 3°C / min in 50 mL / min dry nitrogen. Modulation of ±0.75°C was performed every 45 seconds.

[0102] Alternatively, DSC was performed using a TA Instruments Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST-traceable indium metal. Samples were placed into Tzero aluminum pans, covered with lids, crimped, and weights accurately recorded. A weighed aluminum pan, designated as the sample pan, was placed on the reference side of the cell. Data acquisition parameters and pan configurations for each thermogram are shown in the images in the data section of this report. Method codes above the thermograms are abbreviations for start and end temperatures and heating rates; for example, -30-250-10 means "-30°C to 250°C at 10°C / min."

[0103] Alternatively, MDSC data were acquired using a TA Instruments Q2000 Differential Scanning Calorimeter equipped with a refrigerant cooling system (RCS). Temperature calibration was performed using NIST-traceable indium metal. Samples were placed into DSC aluminum pans and the weights were accurately recorded. The pans were covered with lids and the lids were crimped. The weighed and crimped aluminum pans were placed into the reference side of the cell. Data were acquired from -30°C to 250°C with an underlying heating rate of 2°C / min, with a modulation amplitude of ±0.8°C over a 60 second period. The glass transition temperatures reported were taken from the inflection point of the step change in the temperature vs. reversible heat flow curve.

[0104] Alternatively, DSC was performed using a Mettler-Toledo DSC3+ Differential Scanning Calorimeter. Temperature calibration was performed using adamantane, phenyl salicylate, indium, tin and zinc. Samples were placed in closed or open DSC aluminum pans and the weight was accurately recorded. A weighed aluminum pan, designated as the sample pan, was placed on the reference side of the cell. Samples were analyzed from -30 to 250°C at a heating rate of 10°C / min. Thermograms were plotted against the reference temperature (x-axis), but results are reported according to the sample temperature.

[0105] Thermal analysis: Thermogravimetric analysis was performed using a TA Instruments Q500 instrument. Sample amounts of approximately 1-5 mg were used in aluminum pans. Samples were heated from ambient temperature to 400 °C at 10 °C / min in 25 mL / min dry nitrogen.

[0106] Alternatively, TG analysis was performed using a TA Instruments Q5000 IR Thermogravimetric Analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in an aluminum pan. The sample was sealed and the lid pierced before being inserted into the TG furnace. The furnace was heated under nitrogen. Data acquisition parameters for each thermogram are shown in the images in the data section of this report. Method symbols above the thermograms are abbreviations for the start and end temperatures and heating rate; for example, 25-350-10 means "25°C to 350°C at 10°C / min."

[0107] Alternatively, thermogravimetric analysis was performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using phenyl salicylate, indium, tin and zinc. Samples were placed in aluminum pans. The open pans were inserted into a TG furnace. The furnace was heated under nitrogen. Each sample was heated from ambient temperature to 350°C at a heating rate of 2, 5 or 10°C / min. Differential thermal analysis curves were plotted against the reference temperature (x-axis) but results are reported according to the sample temperature.

[0108] Hygroscopicity: Hygroscopicity data was collected at 25°C using a VTI moisture sorption / desorption instrument. Sample amounts of approximately 4-10 mg were used in platinum pans. Hygroscopicity was evaluated from 5 to 95% RH in 5% RH increments. Data was collected for adsorption / desorption cycles. Equilibrium criteria were set at ±0.001% weight change in 10 minutes with a maximum equilibration time of 180 minutes.

[0109] NMR: Solution proton NMR spectra were obtained at 25° C. using a Varian UNITYINOVA-400 spectrometer from Spectral Data Services, Champaign, Ill. Samples were dissolved in DMSO-d6. In some cases, solution NMR spectra were obtained using deuterated DMSO or methanol using an Agilent DD2-400 spectrometer at SSCI.

[0110] 600MHz ( 1 H) Bruker DSX spectrometer 13 C SSNMR data were collected. A 4 mm H / F / X spinning probe operated at a spinning frequency of 14 kHz was used for all experiments. CPMAS was performed using the TOSS program with a repeat delay of 10 s. 1 H 90° pulse and 8μs 13 A C 180° pulse was used. A spinal 64 pulse sequence was used for decoupling. 4096 transients were acquired and averaged. Data were processed with Topspin 3.0 software.

[0111] Example 1: AMG176 Ammonium Salt AMG176 free acid was dissolved in acetonitrile at 50°C at a concentration of 25mg / mL, followed by the addition of 2M ammonia in methanol. The solution was dispersed in an ultrasonic bath for 2 hours to obtain a precipitate. The solid was confirmed to be crystalline by XRPD.

[0112] [Table 1]

[0113] Example 2: AMG176 Diethylamine Salt Form A (Diethylamine Salt Toluene Solvate) AMG176 was suspended in toluene. Diethylamine (1.0 eq) was charged to the solution and the mixture was stirred at room temperature for 3 days. The solid was confirmed to be crystalline by XRPD.

[0114] [Table 2]

[0115] [Table 3]

[0116] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δppm0.84(d,J=6.39Hz,2H)1.09-1.20(m,4H)1.24-1.45(m,1H)1.60-1.88(m,3H)1.90-2 .16(m,2H)2.19-2.41(m,2H)2.59-2.85(m,1H)2.87-3.00(m,2H)3.06-3.12(m,1H)3.16(brd,J=13.85Hz,1H)3. 38-3.61(m,5H)3.72(brd,J=14.49Hz,4H)3.82-4.06(m,6H)5.35(brdd,J=15.34,9.16Hz,2H)5.93-6.09(m,2H) 6.72(d,J=8.10Hz,2H)6.83-6.95(m,2H)6.99(dd,J=7.99,1.60Hz,2H)7.11-7.28(m,6H)7.69(d,J=8.52Hz,1H).

[0117] [Table 4]

[0118] Example 3: AMG176 Diethylamine Salt Form B (Diethylamine Salt Anhydrous) AMG176 diethylamine salt Form A (diethylamine toluene solvate) was dried under vacuum at 50° C. The solid was determined to be crystalline by XRPD.

[0119] [Table 5]

[0120] 1 H NMR data 1 H NMR(400MHz,chloroform-d)δppm1.04(d,J=6.82Hz,3H)1.21-1.32(m,5H)1.40(d,J=7.03Hz,3H)1.48-1.69(m,2H )1.72-1.90(m,3H)1.90-2.09(m,3H)2.09-2.26(m,3H)2.27-2.51(m,4H)2.61-2.86(m,3H)2.86-3.05(m,5H)3 .16-3.33(m,4H)3.59-3.76(m,2H)3.92-4.11(m,3H)5.57(brdd,J=15.45,8.42Hz,2H)5.90(ddd,J=15.24,7.6 7,4.58Hz,2H)6.74-6.94(m,2H)6.94-7.12(m,2H)7.12-7.24(m,2H)7.44-7.64(m,4H)7.72(d,J=8.52Hz,1H).

[0121] [Table 6]

[0122] Example 4: AMG176 Diethanolamine Salt Toluene Solvate AMG176 was suspended in toluene. Diethanolamine (1.0 eq) was charged to the solution and the mixture was stirred at room temperature for 3 days. The solid was confirmed to be crystalline by XRPD.

[0123] [Table 7]

[0124] [Table 8]

[0125] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δppm0.84(d,J=6.39Hz,1H)1.12(d,J=7.25Hz,1H)1.20-1.43(m,1H)1.61-1.89(m,2H)1. 89-2.09(m,2H)2.20-2.41(m,2H)2.64-2.84(m,1H)2.85-3.09(m,3H)3.09-3.20(m,1H)3.38-3.62(m,4H)3.62-3 .81(m,1H)3.81-4.07(m,2H)4.96(brs,2H)5.35(brdd,J=15.34,9.16Hz,1H)5.91-6.07(m,1H)6.71(d,J=8.10Hz ,1H)6.79-6.95(m,1H)6.99(dd,J=7.99,1.60Hz,1H)7.08-7.21(m,2H)7.21-7.35(m,2H)7.69(d,J=8.52Hz,1H).

[0126] [Table 9]

[0127] Example 5: AMG176 Diethanolamine Salt Anhydrous Form The AMG176 diethanolamine toluene solvate was dried in vacuum at 50° C. The solid was determined to be crystalline by XRPD.

[0128] [Table 10]

[0129] [Table 11]

[0130] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δppm0.85(d,J=6.62Hz,4H)1.14(d,J=7.27Hz,4H)1.27-1.46(m,1H)1.58-1.79(m,4H)1.79-2.04(m,8H)2. 21-2.45(m,3H)2.64-2.91(m,3H)2.91-3.04(m,5H)3.09(s,3H)3.17(brd,J=14.10Hz,1H)3.42-3.59(m,3H)3.64(brt,J=4.92Hz,4 H)3.73(brd,J=14.75Hz,1H)3.83-4.08(m,4H)5.00-5.22(m,2H)5.36(dd,J=15.39,9.19Hz,1H)5.90-6.09(m,1H)6.74(d,J=7.91H) z,1H)6.87-6.95(m,1H)7.00(dd,J=8.12,1.71Hz,1H)7.16(d,J=2.35Hz,1H)7.27(dd,J=8.44,2.46Hz,1H)7.69(d,J=8.55Hz,1H).

[0131] [Table 12]

[0132] Example 6: AMG176 1,4-dioxane solvate AMG176 was slurried in 1,4-dioxane / water (70:30) for 14 days at 2-8° C. The solid was confirmed to be crystalline by XRPD.

[0133] [Table 13]

[0134] [Table 14]

[0135] [Table 15]

[0136] Example 7: AMG176 Imidazole Salt Form A (Imidazole Salt Acetone Solvate) AMG176 and imidazole (1 eq) were dissolved in acetone. The solution was cooled below ambient temperature to allow crystallization. The solid was confirmed to be crystalline by XRPD.

[0137] [Table 16]

[0138] [Table 17]

[0139] [Table 18]

[0140] Example 8: AMG176 hemimagnesium salt dihydrate AMG176 (827 mg) was dissolved in ethanol (16.54 mL) and heated to 55° C. Magnesium methoxide (0.742 mmol) was charged to the mixture, which was then kept at 55° C. for 3 hours and then cooled to room temperature. The solid was confirmed to be crystalline by XRPD.

[0141] [Table 19]

[0142] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δppm0.86(brs,3H)1.04-1.18(m,3H)1.32-1.42(m,1H)1.61-1.79(m,3H)1.85(brs,3H)1 .99(brd,J=12.32Hz,4H)2.28(brs,1H)2.31-2.41(m,1H)2.65-2.84(m,2H)2.93-3.08(m,1H)3.10(s,3H)3.14- 3.29(m,1H)3.54(brd,J=13.89Hz,2H)3.68-3.82(m,1H)3.82-4.03(m,3H)5.31-5.43(m,1H)6.73(d,J=8.02Hz, 1H)6.92-6.99(m,1H)7.02(brs,1H)7.16(d,J=2.15Hz,1H)7.26(dd,J=8.41,1.96Hz,1H)7.70(d,J=8.41Hz,1H).

[0143] Example 9: AMG176 methyl tert-butyl ether solvate AMG176 was slurried in methyl tert-butyl ether (MTBE) at room temperature for 1 day, and the solid was determined to be crystalline by XRPD.

[0144] [Table 20]

[0145] [Table 21]

[0146] [Table 22]

[0147] Example 10: AMG176 2-methyltetrahydrofuran solvate AMG176 (673 mg) was slurried in 2-MeTHF (10 mL) at room temperature for 1 day, and the solid was determined to be crystalline by XRPD.

[0148] [Table 23]

[0149] [Table 24]

[0150] [Table 25]

[0151] Example 11: AMG176 Potassium Salt Hydrate AMG176 (200 mg) was dissolved in THF (2 mL), and 10 mg of KOH was added and stirred to form a solution. Heptane (18 mL) was added to precipitate a solid. The solid was confirmed to be crystalline by XRPD.

[0152] [Table 26]

[0153] Example 12: AMG176 potassium salt isopropanol solvate AMG176 (200 mg) was dissolved in THF (2 mL), followed by addition of KOH (10 mg) and stirring to form a solution. A solid was precipitated by charging heptane (18 mL). The solid was isolated and then slurried in IPA:water (1:1). The solid was confirmed to be crystalline by XRPD.

[0154] [Table 27]

[0155] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δppm0.82-0.95(m,5H)1.05(d,J=6.06Hz,3H)1.17-1.42(m,7H)1.62-1.80(m,3H)1.80-2.08(m,7H) 2.17-2.33(m,1H)2.39(brd,J=6.85Hz,1H)2.65-2.83(m,2H)2.94-3.07(m,1H)3.10(s,3H)3.14-3.30(m,1H)3.51-3.58(m ,2H)3.69-3.82(m,2H)3.99(q,J=12.26Hz,3H)4.33(d,J=4.11Hz,1H)5.42(brdd,J=14.67,9.39Hz,1H)5.89(brs,1H)6.76 -6.83(m,1H)6.86(brs,1H)7.02(d,J=8.02Hz,1H)7.15-7.19(m,1H)7.27(dd,J=8.51,2.05Hz,1H)7.68(d,J=8.41Hz,1H).

[0156] Example 13: AMG176 Tetrahydrofuran Solvate AMG176 (200 mg) was dissolved in tetrahydrofuran (THF, 2 mL). Heptane (18 mL) was added to the mixture to precipitate a solid. The solid was confirmed to be crystalline by XRPD.

[0157] [Table 28]

[0158] [Table 29]

[0159] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δppm0.97(d,J=6.85Hz,3H)1.30-1.44(m,4H)1.66-1.84(m,7H)1.88(brd,J=7.63Hz,4H)1.99(brd, J=14.67Hz,1H)2.06-2.27(m,3H)2.39-2.49(m,1H)2.67-2.84(m,2H)3.02-3.13(m,4H)3.17-3.31(m,1H)3.53-3.65(m,6H) 3.75(brd,J=15.06Hz,1H)3.99-4.12(m,3H)5.51(brdd,J=14.67,8.80Hz,1H)5.74(brs,1H)6.78(s,1H)6.91(d,J=8.02Hz, 1H)7.05(dd,J=8.12,1.66Hz,1H)7.19(d,J=2.15Hz,1H)7.29(dd,J=8.51,2.25Hz,1H)7.67(d,J=8.61Hz,1H)11.92(s,1H).

[0160] [Table 30]

[0161] Example 14: AMG176 sodium salt acetonitrile solvate AMG176 was slurried in acetonitrile containing 1 eq NaOH at room temperature for 12 days. The solid was determined to be crystalline by XRPD.

[0162] [Table 31]

[0163] The foregoing description is presented merely for purposes of clarity of understanding, and no unnecessary limitations should be construed therefrom, since modifications within the scope of the invention may be apparent to those skilled in the art.

[0164] Throughout this specification and the claims which follow, unless the context requires otherwise, the term "comprise" and variations such as "comprises" and "comprising" will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0165] Throughout this specification, when a composition is described as comprising components or materials, it is contemplated that the composition may consist essentially of or consist of any combination of the listed components or materials, unless otherwise stated. Similarly, when a method is described as comprising particular steps, it is contemplated that the method may consist essentially of or consist of any combination of the listed steps, unless otherwise stated. The invention illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0166] As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope and spirit of the disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0167] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with the aid of automation provided by electronic equipment. Although the methods have been described with respect to specific embodiments, those skilled in the art will readily appreciate that other ways of performing the acts associated with the methods can be used. For example, the order of various steps can be changed without departing from the scope or spirit of the method unless otherwise stated. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0168] Use of the terms "a," "an," "the," and similar referents in connection with the disclosure herein (especially in connection with the claims) should be construed to include both the singular and the plural, unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. The use of any examples or exemplary language provided herein (e.g., "such as") is intended to more fully describe the disclosure herein and is not intended to limit the scope of the disclosure herein, unless otherwise indicated. No language herein should be construed as indicating any non-claimed element as essential to the practice of the disclosure herein.

[0169] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between this disclosure and the incorporated patents, publications, and references, this disclosure shall control.

Claims

1. A crystalline form of AMG176 as an ammonium salt, characterized by peaks at 16.6, 17.6, and 18.4 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

2. The crystal morphology according to claim 1, further characterized by peaks at 19.2, 21.6, 22.4, and 23.8 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

3. The crystal morphology according to claim 2, further characterized by peaks at 7.9, 10.1, 11.0, 12.7, 13.9, 20.2, 24.9, 27.7, and 29.8 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

4. The crystal morphology according to claim 1, which exhibits an endothermic transition at 156°C ± 3°C in differential scanning calorimetry.

5. The crystalline form of AMG176 as a diethylamine salt is characterized by an XRPD pattern as shown in Figure 5 ("Diethylamine Form A").

6. The crystal morphology according to claim 5, which exhibits an endothermic transition at 151°C ± 3°C in differential scanning calorimetry.

7. The crystalline form of AMG176 as a diethylamine salt is characterized by an XRPD pattern as shown in Figure 7 ("Diethylamine Form B").

8. The crystal morphology according to claim 7, which exhibits an endothermic transition between 140°C and 260°C in differential scanning calorimetry.

9. The crystal morphology according to claim 8, which exhibits an endothermic transition at 140°C ± 3°C in differential scanning calorimetry.

10. The crystalline form of AMG176 as a diethanolamine salt is characterized by an XRPD pattern as shown in Figure 9 ("Diethanolamine Salt Toluene Solvate").

11. The crystal morphology according to claim 10, which exhibits an endothermic transition between 134°C and 230°C in differential scanning calorimetry.

12. The crystal morphology according to claim 10, which exhibits an endothermic transition at 134°C ± 3°C in differential scanning calorimetry.

13. The crystalline form of AMG176 as a diethanolamine salt is characterized by an XRPD pattern as shown in Figure 11 ("diethanolamine anhydride").

14. The crystal morphology according to claim 13, which exhibits an endothermic transition between 126°C and 240°C in differential scanning calorimetry.

15. The crystal morphology according to claim 13, which exhibits an endothermic transition at 126°C ± 3°C in differential scanning calorimetry.

16. The crystalline form of AMG176 as a 1,4-dioxane solvate, characterized by peaks at 12.4, 12.8, 15.8, and 17.7 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

17. The crystalline morphology according to claim 16, further characterized by peaks at 18.0, 19.4, 20.2, and 22.3 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

18. The crystal morphology according to claim 16, further characterized by peaks at 8.1, 10.1, 14.0, 16.2, 16.7, 17.4, 19.0, 20.3, 20.9, 21.5, 22.8, 23.5, 24.0, 25.0, 25.7, 26.7, and 27.1 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

19. The crystalline form of AMG176 as an imidazole salt acetone solvate, characterized by peaks at 4.2, 8.1, and 20.7 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

20. The crystal morphology according to claim 19, further characterized by peaks at 8.7, 12.9, 16.4, and 17.4(2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

21. The crystal morphology according to claim 19, further characterized by peaks at 6.4, 7.0, 8.5, 9.1, 10.7, 13.8, 14.1, 15.1, 15.5, 16.7, 18.8, 19.7, 19.9, 21.0, 22.4, and 23.6 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

22. The crystal morphology according to claim 19, which exhibits an endothermic transition at 110°C ± 3°C in differential scanning calorimetry.

23. The crystalline form of AMG176 as a hemimagnesium salt dihydrate is characterized by peaks at 3.8, 5.8, and 7.5 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

24. The crystal morphology according to claim 23, further characterized by peaks at 10.3, 12.3, 13.7, 15.1, 16.7, 19.7, 20.7 and 23.5 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

25. The crystal morphology according to claim 23, which exhibits an endothermic transition at 84°C ± 3°C and 115°C ± 3°C in differential scanning calorimetry.

26. The crystalline form of AMG176 as a methyl tert-butyl ether solvate, characterized by peaks at 12.4, 15.6, and 20.1 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

27. The crystalline morphology according to claim 26, further characterized by peaks at 8.0, 12.6, 17.7, 17.9, 19.3, and 22.0 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

28. The crystal morphology according to claim 26, further characterized by peaks at 10.8, 13.8, 16.1, 16.3, 16.6, 17.2, 18.7, 20.9, 21.4, 22.6, 23.2, 24.9, 25.3, 26.3, and 26.4(2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

29. The crystalline form of AMG176 as a 2-methyltetrahydrofuran solvate, characterized by peaks at 12.4, 15.6, and 20.1 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

30. The crystal morphology according to claim 29, further characterized by peaks at 12.6, 17.8, 19.4, and 21.9 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

31. The crystal morphology according to claim 29, further characterized by peaks at 8.1, 13.7, 16.2, 16.7, 17.9, 18.7, 21.0, 21.4, 22.6, and 23.1 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

32. The crystalline form of AMG176 as a potassium salt hydrate is characterized by peaks at 5.9, 7.6, and 23.5 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

33. The crystalline morphology according to claim 32, further characterized by peaks at 11.2, 13.6, 15.3, 16.9, 18.5, and 22.5 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

34. The crystal morphology according to claim 32, which exhibits an endothermic transition at 58°C ± 3°C and 182°C ± 3°C in differential scanning calorimetry.

35. The crystalline form of AMG176 as a potassium salt isopropanol solvate, characterized by peaks at 5.8, 18.7, 22.5, and 23.5 (2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

36. The crystal morphology according to claim 35, further characterized by peaks at 11.0, 12.0, 13.6, 14.7, 17.4, 19.4, 20.4 and 29.2 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

37. The crystal morphology according to claim 35, which exhibits an endothermic transition at 64°C ± 3°C and 180°C ± 3°C in differential scanning calorimetry.

38. The crystalline form of AMG176 as a tetrahydrofuran solvate, characterized by peaks at 12.5, 15.8, and 17.8(2θ) ±0.2° in the XRPD pattern obtained using CuKα radiation.

39. The crystal morphology according to claim 38, further characterized by peaks at 12.8, 16.2, 18.0, 19.4, 20.3, 20.4, and 22.3(2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

40. The crystal morphology according to claim 38, further characterized by peaks at 8.1, 10.1, 14.0, 19.0, 21.0, 21.6, 22.9, 23.5, 25.7, and 26.8 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

41. The crystal morphology according to claim 38, which exhibits an endothermic transition at 174°C ± 3°C in differential scanning calorimetry.

42. The crystalline form of AMG176 as a sodium salt acetonitrile solvate is characterized by peaks at 3.4, 3.7, and 16.7(2θ) ± 0.2° in the XRPD pattern obtained using CuKα radiation.

43. The crystal morphology according to claim 42, further characterized by peaks at 17.1, 17.9, 21.0, 21.4, and 21.7 (2θ) ± 0.2° in an XRPD pattern obtained using CuKα radiation.

44. The crystal morphology according to claim 42, further characterized by peaks at 6.9, 7.4, 13.5, 14.4, 14.7, 16.4, 17.6, 18.7, 19.1, 19.3, 20.2, 22.4, 23.9, 24.2, and 24.7(2θ)±0.2° in an XRPD pattern obtained using CuKα radiation.

45. The crystal morphology according to claim 42, which exhibits an endothermic transition at 58°C ± 3°C and 223°C ± 3°C in differential scanning calorimetry.

46. A pharmaceutical preparation comprising a crystalline or amorphous form according to any one of claims 1 to 45 and an excipient that is acceptable as a drug.

47. A method for treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the crystalline or amorphous form described in any one of claims 1 to 45.

48. The method according to claim 47, wherein the cancer is multiple myeloma, non-Hodgkin lymphoma, or acute myeloid leukemia.

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