Crystalline forms of Mcl-1 inhibitors

Abstract

As used herein, (4S,7aR,9aR,10R,11E,14S,15R)-6'-chloro-10-methoxy-14,15-dimethyl-10-{[(9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]methyl}-3',4',7a,8,9,9a,10,13,14,15-decahydro-2'H,3H,5H-spiro[1,19-etheno-1616-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG 397): TIFF2025505141000037.tif35170 (AMG 397), hydrates and solvates thereof are disclosed. Methods of making the crystalline forms and methods of treating diseases and disorders with the crystalline forms are also disclosed.

Description

[Technical field]

[0001] The present disclosure relates to (4S,7aR,9aR,10R,11E,14S,15R)-6'-chloro-10-methoxy-14,15-dimethyl-10-{[(9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]methyl}-3',4',7a,8,9,9a,10,13,14,15-decahydro-2'H,3H,5H-spiro[1,19-etheno-16l6-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG), which functions as an inhibitor of myeloid cell leukemia 1 protein (Mcl-1). 397), with respect to the crystalline forms of its hydrates and solvates. [Background technology]

[0002] The compound (4S,7aR,9aR,10R,11E,14S,15R)-6'-chloro-10-methoxy-14,15-dimethyl-10-{[(9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]methyl}-3',4',7a,8,9,9a,10,13,14,15-decahydro-2'H,3H,5H-spiro[1,19-etheno-16l6-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG 397): [ka] are useful as inhibitors of myeloid cell leukemia 1 ("Mcl-1").

[0003] One common characteristic of human cancers is overexpression of Mcl-1, which prevents cancer cells from undergoing programmed cell death (apoptosis), allowing the cells to survive despite extensive genetic damage.

[0004] Mcl-1 is a member of the Bcl-2 family of proteins. The Bcl-2 family includes pro-apoptotic members (such as BAX and BAK) that form homo-oligomers in the outer mitochondrial membrane immediately after activation, which leads to apoptosis-triggering steps such as pore formation and mitochondrial content escape. Anti-apoptotic members of the Bcl-2 family (such as Bcl-2, Bcl-XL and Mcl-1) block the activity of BAX and BAK. Other proteins (such as BID, BIM, BIK and BAD) show additional regulatory functions. Studies have shown that Mcl-1 inhibitors may be useful for the treatment of cancer. Mcl-1 is overexpressed in many cancers.

[0005] U.S. Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses AMG 397 as an Mcl-1 inhibitor and provides methods for its preparation. However, alternative forms of AMG 397 with improved properties are desirable, particularly for clinical use of AMG 397. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 10,300,075 Summary of the Invention [Means for solving the problem]

[0007] Provided herein are crystalline forms of AMG 397, its hydrates and solvates, AMG 397 having the structure [ka] has.

[0008] As used herein, 5.65, 15.29, 18.06, 21.54, 24.20, 24.87, 28.91, 29.87, 36.86, 37.74, 39.09, 43.79, 44.59, 48.25, 49.01, 51.76, 54.33, 55.45, 57.50, 60.39, 64.99, Solids at 66.40, 80.11, 82.55, 83.01, 115.39, 121.81, 124.57, 127.61, 129.92, 132.04, 133.60, 135.32, 140.41, 142.61, 143.54, 153.09, 173.18 and 174.17 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate, characterized by C NMR peaks, is also provided ("Hydrate Form 2").

[0009] In this specification, 7.07, 17.2, 21.14, 22.75, 23.74, 27.01, 27.79, 29.13, 30.12, 32.09, 33.0, 35.45, 37.96, 45.21, 45.88, 50.0, 54.43, 55.23, 57.5, 59.23, 61.66, Solids at 63.31, 64.14, 69.06, 76.48, 82.72, 116.84, 119.24, 121.1, 126.62, 130.68, 132.8, 136.76, 139.39, 140.98, 141.7, 151.61, 172.8 and 173.61 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate, characterized by C NMR peaks, is also provided ("Hydrate Form 3").

[0010] As used herein, the solids at 5.55, 17.86, 24.02, 24.95, 29.56, 37.70, 44.44, 47.61, 48.86, 51.26, 54.92, 56.72, 57.48, 58.58, 64.86, 82.34, 114.99, 121.30, 127.31, 131.61, 133.04, 135.02, 139.77, 141.92, 152.71 and 173.08 ± 0.5 ppm 13 A crystalline form of anhydrous AMG 397, characterized by C NMR peaks, is also provided ("Anhydrous Form 4").

[0011] As used herein, the solids at 5.90, 15.93, 21.71, 24.33, 24.99, 25.92, 28.37, 29.16, 30.25, 31.00, 37.10, 39.31, 44.09, 48.49, 49.30, 51.99, 54.58, 55.81, 56.34, 57.73, 60.59, 66.60, 80.42, 83.22, 115.55, 122.14, 124.75, 127.82, 130.10, 132.40, 133.76, 140.62, 142.89, 143.63, 153.36 and 174.41 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate, characterized by C NMR peaks, is also provided ("Hydrate Form 5").

[0012] Also provided herein is a crystalline form of anhydrous AMG 397 characterized by an XRPD pattern peaks at 8.3, 15.7, 16.0, 18.6 and 20.1±0.2 degrees 2θ using Cu Kα radiation ("Anhydrous Form 6").

[0013] Also provided herein is a crystalline form of AMG 397 as a hydrate, characterized by an XRPD pattern peaks at 8.3, 10.7, and 10.8±0.2 degrees 2θ using Cu Kα radiation ("Hydrate Form 7").

[0014] Also provided herein is a crystalline form of AMG 397 as an ethanol solvate, characterized by an XRPD pattern peaks at 9.9, 16.9 and 20.0±0.2 degrees 2θ using Cu Kα radiation ("Ethanol Solvate Form 8").

[0015] Also provided herein is a crystalline form of AMG 397 as a hydrate, characterized by an XRPD pattern peaks at 10.0, 17.0 and 20.2±0.2 degrees 2θ using Cu Kα radiation ("Hydrate Form 9").

[0016] Also provided herein is a crystalline form of AMG 397 as a hydrate, characterized by an XRPD pattern peaks at 10.1, 20.2, 20.3±0.2 degrees 2θ using Cu Kα radiation ("Hydrate Form 10").

[0017] Also provided herein are pharmaceutical formulations comprising the crystalline forms of AMG 397, and hydrates and solvates thereof, as described herein, and a pharma- ceutically acceptable excipient.

[0018] Also provided herein is a method of treating a subject suffering from cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising a crystalline form of AMG 397, and hydrates and solvates thereof, as described herein, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0019] [Figure 1] 1 shows the X-ray powder diffraction ("XRPD") pattern of amorphous AMG 397. [Diagram 2] 1 shows a differential scanning calorimetry ("DSC") thermograph of amorphous AMG 397, showing a Tg of 195.90°C. [Diagram 3] 1 shows a thermogravimetric analysis ("TGA") trace of amorphous AMG 397, showing a weight loss of 0.86% up to 175° C. before decomposition. [Figure 4] 1 shows the hygroscopicity profile (DVS) of amorphous AMG 397, showing approximately 6.4% weight gain with 95% relative humidity. [Diagram 5] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate Form 1 of AMG 397. [Figure 6] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate Form 1 of AMG 397, showing a Tm of 221°C. [Figure 7] Figure 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate Form 1 of AMG 397, showing a 2.0% weight loss up to approximately 200°C before melting / decomposition. The single crystal structure confirms hydration variations, with water contents between 0.6% and 2% observed. [Figure 8] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline hydrate Form 1 of AMG 397, showing a weight gain of about 3.3% with 95% relative humidity. [Figure 9] 1 shows the solid state 13C NMR of crystalline hydrate form 1 of AMG 397. [Figure 10] 1 shows the single crystal X-ray crystal structure of crystalline hydrate Form 1 of AMG 397. [Figure 11] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate Form 2 of AMG 397. [Figure 12] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate Form 2 of AMG 397, showing a Tm of 248°C. [Figure 13] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate Form 2 of AMG 397, showing a weight loss of 1.8% up to 225° C. before melting / decomposition. [Figure 14] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline hydrate Form 2 of AMG 397, showing a weight gain of approximately 3.0% with 95% relative humidity. [Figure 15] 1 shows the solid state 13C NMR of crystalline hydrate form 2 of AMG 397. [Figure 16] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate Form 3 of AMG 397. [Figure 17] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate Form 3 of AMG 397, showing a Tm of 237°C. [Figure 18] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate Form 3 of AMG 397, showing a 6.2% weight loss up to 230° C. before melting / decomposition. [Figure 19] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline hydrate Form 3 of AMG 397, showing a weight gain of approximately 1.9% with 95% relative humidity. [Figure 20] 1 shows the solid state 13C NMR of crystalline hydrate form 3 of AMG 397. [Figure 21]1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline anhydrous Form 4 of AMG 397. [Figure 22] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline anhydrous Form 4 of AMG 397, showing a Tm of 242°C. [Figure 23] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline anhydrous Form 4 of AMG 397, showing a weight loss of 0.6% up to 225° C. before melting / decomposition. [Figure 24] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline anhydrous Form 4 of AMG 397, showing approximately 4.5% weight gain with 95% relative humidity. [Diagram 25] 1 shows the solid state 13C NMR of crystalline anhydrous Form 4 of AMG 397. [Figure 26] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate Form 5 of AMG 397. [Figure 27] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate form 5 of AMG 397, showing a Tm of 237°C. [Figure 28] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate Form 5 of AMG 397, showing a 2.3% weight loss up to 225° C. before melting / decomposition. [Figure 29] 1 shows the solid state 13C NMR of crystalline hydrate form 5 of AMG 397. [Diagram 30] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline anhydrous Form 6 of AMG 397. [Diagram 31] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline anhydrous Form 6 of AMG 397, showing a Tm of 234°C. [Diagram 32] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline anhydrous Form 6 of AMG 397, showing a weight loss of 0.3% from 25 to 120° C. before melting / decomposition. [Diagram 33] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline anhydrous Form 6 of AMG 397, showing a weight gain of approximately 0.5% from 0-50% relative humidity and 10% from 50-95% relative humidity. [Diagram 34] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate Form 7 of AMG 397. [Diagram 35] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate Form 7 of AMG 397. Hot stage microscopy confirms melting at 216.9-223.8°C. [Diagram 36] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate Form 7 of AMG 397, showing a weight loss of 4.15% up to 150° C. before melting / decomposition. [Figure 37] FIG. 1 shows the hygroscopicity profile (DVS) of crystalline hydrate form 7 of AMG 397, showing varying moisture contents from 0 to 12 wt%. [Figure 38] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline ethanol solvate Form 8 of AMG 397. [Figure 39] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline ethanol solvate Form 8 of AMG 397, showing a Tm onset of 67°C (peak at 91°C) and a Tm onset of 236°C. [Diagram 40] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline ethanol solvate Form 8 of AMG 397, showing a 31.3% weight loss from 37-140°C before melting / decomposition. [Diagram 41] 1 shows the single crystal X-ray crystal structure of the crystalline ethanol solvate form 8 of AMG 397. [Diagram 42] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate form 9 of AMG 397. [Diagram 43] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate form 9 of AMG 397, showing a Tm onset of 234°C. [Diagram 44] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate form 9 of AMG 397, exhibiting a weight loss of 1.8% between 37 and 130°C before melting / decomposition. [Diagram 45] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline hydrate form 10 of AMG 397. [Figure 46]1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline hydrate form 10 of AMG 397, showing a Tm onset of 233°C. [Figure 47] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrate form 10 of AMG 397, exhibiting a weight loss of 1.63% from 25 to 220° C. before melting / decomposition. [Figure 48] 1 shows an overlay of XRPD patterns of anhydrous and hydrate forms of AMG 397: (forms 1-9 from top to bottom). [Figure 49] 1 shows characteristic XRPD peaks for anhydrous and hydrate forms of AMG 397. [Figure 50] 1 shows an overlay of solid-state 13C NMR traces of the crystalline anhydrous form and hydrate forms 1-5 of AMG 397. [Figure 51] 1 shows a process for the form conversion of AMG 397 free base. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] As used herein, (4S,7aR,9aR,10R,11E,14S,15R)-6'-chloro-10-methoxy-14,15-dimethyl-10-{[(9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl]methyl}-3',4',7a,8,9,9a,10,13,14,15-decahydro-2'H,3H,5H-spiro[1,19-etheno-1616-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG 397): [ka] (AMG 397) and its hydrate crystalline forms are disclosed. Anhydrous Form 4 of AMG 397 is the thermodynamically stable form. Hydrate forms of crystalline AMG 397, such as crystalline hydrate Form 1 of AMG 397, may be advantageous over AMG 397 anhydrous Form 4 due to higher solubility, bioavailability and robust crystallization process.

[0021] Also provided herein are pharmaceutical formulations of the crystalline form of AMG 397 and methods of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of the crystalline form as disclosed herein.

[0022] US Pat. No. 10,300,075, the entirety of which is incorporated herein by reference, discloses synthetic procedures for synthesizing Mcl-1 inhibitors such as AMG 397.

[0023] Further provided herein are crystalline hydrate forms of AMG 397, pharmaceutical formulations thereof and methods of treating a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the crystalline hydrate form as disclosed herein.

[0024] The compounds disclosed herein may be identified herein by either their chemical structure and / or chemical name. In the event that the chemical structure and the chemical name conflict, the chemical structure is determinative of the compound's identity.

[0025] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0026] As used herein, dashed and bold line connections (i.e. [ka] Chemical structures containing one or more stereocenters, represented by a single solid line symbol, are meant to depict the absolute configuration of the stereocenters present in the chemical structure. As used herein, bonds represented by simple line symbols do not denote stereogenic preference. Unless specifically indicated to the contrary, 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 with a single solid or dashed line and at least one additional simple line encompass a single enantiomeric series of all possible diastereomers.

[0027] The term "about" is intended to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term "about," unless expressly stated otherwise, whether or not this term is expressly used. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0028] "Treatment" or "treating" refers to any treatment of a disease in a patient, including a) preventing the disease, i.e., not allowing 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 such treatment, such as for example, cancer.

[0029] The term "therapeutically effective amount" means an amount effective when administered to a human or non-human patient to treat a disease, e.g., a therapeutically effective amount can be an amount sufficient to treat a disease or disorder responsive to Mcl-1 inhibition. A therapeutically effective amount can be ascertained experimentally, e.g., by assaying blood levels of a chemical, or theoretically, or by calculating bioavailability.

[0030] The term "solvate" refers to a chemical entity formed by the interaction of a solvent with a compound. Crystalline solvates of AMG 397 used in the formulations herein are specifically contemplated. Solvents that can form crystalline solvate forms of AMG 397 include, but are not limited to, ethanol. In some cases, the solvent has 0.5 to 2 solvent molecules per AMG 397 molecule.

[0031] The term "hydrate" is a specific type of solvate in which the solvent is water. Hydrates, as used herein, can have variable amounts of water, including, for example, hemihydrates, monohydrates, dihydrates, trihydrates, and the like. Crystalline hydrates of AMG 397 are specifically contemplated for use in the formulations disclosed herein. In some cases, the hydrates have 0.5 to 2 water molecules per AMG 397 molecule.

[0032] The term "polymorphs" as used herein includes all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous) and conformational polymorphs, and mixtures thereof, unless a specific crystalline or amorphous form is referenced. In some embodiments, the present disclosure provides crystalline forms of AMG 397, including, for example, crystalline polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrous) and conformational polymorphs, and mixtures thereof, unless a specific crystalline form is referenced.

[0033] Crystal morphology Amorphous Form: Amorphous forms of AMG 397 may be characterized by X-ray powder diffraction, obtained as described in the Examples, using Cu Kα radiation. In some embodiments, the amorphous form 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 art of XRPD that the relative peak heights in a spectrum depend on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0034] For the amorphous form of AMG397, a differential scanning calorimetry (DSC) thermogram was obtained as described in the Examples. The DSC curve shows an endothermic transition at 195.9° C.±3° C. Thus, in some embodiments, the amorphous form of AMG397 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 192.9° C.-198.9° C. For example, in some embodiments, the amorphous form of AMG397 may be characterized by a DSC as shown in FIG. 2.

[0035] The amorphous form of AMG 397 may also be characterized by thermogravimetric analysis (TGA). Thus, the amorphous form of AMG 397 may be characterized by a weight loss ranging from about 0% to about 0.86% with an onset temperature of about 175° C. In some embodiments, the amorphous form of AMG 397 has a thermogravimetric analysis substantially as shown in FIG. 3, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0036] The amorphous form of AMG397 may be characterized by a hygroscopicity profile. For example, in some embodiments, the amorphous form of AMG397 is characterized by a hygroscopicity profile as shown in FIG. 4, which shows a weight gain of 6.4% with 95% RH.

[0037] Hydrate form 1: Hydrate form 1 has the following concentrations: 13.57, 19.13, 20.39, 24.04, 25.54, 27.75, 30.09, 31.05, 36.84, 38.27, 39.48, 43.15, 49.53, 50.30, 51.84, 54.40, 56.15, 57.28, 57.78, 60.23, 61.80, A solid obtained as described in the examples having peaks at 65.65, 78.05, 85.23, 115.91, 123.10, 124.60, 128.11, 130.53, 133.18, 133.87, 134.99, 139.72, 141.47, 143.08, 151.76 and 174.30±0.5 ppm. 13 In some embodiments, hydrate Form 1 may be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0038] Hydrate Form 1 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 10.3, 16.3, and 17.1±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 10.7, 12.5, 13.3, 15.1, 17.7, 18.2, and 20.3±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 8.1, 12.0, 14.4, 14.7, 19.8, 20.9, 21.9, 25.0, and 25.4±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 1 has 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 field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0039] A differential scanning calorimetry (DSC) thermogram of hydrate form 1 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 221° C.±3° C. Thus, in some embodiments, hydrate form 1 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 218° C.-224° C. For example, in some embodiments, hydrate form 1 is characterized by a DSC as shown in FIG. 6.

[0040] Hydrate Form 1 may be characterized by thermogravimetric analysis (TGA). Thus, Hydrate Form 1 may be characterized by a weight loss ranging from about 0% to about 3% with an onset temperature of 218° C. to 224° C. For example, Hydrate Form 1 may be characterized by a weight loss of about 2% up to about 200° C. In some embodiments, Hydrate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 7, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0041] Hydrate Form 1 may be characterized by a hygroscopicity profile. For example, in some embodiments, Hydrate Form 1 is characterized by a hygroscopicity profile as shown in Figure 8, which shows a weight gain of 3.3% with 95% RH.

[0042] Hydrate Form 1 may be characterised by a single crystal structure substantially as shown in Figure 10 or as described in the Examples.

[0043] Hydrate form 2: Hydrate form 2 has the following concentrations: 5.65, 15.29, 18.06, 21.54, 24.20, 24.87, 28.91, 29.87, 36.86, 37.74, 39.09, 43.79, 44.59, 48.25, 49.01, 51.76, 54.33, 55.45, 57.50, 60.39, 64.99, 66.40, 8 A solid obtained as described in the examples having peaks at 0.11, 82.55, 83.01, 115.39, 121.81, 124.57, 127.61, 129.92, 132.04, 133.60, 135.32, 140.41, 142.61, 143.54, 153.09, 173.18 and 174.17±0.5 ppm.13 In some embodiments, hydrate Form 2 may be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0044] Hydrate Form 2 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 6.2, 7.4, and 15.7±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 11.4, 16.0, 18.0, and 22.1±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 10.2, 10.6, 11.9, 17.1, 18.5, 19.2, 19.7, 20.3, 20.9, and 21.8.0±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 2 has 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 peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0045] A differential scanning calorimetry (DSC) thermogram of hydrate form 2 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 248° C.±3° C. Thus, in some embodiments, hydrate form 2 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 245° C.-251° C. For example, in some embodiments, hydrate form 2 is characterized by a DSC as shown in FIG. 12.

[0046] Hydrate Form 2 may be characterized by thermogravimetric analysis (TGA). Thus, Hydrate Form 2 may be characterized by a weight loss ranging from about 0% to about 1.8% with an onset temperature of about 225° C. In some embodiments, Hydrate Form 2 has a thermogravimetric analysis substantially as shown in FIG. 13, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0047] Hydrate Form 2 may be characterized by a hygroscopicity profile. For example, in some embodiments, Hydrate Form 2 is characterized by a hygroscopicity profile as shown in Figure 14, which shows a 3% weight gain with 95% RH.

[0048] Hydrate form 3: Hydrate form 3 has the following concentrations: 7.07, 17.2, 21.14, 22.75, 23.74, 27.01, 27.79, 29.13, 30.12, 32.09, 33.0, 35.45, 37.96, 45.21, 45.88, 50.0, 54.43, 55.23, 57.5, 59.23, 61.66, 63.31, A solid obtained as described in the examples having peaks at 64.14, 69.06, 76.48, 82.72, 116.84, 119.24, 121.1, 126.62, 130.68, 132.8, 136.76, 139.39, 140.98, 141.7, 151.61, 172.8 and 173.61±0.5 ppm. 13 In some embodiments, hydrate Form 3 may be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0049] Hydrate Form 3 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 13.6, 15.4, and 18.1±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 16.5, 18.9, 21.9, 22.6, and 24.2±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 12.3, 13.0, 16.0, 16.8, 17.5, 18.5, 19.5, 23.0, 27.2, and 28.0±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 3 has an X-ray powder diffraction pattern substantially as shown in Figure 16, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0050] A differential scanning calorimetry (DSC) thermogram of hydrate form 3 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 237° C.±3° C. Thus, in some embodiments, hydrate form 3 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 234° C.-240° C. For example, in some embodiments, hydrate form 3 is characterized by a DSC as shown in FIG. 17.

[0051] Hydrate Form 3 may be characterized by thermogravimetric analysis (TGA). Thus, Hydrate Form 3 may be characterized by a weight loss ranging from about 0% to about 6.2% with an onset temperature of about 230° C. In some embodiments, Hydrate Form 3 has a thermogravimetric analysis substantially as shown in FIG. 18, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0052] Hydrate Form 3 may be characterized by a hygroscopicity profile. For example, in some embodiments, Hydrate Form 3 is characterized by a hygroscopicity profile as shown in Figure 19, which shows a weight gain of 1.9% with 95% RH.

[0053] Anhydrous Form 4: Anhydrous Form 4 is a solid obtained as described in the Examples having peaks at 5.55, 17.86, 24.02, 24.95, 29.56, 37.70, 44.44, 47.61, 48.86, 51.26, 54.92, 56.72, 57.48, 58.58, 64.86, 82.34, 114.99, 121.30, 127.31, 131.61, 133.04, 135.02, 139.77, 141.92, 152.71 and 173.08±0.5 ppm. 13 In some embodiments, the anhydrous Form 4 can be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0054] Anhydrous Form 4 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 11.2, 15.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 12.9, 14.4, 16.8, and 18.2±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 10.7, 13.4, 15.4, 17.3, 18.5, 20.1, 20.4, 20.6, 21.7, 22.3, 24.9, and 26.5±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, anhydrous Form 4 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 peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0055] A differential scanning calorimetry (DSC) thermogram of anhydrous Form 4 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 242° C.±3° C. Thus, in some embodiments, anhydrous Form 4 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 239° C.-245° C. For example, in some embodiments, anhydrous Form 4 is characterized by a DSC as shown in FIG.

[0056] Anhydrous Form 4 may be characterized by thermogravimetric analysis (TGA). Thus, anhydrous Form 4 may be characterized by a weight loss ranging from about 0% to about 0.6% with an onset temperature of about 225° C. In some embodiments, anhydrous Form 4 has a thermogravimetric analysis substantially as shown in FIG. 23, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0057] Anhydrous Form 4 may be characterized by a hygroscopicity profile. For example, in some embodiments, anhydrous Form 4 is characterized by a hygroscopicity profile as shown in Figure 24, which shows a 4.5% weight gain with 95% RH.

[0058] Hydrate form 5: Hydrate form 5 has the following properties: 5.90, 15.93, 21.71, 24.33, 24.99, 25.92, 28.37, 29.16, 30.25, 31.00, 37.10, 39.31, 44.09, 48.49, 49.30, 51.99, 54.58, 55.81, 56.34, 57.73, 60. 59, 66.60, 80.42, 83.22, 115.55, 122.14, 124.75, 127.82, 130.10, 132.40, 133.76, 140.62, 142.89, 143.63, 153.36 and 174.41±0.5 ppm. 13 In some embodiments, hydrate Form 5 may be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0059] Hydrate Form 5 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 15.8, 16.8, and 19.4±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 11.3, 14.5, 18.2, 20.6, and 22.3±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 6.4, 10.7, 12.5, 13.0, 13.5, 16.1, 17.3, 18.6, 19.8, 20.1, 21.8, 24.9, and 26.6±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 5 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 peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0060] A differential scanning calorimetry (DSC) thermogram of hydrate form 5 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 237° C.±3° C. Thus, in some embodiments, hydrate form 5 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 234° C.-240° C. For example, in some embodiments, hydrate form 5 is characterized by a DSC as shown in FIG. 27.

[0061] Hydrate Form 5 may be characterized by thermogravimetric analysis (TGA). Thus, Hydrate Form 5 may be characterized by a weight loss ranging from about 0% to about 2.3% with an onset temperature of about 225° C. In some embodiments, Hydrate Form 5 has a thermogravimetric analysis substantially as shown in FIG. 28, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0062] Anhydrous Form 6: Anhydrous Form 6 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 8.3, 15.7, 16.0, 18.6, and 20.1±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 11.0, 12.5, 14.0, 18.4, 19.5, and 23.9±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 8.6, 13.1, 14.3, 14.7, 15.4, 17.2, 17.6, 18.1, 21.9, 22.2, 22.5, 22.7, and 28.2±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, anhydrous Form 6 has an X-ray powder diffraction pattern substantially as shown in Figure 30, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0063] A differential scanning calorimetry (DSC) thermogram of anhydrous Form 6 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 234° C.±3° C. Thus, in some embodiments, anhydrous Form 6 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 231° C.-237° C. For example, in some embodiments, anhydrous Form 6 is characterized by a DSC as shown in FIG.

[0064] Anhydrous Form 6 may be characterized by thermogravimetric analysis (TGA). Thus, anhydrous Form 6 may be characterized by a weight loss ranging from about 0% to about 0.3% with an onset temperature of about 25-120° C. In some embodiments, anhydrous Form 6 has a thermogravimetric analysis substantially as shown in FIG. 32, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0065] Anhydrous Form 6 may be characterized by a hygroscopicity profile. For example, in some embodiments, anhydrous Form 6 is characterized by a hygroscopicity profile as shown in Figure 33, which shows a weight gain of 0.5% from 0-50% RH and 10% by 95% RH.

[0066] Hydrate Form 7: Hydrate Form 7 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 8.3, 10.7, and 10.8±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 1.0, 12.5, 13.9, 16.8, 17.3, 18.7, and 19.3±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 6.3, 13.7, 14.2, 16.6, 18.9, 20.5, 20.6, 21.1, 21.7, 23.6, and 23.8±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 7 has an X-ray powder diffraction pattern substantially as shown in Figure 34, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0067] A differential scanning calorimetry (DSC) thermogram of hydrate form 7 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 220° C.±3° C. Thus, in some embodiments, hydrate form 7 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 216° C.-224° C. For example, in some embodiments, hydrate form 7 is characterized by a DSC as shown in FIG.

[0068] Hydrate Form 7 may be characterized by thermogravimetric analysis (TGA). Thus, hydrate form 7 may be characterized by a weight loss ranging from about 0% to about 4.15% with an onset temperature of about 150° C. In some embodiments, hydrate form 7 has a thermogravimetric analysis substantially as shown in FIG. 36, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0069] Hydrate Form 7 may be characterized by a hygroscopicity profile, for example, in some embodiments, Hydrate Form 7 is characterized by a hygroscopicity profile as shown in Figure 37, which exhibits a weight gain of 0-12% with 95% RH.

[0070] Ethanol solvate Form 8: Ethanol solvate Form 8 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 9.9, 16.9, and 20.0±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 12.6, 14.1, 14.7, 17.8, and 18.1±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 6.4, 8.5, 14.3, 14.4, 15.2, 16.6, 19.3, 20.3, 20.4, 20.8, 22.1, and 23.0±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, the ethanol solvate Form 8 has an X-ray powder diffraction pattern substantially as shown in Figure 38, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0071] A differential scanning calorimetry (DSC) thermogram of ethanol solvate Form 8 was obtained as described in the Examples. The DSC curve shows endothermic transitions at 67° C. and 236° C.±3° C. Thus, in some embodiments, ethanol solvate Form 8 may be characterized by a DSC thermogram having transition endotherms with onset temperatures of 64° C.-70° C. and 233° C.-239° C. For example, in some embodiments, ethanol solvate Form 8 is characterized by a DSC as shown in FIG.

[0072] Ethanol solvate Form 8 may be characterized by thermogravimetric analysis (TGA). Thus, ethanol solvate Form 8 may be characterized by a weight loss ranging from about 0% to about 31.3% with an onset temperature of about 37-140° C. In some embodiments, ethanol solvate Form 8 has a thermogravimetric analysis substantially as shown in FIG. 40, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0073] The ethanol solvate Form 8 may be characterized by a single crystal structure substantially as shown in FIG. 41 or as described in the Examples.

[0074] Hydrate Form 9: Hydrate Form 9 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 10.0, 17.0, and 20.2±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 6.4, 14.3, 14.9, 17.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 8.8, 10.9, 12.7, 14.8, 15.5, 16.8, 18.1, 18.8, 22.3, and 23.4±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, Hydrate Form 9 has an X-ray powder diffraction pattern substantially as shown in Figure 42, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum depend on many factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0075] A differential scanning calorimetry (DSC) thermogram of hydrate form 9 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 234° C.±3° C. Thus, in some embodiments, hydrate form 9 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 231° C.-237° C. For example, in some embodiments, hydrate form 9 is characterized by a DSC as shown in FIG.

[0076] Hydrate Form 9 may be characterized by thermogravimetric analysis (TGA). Thus, hydrate form 9 may be characterized by a weight loss ranging from about 0% to about 1.8% with an onset temperature of about 37-130° C. In some embodiments, hydrate form 9 has a thermogravimetric analysis substantially as shown in FIG. 44, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0077] Hydrate Form 10: Hydrate Form 10 may be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 10.1, 20.2, and 20.3±0.2 degrees 2θ using Cu Kα radiation, and optionally further characterized by additional peaks at 14.4, 14.9, 17.1, 17.9, and 18.3±0.2 degrees 2θ using Cu Kα radiation and / or additional peaks at 6.4, 6.6, 8.5, 10.7, 12.8, 15.4, 16.3, 16.7, 19.4, 19.8, 21.1, 22.3, 23.2, 25.7, 26.5, and 26.9±0.2 degrees 2θ using Cu Kα radiation. In some embodiments, hydrate form 10 has an X-ray powder diffraction pattern substantially as shown in Figure 45, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the art of XRPD that the relative peak heights in a spectrum depend on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0078] A differential scanning calorimetry (DSC) thermogram of hydrate form 10 was obtained as described in the Examples. The DSC curve shows an endothermic transition at 233° C.±3° C. Thus, in some embodiments, hydrate form 10 may be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 230° C.-236° C. For example, in some embodiments, hydrate form 10 is characterized by a DSC as shown in FIG.

[0079] Hydrate form 10 may be characterized by thermogravimetric analysis (TGA). Thus, hydrate form 10 may be characterized by a weight loss ranging from about 0% to about 1.63% with an onset temperature of about 25-220° C. In some embodiments, hydrate form 10 has a thermogravimetric analysis substantially as shown in FIG. 47, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0080] Pharmaceutical preparations Provided herein is a pharmaceutical formulation comprising a crystalline form as disclosed herein and a pharma- ceutically acceptable excipient.

[0081] In some embodiments, the pharmaceutical formulation is in the form of a tablet. In some embodiments, the pharmaceutical formulation is in the form of an immediate release tablet. Solid oral drug compositions (e.g., tablets) or preparations have various release profiles, including immediate release profiles as referred to by FDA guidelines ("Dissolution Testing of Immediate Release Solid Oral Dosage Forms" August 1997 issued, Section IV-A). In the dissolution testing guidelines for immediate release profiles, a material that dissolves at least 80% in the first 30-60 minutes in solution is considered an immediate release profile. Thus, an immediate release solid dosage form releases most or all of the active ingredient over a short period of time, such as 60 minutes or less, allowing for rapid absorption of the drug. In contrast, sustained release solid oral dosage forms maintain therapeutically effective plasma levels over a similarly long time interval, allowing for the release of the active ingredient over an extended period of time to improve dosing compliance and / or to alter other pharmacokinetic properties of the active ingredient.

[0082] "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 formulations because they either impart or enhance the stability, delivery and manufacturability of the drug product, and are physiologically harmless to the recipient. Regardless of the reason for including an excipient, it is an essential component of the drug product 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 will easily vary the amount or range of excipients without increasing the viscosity to undesirable levels. Excipients can 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, vehicles, anti-adherents, glidants, disintegrants, flavors, 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 can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0083] As used herein, the term "excipient" is intended to refer to, among others, basifying agents, solubilizing agents, glidants, fillers, binders, lubricants, diluents, preservatives, surfactants, dispersing agents, etc. The term also includes substances such as sweeteners, flavoring agents, coloring agents and preservatives. Such components are generally present in admixture within the tablet.

[0084] Examples of solubilizing agents include, but are not limited to, sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and ionic surfactants (including both ionic and non-ionic surfactants) such as macrogols.

[0085] 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.

[0086] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, croscarmellose sodium, and the like.

[0087] 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 may be used in anhydrous or hydrated form (e.g., monohydrate), and is generally prepared by spray drying, fluidized bed granulation, or roller drying.

[0088] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, starch, and the like.

[0089] In some embodiments, the pharma- ceutically acceptable excipient may include one or more diluents, binders, or disintegrants. In embodiments, the pharma-ceutically acceptable excipient 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.

[0090] The tablets provided herein may be uncoated or coated (in which case they include a coating). Although uncoated tablets may be used, it is more common to provide coated tablets, in which case a conventional non-enteric coating may be used. Film coatings are known in the art and may be composed of hydrophilic polymeric materials, including but not limited to polysaccharide materials such as hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), poly(vinyl alcohol-co-ethylene glycol) and other water-soluble polymers. Although the water-soluble material included in the film coating of the present invention may include a single polymeric material, it 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 (including partially hydrolyzed PVA, titanium dioxide, macrogol 3350, and talc with optional coloring agents such as iron oxide or indigo carmine or iron oxide yellow or FD&C yellow #6), such as those including polyvinyl alcohol, for example "Opadry® II". The amount of coating is generally 2-4% of the core weight, and in certain specific embodiments 3%. Unless specifically stated otherwise, if the dosage form is coated, it should be understood that references to the weight % of the tablet mean the % of the total tablet, i.e., weight including the coating.

[0091] The pharmaceutical compositions disclosed herein may further comprise a surfactant. As used herein, a surfactant may be cationic, anionic, or nonionic. In some embodiments, the pharmaceutical formulation may comprise a nonionic 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.

[0092] Method of Treating a 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 crystalline form as disclosed herein, optionally in a pharmaceutical formulation as disclosed herein, in some embodiments, the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

[0093] Preparation of Crystalline Forms The crystalline forms disclosed herein can be prepared by various methods known to those skilled in the art. For example, the crystalline forms can be prepared from an amorphous form, a crude form, or another crystalline form of AMG 397. In some embodiments, AMG 397 is combined with a solvent to form the desired crystalline form, for example, as discussed in the Examples below. In some embodiments, AMG 397 is dissolved in a solvent or combined with a solvent to form a slurry. In some embodiments, AMG 397 is combined with a solvent and the solution or slurry so formed is aged to form the crystalline form. In some embodiments, the solution or slurry is heated prior to aging or crystal formation. EXAMPLES

[0094] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0095] Materials and Methods Unless otherwise stated, commercially available reagents are used as received without further purification.

[0096] The synthesis of the starting material (AMG 397) for the following process is disclosed in U.S. Patent No. 10,300,075. The crystalline forms disclosed herein may be characterized using conventional means, including physical constants and spectral data.

[0097] X-ray powder diffraction: XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer or a PANalytical Empyrean diffractometer using an incident beam of Cu radiation generated using an Optix long microfocus source. An ellipsoidal multilayer mirror was used to focus the Cu Kα X-rays through the specimen and onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed Si(111) peak position matches the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short anti-scatter magnification, and anti-scatter knife edges were used to minimize background caused by the atmosphere. Soller slits of the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using an operational position sensitive detector (X'Celerator) located 240 mm away from the specimen and data collection software v.2.2b or software v.5.5.

[0098] Alternatively, X-ray powder diffraction (XRPD) data were obtained on a PANalytical X'Pert PRO X-ray diffraction system equipped with a RTMS detector. Samples were scanned at ambient temperature in continuous mode from 5 to 45° (2θ) with a step size of 0.0334° at 45 kV and 40 mA with a time per step of 50 s using Cu Kα radiation (1.541874 Å).

[0099] XRPD indexing was performed using the proprietary SSCI software TRIADS™ disclosed in US Pat. No. 8,576,985.

[0100] Differential Scanning Calorimetry: Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. A tau lag adjustment is performed with indium, tin, and zinc. The temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin, and zinc. The adjustment is then confirmed with octane, phenyl salicylate, indium, tin, and zinc. Samples were placed in hermetically sealed aluminum DSC pans and the weights were accurately recorded. The lids of the pans were punctured with an instrument and then inserted into the DSC cell for analysis. A weighed aluminum pan configured as the sample pan was placed in the reference side of the cell.

[0101] Alternatively, differential scanning calorimetry (DSC) analyses were performed on TA Instruments Q and Discovery Series calorimeters from 25 to 250-350° C. at 10° C. / min in aluminum pans under dry nitrogen at 50 ml / min.

[0102] Thermal Analysis: Thermogravimetric analysis (TGA) and TGA / DSC Combo analysis were performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were performed using indium, tin and zinc, then checked with indium. Balance was checked with calcium oxalate. Samples were placed in open aluminum pans. The pans were hermetically sealed, the lids were pierced, and then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen.

[0103] Alternatively, thermogravimetric analysis (TGA) was performed on TA Instruments Q and Discovery Series analyzers at 10° C. / min from ambient temperature to 250-350° C. in platinum pans under dry nitrogen at 25 ml / min.

[0104] Hygroscopicity: Hygroscopicity data was collected using a VTI SGA 100 Symmetric Vapor Sorption Analyzer. Sample sizes of approximately 5-10 mg were used in platinum pans. Hygroscopicity was evaluated from 5 to 95% RH in 5% RH increments. Data was collected for adsorption and desorption cycles. Equilibrium criteria were set at 0.001% weight change in 10 minutes with a maximum equilibration time of 180 minutes.

[0105] NMR: Solution proton NMR spectra were acquired by Spectral Data Services (Champaign, IL) using a Varian UNITYINOVA-400 spectrometer at 25° C. Samples were dissolved in DMSO-d6. In some cases, solution NMR spectra were acquired on an Agilent DD2-400 spectrometer with SSCI using deuterated DMSO or methanol.

[0106] 13 C SSNMR data was obtained from 600MHz ( 1 1H 90° 2.5μs and 8μs 1H 90° 30° pulses were used. 13 A C 180° pulse was used. Decoupling was performed using the spinal64 sequence. 4096 transient structures were acquired for signal integration. Data were processed using Topspin 3.0 software.

[0107] Example 1: Amorphous AMG 397 Amorphous AMG 397 was prepared by dissolving 1031.06 mg of AMG 397 in 52 mL of tetrahydrofuran (THF) and shaking to form a solution. The solution was then spray dried at a spray rate of 2.5 mL / min with an inlet temperature of 63° C., an outlet temperature of 50° C., an aspirator at 97%, an air flow at 0.58 kg / min, nozzle air at 7.0 SI / m, nozzle cooling at 20° C. and cyclone cooling at 30° C. The product was collected and dried under a vacuum oven at 30° C. with a pressure of −10 bar for 2 days to remove residual THF.

[0108] Example 2: Hydrate Form 1 of AMG 397 Hydrate Form 1 of AMG 397 was formed by combining AMG 397 with approximately 10 volumes of 95:5 ethanol / water. The solution was thermocycled to 70° C. for 15 minutes in a sealed vial and then cooled to form hydrate Form 1 of AMG 397, which was characterized as shown in the table below.

[0109] [Table 1]

[0110] [Table 2]

[0111] Single Crystal Data: A dry powder sample of Form 1 of AMG 397 was used for single crystal structure determination. The specimen selected for data collection had approximate dimensions of 0.002 × 0.008 × 0.025 mm. 3 The crystals were needle-shaped crystals of 100 nm. The crystals were mounted in a MiTeGen™ fixture with mineral oil (STP Oil Treatment). The initial diffraction pattern showed that the crystals were of marginal quality, elongated with smears, giving rise to isolated reflections, and diffracting only very weakly.

[0112] Diffraction data (φ- and ω-scans) were collected at 100 K on a Bruker-AXS X8 Kappa diffractometer coupled to a Bruker APEX2 CCD detector using CuKα radiation (λ=1.54178 Å) from an IμS microsource. Data reduction was performed using the program SAINT [1] and equivalent-based semi-empirical absorption corrections were made using the program SADABS [2]. A summary of crystal properties and data / fine-tuning statistics is given in Table 3.

[0113] The structure of AMG 397 Form 1 was determined at 100K in the monoclinic chiral space group P21 with one molecule of compound A and 80% of water molecules in the asymmetric unit.

[0114] [Table 3]

[0115] Example 3: Hydrate Form 2 of AMG 397 Hydrate Form 2 of AMG 397 was formed by slurrying 630 mg of AMG 397 in 6.5 mL of MeTHF and 6 mL of water (biphasic). The slurry was heated to 78° C. for about 5 hours and then cooled. The material was then filtered and the cake was dried on a frit using vacuum to provide hydrate Form 2 of AMG 397, which was characterized as shown in the table below.

[0116] [Table 4]

[0117] [Table 5]

[0118] [Table 6]

[0119] Example 4: Hydrate Form 3 of AMG 397 Hydrate Form 3 of AMG 397 was formed by slurrying approximately 705 mg of AMG 397 in 7 mL of IPA at 80° C. on a heating block in a sealed vial with stirring at 50 rpm. After cooling to room temperature, the material was heated twice back to 80° C. and then cooled on the heating block and left at room temperature overnight. The sample was reheated to 60° C. as a slurry, then rapidly cooled to room temperature, filtered, and washed with 1 mL of isopropyl alcohol to provide hydrate Form 3 of AMG 397, which was characterized as shown in the table below.

[0120] [Table 7]

[0121] [Table 8]

[0122] Example 5: Anhydrous Form 4 of AMG 397 Anhydrous Form 4 of AMG 397 was formed by slurrying about 2.5 g of AMG 397 in a 150 ml flask by azeotropically drying the material with MeTHF solvent. After removing the sample and drying, about 25 mL of MeTHF and 1 mL of water were added to the flask. The flask was heated to about 73° C., filtered, washed with additional solvent, and then dried under nitrogen and vacuum for about 3 days to provide anhydrous Form 4 of AMG 397, which was characterized as shown in the table below.

[0123] [Table 9]

[0124] [Table 10]

[0125] [Table 11]

[0126] Example 6: Hydrate Form 5 of AMG 397 Hydrate form 5 of AMG 397 was formed by slurrying about 20 g of AMG 397 in 8 volumes of MeTHF in a 500 mL reactor with the jacket heated to 70° C. To this was added 1 volume (20 mL of water) and after dissolving most of the slurry, crystalline material began to rapidly emerge from solution. After about 20 minutes, the addition of 40 mL of heptane was started over about 20 minutes. The slurry was then cooled to 20° C. and stirred slowly. After about 3 hours, an additional 20 mL of heptane was added and the slurry was simultaneously heated again to 70° C. over about 45 minutes, then cooled to 20° C. and aged overnight. The material was then filtered, washed with 100 mL of 70:30 MeTHF / heptane, and dried on a frit using vacuum and air for about 6 hours.

[0127] [Table 12]

[0128] [Table 13]

[0129] Example 7: Anhydrous Form 6 of AMG 397 Anhydrous Form 6 of AMG 397 was prepared by charging approximately 1 g of AMG 397 with 1-propanol and slurrying for 3 days at 55° C. The isolated solid was then dried under vacuum at 106-108° C. for 3 days.

[0130] [Table 14]

[0131] [Table 15]

[0132] [Table 16]

[0133] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.91(br d,J=6.61Hz,3H)1.18(br s,2H)1.21-1.29(m,1H)1.30-1.47(m,3H)1.48-1.72(m,4H)1.73-1.88(m,2H)2.00(br d,J=13.85Hz,2H)2.12-2.29(m,3H)2.29-2.39(m,1H)2.39-2.48(m,2H)2.54-2.82(m,4H)2.8 6-3.01(m,2H)3.01-3.16(m,1H)3.17-3.26(m,3H)3.46-3.66(m,3H)3.66-3.79(m,2H)3.86(br d,J=14.28Hz,2H)3.91-4.08(m,3H)5.23-5.52(m,2H)5.61(br d,J=15.77Hz,1H)6.81(br d,J=8.10Hz,1H)6.91-7.12(m,2H)7.17(d,J=2.13Hz,2H)7.27(dd,J=8.42,2.24Hz,1H)7.67(d,J=8.52Hz,1H).

[0134] [Table 17]

[0135] Example 8: Hydrate Form 7 of AMG 397 AMG 397 hydrate form 7 was prepared by charging approximately 4 g of AMG 397 with 1-propanol and then slurrying at 55° C. for 4 days. The isolated solid was then dried under vacuum at 95-105° C. for 7 days. Moisture content by KF was initially 0.9% and after equilibration at ambient conditions was 5.6%. DVS shows moisture content varying from 0-12% based on environment.

[0136] [Table 18]

[0137] [Table 19]

[0138] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.91(br d,J=6.61Hz,2H)1.17(br d,J=6.61Hz,3H)1.21-1.29(m,1H)1.29-1.49(m,3H)1.49-1.70(m,4H)1.70-1.91(m,3H)1.92-2.11(m,2H)2.11-2.37(m ,4H)2.39-2.48(m,2H)2.53-2.82(m,4H)2.86-3.01(m,2H)3.01-3.17(m,2H)3.17-3.26(m,3H)3.42-3.64(m,2H)3.72(br s,2H)3.78-3.91(m,2H)3.91-4.07(m,2H)5.32-5.52(m,1H)5.52-5.77(m,2H)6.81(br d,J=8.10Hz,2H)6.94-7.13(m,1H)7.17(d,J=2.34Hz,2H)7.26(dd,J=8.52,2.13Hz,1H)7.67(d,J=8.74Hz,1H).

[0139] [Table 20]

[0140] Example 9: Ethanol solvate form 8 of AMG 397 The ethanol solvate form 8 of AMG 397 was prepared by charging AMG 397 with EtOH and stirring at 55° C. for 3 days.

[0141] For single crystals, the ethanol solvate of AMG 397 was formed by dissolving approximately 500 mg of AMG 397 in 5 mL of ethanol and 1.5 equivalents of 5N NaOH. The sample was heated to 60° C. on a hot plate. 0.75 equivalents of 6M acetic acid were then added to the solution with stirring. The solution was then aged at 60° C. without stirring. An additional 0.25 equivalents of 6M acetic acid was added and the sample was aged overnight in a closed vial. The vial was cooled to 50° C. and held overnight, then cooled to 40° C. and held overnight. The sample was then cooled to 30° C. once crystals precipitated.

[0142] [Table 21]

[0143] [Table 22]

[0144] [Table 23]

[0145] 1 H NMR data 1 H NMR - 0.02 mol EtOH (partially desolvated to dryness) 1H NMR(400MHz,DMSO-d6)δ ppm 0.73-0.98(m,2H)0.98-1.12(m,1H)1.00-1.10(m,1H)1.00-1.10(m,1H)1.12-1.20(m,1H)1.2 0-1.29(m,1H)1.29-1.45(m,1H)1.45-1.56(m,1H)1.56-1.70(m,2H)1.70-1.82(m,1H)1.85(br s,1H)1.91(s,1H)2.00(br d,J=13.27Hz,1H)2.12-2.29(m,2H)2.33(dt,J=3.65,1.80Hz,1H)2.52- 2.62(m,1H)2.63-2.85(m,2H)2.86-3.00(m,1H)3.00-3.14(m,1H)3.14-3 .28(m,2H)3.35-3.59(m,1H)3.50-3.62(m,1H)3.78-3.90(m,1H)3.91-4 .16(m,3H)4.17-4.40(m,1H)4.50-4.84(m,2H)5.32-5.52(m,2H)5.59(br s,2H)6.81(br s,1H)6.90-7.09(m,1H)7.09-7.21(m,2H)7.27(br dd,J=8.58,2.24Hz,2H)7.67(d,J=8.58Hz,1H).

[0146] [Table 24]

[0147] [Table 25]

[0148] Example 10: Hydrate Form 9 of AMG 397 Hydrate form 9 of AMG 397 was prepared by charging AMG 397 with anhydrous MeOH or MeOH / HO (94:6) and stirring at room temperature for 2 weeks. The solid isolated was hydrate form 9.

[0149] [Table 26]

[0150]

Table 27

[0151]

Table 28

[0152] 1H NMR detector 1H NMR(400MHz,DMSO-d6)δ ppm 0.84-1.06(m,2H)1.06-1.26(m,3H)1.26-1.49(m,3H)1.49-1.88(m,6H)1.91(s,1H)1.95-2.08(m,2H)2.08-2 .34(m,4H)2.39-2.48(m,1H)2.54-2.82(m,4H)2.86-3.01(m,2H)3.01-3.16(m,1H)3.16-3.26(m,3H)3.55(br d,J=14.07Hz,2H)3.65-3.78(m,1H)3.86(br d,J=14.39Hz,2H)3.91-4.04(m,2H)4.04-4.21(m,1H)5.32-5.52(m,2H)5.61(br d,J=16.04Hz,2H)6.72-6.91(m,2H)6.91-7.12(m,2H)7.12-7.21(m,2H)7.27(dd,J=8.50,2.26Hz,1H)7.67(d,J=8.58Hz,1H).

[0153]

Table 29

[0154] Example 11: AMG 397 water mixture form 10 Hydrate form 10 of AMG 397 was prepared by extracting AMG 397 from a 100 mg pharmaceutical tablet using Me-THF, exchanging the solvent into ethanol, and then adding NaOH to form the sodium salt. The slurry was filtered to collect the cloudy filtrate, and it was noted that some crystalline material had grown on the sides of the flask holding the EtOH filtrate. ICP-MS analysis confirmed that the compound was the free base form.

[0155] [Table 30]

[0156] [Table 31]

[0157] The above description is merely given for 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.

[0158] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "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 integers or steps or group of integers or steps.

[0159] Throughout this specification, when a composition is described as comprising ingredients or raw materials, it is understood that the composition may consist essentially of or may consist of any combination of the listed ingredients or raw materials, unless otherwise stated. Similarly, when a method is described as comprising specific steps, it is also contemplated that the method may consist essentially of or may 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.

[0160] 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 distinct 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 present disclosure. Any recited method may be carried out in the order of events recited or in any other order which is logically possible.

[0161] The implementation of the methods disclosed herein and their individual steps may be performed manually and / or using automation provided by electronic equipment. Although the methods have been described with respect to specific embodiments, one skilled in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various steps may be altered without departing from the scope or spirit of the methods, unless otherwise noted. In addition, some of the individual steps may be combined, omitted, or further subdivided into additional steps.

[0162] In the context of this disclosure (especially in the context of the claims), the use of the terms "a," "an," "the," and similar referents should be construed to include both the singular and the plural, unless otherwise specified. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is incorporated herein as if it were individually recited herein. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better illustrate the disclosure herein and is not a limitation on the scope of the disclosure herein, unless otherwise specified. No language herein should be construed as indicating any non-claimed element is essential to the practice of the disclosure herein.

[0163] 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.

[0164] Embodiment The foregoing disclosure may be better understood through the following embodiments.

[0165] In the embodiment 1.5.65, 15.29, 18.06, 21.54, 24.20, 24.87, 28.91, 29.87, 36.86, 37.74, 39.09, 43.79, 44.59, 48.25, 49.01, 51.76, 54.33, 55.45, 57.50, 60.39, 64.99, 6 Solids at 6.40, 80.11, 82.55, 83.01, 115.39, 121.81, 124.57, 127.61, 129.92, 132.04, 133.60, 135.32, 140.41, 142.61, 143.54, 153.09, 173.18 and 174.17 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate ("Hydrate Form 2"), characterized by C NMR peaks.

[0166] Embodiment 2. The crystalline form of embodiment 1, further characterized by an XRPD pattern peaks at 6.2, 7.4, and 15.7±0.2 degrees 2θ using Cu Kα radiation.

[0167] Embodiment 3. The crystalline form of embodiment 2, further characterized by an XRPD pattern peaks at 11.4, 16.0, 18.0, and 22.1±0.2 degrees 2θ using Cu Kα radiation.

[0168] Embodiment 4. The crystalline form of embodiment 3, further characterized by an XRPD pattern peaks at 10.2, 10.6, 11.9, 17.1, 18.5, 19.2, 19.7, 20.3, 20.9, and 21.8±0.2 degrees 2θ using Cu Kα radiation.

[0169] Embodiment 5. The crystalline form of any one of embodiments 1-4, having an XRPD pattern substantially as shown in FIG.

[0170] Embodiment 6. The crystalline form of any one of embodiments 1 to 5, having an endothermic transition at 245° C. to 251° C. as measured by differential scanning calorimetry.

[0171] Embodiment 7. The crystalline form of embodiment 6, wherein the endothermic transition is at 248° C.±3° C.

[0172] Embodiment 8. The crystalline form of any one of embodiments 1-7, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 13.

[0173] In the embodiments 9.7.07, 17.2, 21.14, 22.75, 23.74, 27.01, 27.79, 29.13, 30.12, 32.09, 33.0, 35.45, 37.96, 45.21, 45.88, 50.0, 54.43, 55.23, 57.5, 59.23, 61.66, Solids at 63.31, 64.14, 69.06, 76.48, 82.72, 116.84, 119.24, 121.1, 126.62, 130.68, 132.8, 136.76, 139.39, 140.98, 141.7, 151.61, 172.8 and 173.61 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate ("Hydrate Form 3"), characterized by C NMR peaks.

[0174] Embodiment 10. The crystalline form of embodiment 9, further characterized by an XRPD pattern peaks at 13.6, 15.4, and 18.1±0.2 degrees 2θ using Cu Kα radiation.

[0175] Embodiment 11. The crystalline form of embodiment 10, further characterized by an XRPD pattern peaks at 16.5, 18.9, 21.9, 22.6, and 24.2±0.2 degrees 2θ using Cu Kα radiation.

[0176] Embodiment 12. The crystalline form of embodiment 11, further characterized by an XRPD pattern peaks at 12.3, 13.0, 16.0, 16.8, 17.5, 18.5, 19.5, 23.0, 27.2, and 28.0±0.2 degrees 2θ using Cu Kα radiation.

[0177] Embodiment 13. The crystalline form of any one of embodiments 9-12, having an XRPD pattern substantially as shown in FIG. 16.

[0178] Embodiment 14. The crystalline form of any one of embodiments 9 to 13, having an endothermic transition at 234° C. to 240° C. as measured by differential scanning calorimetry.

[0179] Embodiment 15. The crystalline form of embodiment 14, wherein the endothermic transition is at 237° C.±3° C.

[0180] Embodiment 16. The crystalline form of any one of embodiments 9-15, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 18.

[0181] Solids in embodiments 17.5.55, 17.86, 24.02, 24.95, 29.56, 37.70, 44.44, 47.61, 48.86, 51.26, 54.92, 56.72, 57.48, 58.58, 64.86, 82.34, 114.99, 121.30, 127.31, 131.61, 133.04, 135.02, 139.77, 141.92, 152.71 and 173.08 ± 0.5 ppm 13 A crystalline form of anhydrous AMG 397 ("Anhydrous Form 4"), characterized by C NMR peaks.

[0182] Embodiment 18. The crystalline form of embodiment 17, further characterized by an XRPD pattern peaks at 11.2, 15.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

[0183] Embodiment 19. The crystalline form of embodiment 18, further characterized by an XRPD pattern peaks at 12.9, 14.4, 16.8, and 18.2±0.2 degrees 2θ using Cu Kα radiation.

[0184] Embodiment 20. The crystalline form of embodiment 19, further characterized by an XRPD pattern peaks at 10.7, 13.4, 15.4, 17.3, 18.5, 20.1, 20.4, 20.6, 21.7, 22.3, 24.9 and 26.5±0.2 degrees 2θ using Cu Kα radiation.

[0185] Embodiment 21. The crystalline form of any one of embodiments 17-20, having an XRPD pattern substantially as shown in FIG. 21.

[0186] Embodiment 22. The crystalline form of any one of embodiments 17 to 21, having an endothermic transition at 239°C to 245°C as measured by differential scanning calorimetry.

[0187] Embodiment 23. The crystalline form of embodiment 22, wherein the endothermic transition is at 242° C.±3° C.

[0188] Embodiment 24. The crystalline form of any one of embodiments 17-23, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 23.

[0189] Solids in embodiments 25.5.90, 15.93, 21.71, 24.33, 24.99, 25.92, 28.37, 29.16, 30.25, 31.00, 37.10, 39.31, 44.09, 48.49, 49.30, 51.99, 54.58, 55.81, 56.34, 57.73, 60.59, 66.60, 80.42, 83.22, 115.55, 122.14, 124.75, 127.82, 130.10, 132.40, 133.76, 140.62, 142.89, 143.63, 153.36 and 174.41 ± 0.5 ppm 13 A crystalline form of AMG 397 as a hydrate ("Hydrate Form 5"), characterized by C NMR peaks.

[0190] Embodiment 26. The crystalline form of embodiment 25, further characterized by an XRPD pattern peaks at 15.8, 16.8, and 19.4±0.2 degrees 2θ using Cu Kα radiation.

[0191] Embodiment 27. The crystalline form of embodiment 26, further characterized by an XRPD pattern peaks at 11.3, 14.5, 18.2, 20.6, and 22.3±0.2 degrees 2θ using Cu Kα radiation.

[0192] Embodiment 28. The crystalline form of embodiment 27, further characterized by an XRPD pattern peaks at 6.4, 10.7, 12.5, 13.0, 13.5, 16.1, 17.3, 18.6, 19.8, 20.1, 21.8, 24.9 and 26.6±0.2 degrees 2θ using Cu Kα radiation.

[0193] Embodiment 29. The crystalline form of any one of embodiments 25-28, having an XRPD pattern substantially as shown in FIG. 26.

[0194] Embodiment 30. The crystalline form of any one of embodiments 25 to 29, having an endothermic transition at 234° C. to 240° C. as measured by differential scanning calorimetry.

[0195] Embodiment 31. The crystalline form of embodiment 30, wherein the endothermic transition is at 237° C.±3° C.

[0196] Embodiment 32. The crystalline form of any one of embodiments 25-31, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 28.

[0197] Embodiment 33. A crystalline form of anhydrous AMG 397 ("Anhydrous Form 6") characterized by an XRPD pattern peaks at 8.3, 15.7, 16.0, 18.6, and 20.1±0.2 degrees 2θ using Cu Kα radiation.

[0198] Embodiment 34. The crystalline form of embodiment 33, further characterized by an XRPD pattern peaks at 11.0, 12.5, 14.0, 18.4, 19.5, and 23.9±0.2 degrees 2θ using Cu Kα radiation.

[0199] Embodiment 35. The crystalline form of embodiment 34, further characterized by an XRPD pattern peaks at 8.6, 13.1, 14.3, 14.7, 15.4, 17.2, 17.6, 18.1, 21.9, 22.2, 22.5, 22.7, and 28.2±0.2 degrees 2θ using Cu Kα radiation.

[0200] Embodiment 36. The crystalline form of any one of embodiments 33-35, having an XRPD pattern substantially as shown in FIG. 30.

[0201] Embodiment 37. The crystalline form of any one of embodiments 33 to 36, having an endothermic transition at 231 ° C. to 237 ° C. as measured by differential scanning calorimetry.

[0202] Embodiment 38. The crystalline form of embodiment 37, wherein the endothermic transition is at 234° C.±3° C.

[0203] Embodiment 39. The crystalline form of any one of embodiments 33-38, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 32.

[0204] Embodiment 40. A crystalline form of AMG 397 as a hydrate ("Hydrate Form 7"), characterized by an XRPD pattern peaks at 8.3, 10.7, and 10.8±0.2 degrees 2θ using Cu Kα radiation.

[0205] Embodiment 41. The crystalline form of embodiment 40, further characterized by an XRPD pattern peaks at 1.0, 12.5, 13.9, 16.8, 17.3, 18.7, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

[0206] Embodiment 42. The crystalline form of embodiment 41, further characterized by an XRPD pattern peaks at 6.3, 13.7, 14.2, 16.6, 18.9, 20.5, 20.6, 21.1, 21.7, 23.6, and 23.8±0.2 degrees 2θ using Cu Kα radiation.

[0207] Embodiment 43. The crystalline form of any one of embodiments 40-42, having an XRPD pattern substantially as shown in FIG. 34.

[0208] Embodiment 44. The crystalline form of any one of embodiments 40 to 43, having an endothermic transition at 216°C to 224°C as measured by differential scanning calorimetry.

[0209] Embodiment 45. The crystalline form of embodiment 44, wherein the endothermic transition is at 220°C ± 3°C.

[0210] Embodiment 46. The crystalline form of any one of embodiments 40-45, having a thermogravimetric analysis ("TGA") substantially as shown in FIG.

[0211] Embodiment 47. A crystalline form of AMG 397 as an ethanol solvate, characterized by an XRPD pattern peaks at 9.9, 16.9, and 20.0±0.2 degrees 2θ using Cu Kα radiation ("Ethanol Solvate Form 8").

[0212] Embodiment 48. The crystalline form of embodiment 47, further characterized by an XRPD pattern peaks at 12.6, 14.1, 14.7, 17.8, and 18.1±0.2 degrees 2θ using Cu Kα radiation.

[0213] Embodiment 49. The crystalline form of embodiment 48, further characterized by an XRPD pattern peaks at 6.4, 8.5, 14.3, 14.4, 15.2, 16.6, 19.3, 20.3, 20.4, 20.8, 22.1, and 23.0±0.2 degrees 2θ using Cu Kα radiation.

[0214] Embodiment 50. The crystalline form of any one of embodiments 47-49, having an XRPD pattern substantially as shown in FIG. 38.

[0215] Embodiment 51. The crystalline form of any one of embodiments 47 to 50, having endothermic transitions at 64°C to 70°C and 233°C to 239°C, as measured by differential scanning calorimetry.

[0216] Embodiment 52. The crystalline form of embodiment 51, wherein the endothermic transitions are at 67° C. and 236° C.±3° C.

[0217] Embodiment 53. The crystalline form of any one of embodiments 47-52, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 40.

[0218] Embodiment 54. The crystalline form of any one of embodiments 47-53, having a single crystal structure substantially as shown in FIG. 41.

[0219] Embodiment 55. A crystalline form of AMG 397 as a hydrate ("Hydrate Form 9"), characterized by an XRPD pattern peaks at 10.0, 17.0, and 20.2±0.2 degrees 2θ using Cu Kα radiation.

[0220] Embodiment 56. The crystalline form of embodiment 55, further characterized by an XRPD pattern peaks at 6.4, 14.3, 14.9, 17.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

[0221] Embodiment 57. The crystalline form of embodiment 56, further characterized by an XRPD pattern peaks at 8.8, 10.9, 12.7, 14.8, 15.5, 16.8, 18.1, 18.8, 22.3, and 23.4±0.2 degrees 2θ using Cu Kα radiation.

[0222] Embodiment 58. The crystalline form of any one of embodiments 55-57, having an XRPD pattern substantially as shown in FIG. 42.

[0223] Embodiment 59. The crystalline form of any one of embodiments 55 to 58, having an endothermic transition at 231 ° C. to 237 ° C. as measured by differential scanning calorimetry.

[0224] Embodiment 60. The crystalline form of embodiment 59, wherein the endothermic transition is at 234°C ± 3°C.

[0225] Embodiment 61. The crystalline form of any one of embodiments 55-60, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 44.

[0226] Embodiment 62. A crystalline form of AMG 397 as a hydrate, characterized by an XRPD pattern peaks at 10.1, 20.2, 20.3±0.2 degrees 2θ using Cu Kα radiation ("Hydrate Form 10").

[0227] Embodiment 63. The crystalline form of embodiment 62, further characterized by an XRPD pattern peaks at 14.4, 14.9, 17.1, 17.9, and 18.3±0.2 degrees 2θ using Cu Kα radiation.

[0228] Embodiment 64. The crystalline form of embodiment 63, further characterized by an XRPD pattern peaks at 6.4, 6.6, 8.5, 10.7, 12.8, 15.4, 16.3, 16.7, 19.4, 19.8, 21.1, 22.3, 23.2, 25.7, 26.5, and 26.9±0.2 degrees 2θ using Cu Kα radiation.

[0229] Embodiment 65. The crystalline form of any one of embodiments 62-64, having an XRPD pattern substantially as shown in FIG. 45.

[0230] Embodiment 66. The crystalline form of any one of embodiments 62 to 65, having an endothermic transition at 230° C. to 236° C. as measured by differential scanning calorimetry.

[0231] Embodiment 67. The crystalline form of embodiment 66, wherein the endothermic transition is at 233° C.±3° C.

[0232] Embodiment 68. The crystalline form of any one of embodiments 62-67, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 47.

[0233] Embodiment 69. A pharmaceutical formulation comprising a crystalline form according to any one of embodiments 1 to 68 and a pharma- ceutically acceptable excipient.

[0234] Embodiment 70. A method for treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a crystalline form according to any one of embodiments 1 to 68 or a pharmaceutical formulation according to embodiment 69.

[0235] Embodiment 71. The method of embodiment 70, wherein the cancer is multiple myeloma, non-Hodgkin's lymphoma or acute myeloid leukemia.

[0236] 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 present disclosure, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 5.65, 15.29, 18.06, 21.54, 24.20, 24.87, 28.91, 29.87, 36.86, 37.74, 39.09, 43.79, 44.59, 48.25, 49.01, 51.76, 54.33, 55.45, 57.50, 60.39, 64.99, 66.4 Solids at 0, 80.11, 82.55, 83.01, 115.39, 121.81, 124.57, 127.61, 129.92, 132.04, 133.60, 135.32, 140.41, 142.61, 143.54, 153.09, 173.18 and 174.17 ± 0.5 ppm １３ A crystalline form of AMG 397 as a hydrate ("Hydrate Form 2"), characterized by a C NMR peak.

2. 10. The crystalline form of claim 1, further characterized by XRPD pattern peaks at 6.2, 7.4, and 15.7±0.2 degrees 2θ using Cu Kα radiation.

3. 3. The crystalline form of claim 2, further characterized by XRPD pattern peaks at 11.4, 16.0, 18.0, and 22.1±0.2 degrees 2θ using Cu Kα radiation.

4. 4. The crystalline form of claim 3, further characterized by XRPD pattern peaks at 10.2, 10.6, 11.9, 17.1, 18.5, 19.2, 19.7, 20.3, 20.9, and 21.8±0.2 degrees 2θ using Cu Kα radiation.

5. 5. The crystalline form of any one of claims 1 to 4, having an XRPD pattern substantially as shown in Figure 11.

6. 10. The crystalline form of claim 1, having an endothermic transition at 245°C to 251°C as measured by differential scanning calorimetry.

7. 7. The crystalline form of claim 6, wherein the endothermic transition is at 248°C ± 3°C.

8. 13. The crystalline form of claim 1, having a thermogravimetric analysis ("TGA") substantially as shown in FIG.

9. 7.07, 17.2, 21.14, 22.75, 23.74, 27.01, 27.79, 29.13, 30.12, 32.09, 33.0, 35.45, 37.96, 45.21, 45.88, 50.0, 54.43, 55.23, 57.5, 59.23, 61.66, 63. Solids at 31, 64.14, 69.06, 76.48, 82.72, 116.84, 119.24, 121.1, 126.62, 130.68, 132.8, 136.76, 139.39, 140.98, 141.7, 151.61, 172.8 and 173.61 ± 0.5 ppm １３ A crystalline form of AMG 397 as a hydrate ("Hydrate Form 3"), characterized by a C NMR peak.

10. 10. The crystalline form of claim 9, further characterized by XRPD pattern peaks at 13.6, 15.4, and 18.1±0.2 degrees 2θ using Cu Kα radiation.

11. 11. The crystalline form of claim 10, further characterized by XRPD pattern peaks at 16.5, 18.9, 21.9, 22.6, and 24.2±0.2 degrees 2θ using Cu Kα radiation.

12. 12. The crystalline form of claim 11, further characterized by XRPD pattern peaks at 12.3, 13.0, 16.0, 16.8, 17.5, 18.5, 19.5, 23.0, 27.2, and 28.0±0.2 degrees 2θ using Cu Kα radiation.

13. 13. The crystalline form of any one of claims 9 to 12, having an XRPD pattern substantially as shown in Figure 16.

14. 10. The crystalline form of claim 9, having an endothermic transition at 234°C to 240°C as measured by differential scanning calorimetry.

15. 15. The crystalline form of claim 14, wherein the endothermic transition is at 237°C ± 3°C.

16. 10. The crystalline form of claim 9, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 18.

17. 5.55, 17.86, 24.02, 24.95, 29.56, 37.70, 44.44, 47.61, 48.86, 51.26, 54.92, 56.72, 57.48, 58.58, 64.86, 82.34, 114.99, 121.30, 127.31, 131.61, 133.04, 135.02, 139.77, 141.92, 152.71 and 173.08 ± 0.5 ppm solids １３ A crystalline form of anhydrous AMG 397 ("Anhydrous Form 4") characterized by a C NMR peak.

18. 18. The crystalline form of claim 17, further characterized by XRPD pattern peaks at 11.2, 15.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

19. 20. The crystalline form of claim 18, further characterized by XRPD pattern peaks at 12.9, 14.4, 16.8, and 18.2±0.2 degrees 2θ using Cu Kα radiation.

20. 20. The crystalline form of claim 19, further characterized by XRPD pattern peaks at 10.7, 13.4, 15.4, 17.3, 18.5, 20.1, 20.4, 20.6, 21.7, 22.3, 24.9, and 26.5±0.2 degrees 2θ using Cu Kα radiation.

21. 21. The crystalline form of any one of claims 17 to 20, having an XRPD pattern substantially as shown in Figure 21.

22. 18. The crystalline form of claim 17, having an endothermic transition at 239°C to 245°C as measured by differential scanning calorimetry.

23. 23. The crystalline form of claim 22, wherein the endothermic transition is at 242°C ± 3°C.

24. 20. The crystalline form of claim 17, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 23.

25. 5.90, 15.93, 21.71, 24.33, 24.99, 25.92, 28.37, 29.16, 30.25, 31.00, 37.10, 39.31, 44.09, 48.49, 49.30, 51.99, 54.58, 55.81, 56.34, 57.73, 60.59, 66.60, 80.42, 83.22, 115.55, 122.14, 124.75, 127.82, 130.10, 132.40, 133.76, 140.62, 142.89, 143.63, 153.36 and 174.41 ± 0.5 ppm solids １３ A crystalline form of AMG 397 as a hydrate ("Hydrate Form 5"), characterized by a C NMR peak.

26. 26. The crystalline form of claim 25, further characterized by XRPD pattern peaks at 15.8, 16.8, and 19.4±0.2 degrees 2θ using Cu Kα radiation.

27. 27. The crystalline form of claim 26, further characterized by XRPD pattern peaks at 11.3, 14.5, 18.2, 20.6, and 22.3±0.2 degrees 2θ using Cu Kα radiation.

28. 28. The crystalline form of claim 27, further characterized by XRPD pattern peaks at 6.4, 10.7, 12.5, 13.0, 13.5, 16.1, 17.3, 18.6, 19.8, 20.1, 21.8, 24.9, and 26.6±0.2 degrees 2θ using Cu Kα radiation.

29. 29. The crystalline form of any one of claims 25 to 28, having an XRPD pattern substantially as shown in Figure 26.

30. 26. The crystalline form of claim 25, having an endothermic transition at 234°C to 240°C as measured by differential scanning calorimetry.

31. 31. The crystalline form of claim 30, wherein the endothermic transition is at 237°C ± 3°C.

32. 26. The crystalline form of claim 25, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 28.

33. A crystalline form of anhydrous AMG 397 ("Anhydrous Form 6") characterized by an XRPD pattern peaks at 8.3, 15.7, 16.0, 18.6, and 20.1±0.2 degrees 2θ using Cu Kα radiation.

34. 34. The crystalline form of claim 33, further characterized by XRPD pattern peaks at 11.0, 12.5, 14.0, 18.4, 19.5, and 23.9±0.2 degrees 2θ using Cu Kα radiation.

35. 35. The crystalline form of claim 34, further characterized by XRPD pattern peaks at 8.6, 13.1, 14.3, 14.7, 15.4, 17.2, 17.6, 18.1, 21.9, 22.2, 22.5, 22.7, and 28.2±0.2 degrees 2θ using Cu Kα radiation.

36. 36. The crystalline form of any one of claims 33 to 35, having an XRPD pattern substantially as shown in Figure 30.

37. 34. The crystalline form of claim 33, having an endothermic transition at 231°C to 237°C as measured by differential scanning calorimetry.

38. 38. The crystalline form of claim 37, wherein the endothermic transition is at 234°C ± 3°C.

39. 34. The crystalline form of claim 33, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 32.

40. A crystalline form of AMG 397 as a hydrate ("Hydrate Form 7"), characterized by XRPD pattern peaks at 8.3, 10.7, and 10.8±0.2 degrees 2θ using Cu Kα radiation.

41. 41. The crystalline form of claim 40, further characterized by XRPD pattern peaks at 1.0, 12.5, 13.9, 16.8, 17.3, 18.7, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

42. 42. The crystalline form of claim 41, further characterized by XRPD pattern peaks at 6.3, 13.7, 14.2, 16.6, 18.9, 20.5, 20.6, 21.1, 21.7, 23.6, and 23.8±0.2 degrees 2θ using Cu Kα radiation.

43. 43. The crystalline form of any one of claims 40 to 42, having an XRPD pattern substantially as shown in Figure 34.

44. 41. The crystalline form of claim 40, having an endothermic transition at 216°C to 224°C as measured by differential scanning calorimetry.

45. 45. The crystalline form of claim 44, wherein the endothermic transition is at 220°C ± 3°C.

46. 41. The crystalline form of claim 40, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 36.

47. A crystalline form of AMG 397 as an ethanol solvate ("Ethanol Solvate Form 8"), characterized by an XRPD pattern peaks at 9.9, 16.9, and 20.0±0.2 degrees 2θ using Cu Kα radiation.

48. 48. The crystalline form of claim 47, further characterized by XRPD pattern peaks at 12.6, 14.1, 14.7, 17.8, and 18.1±0.2 degrees 2θ using Cu Kα radiation.

49. 49. The crystalline form of claim 48, further characterized by XRPD pattern peaks at 6.4, 8.5, 14.3, 14.4, 15.2, 16.6, 19.3, 20.3, 20.4, 20.8, 22.1, and 23.0±0.2 degrees 2θ using Cu Kα radiation.

50. 50. The crystalline form of any one of claims 47 to 49, having an XRPD pattern substantially as shown in Figure 38.

51. 48. The crystalline form of claim 47, having endothermic transitions at 64°C to 70°C and 233°C to 239°C as measured by differential scanning calorimetry.

52. 52. The crystalline form of claim 51, wherein the endothermic transitions are at 67°C and 236°C ± 3°C.

53. 48. The crystalline form of claim 47, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 40.

54. 48. The crystalline form of claim 47, having a single crystal structure substantially as shown in Figure 41.

55. A crystalline form of AMG 397 as a hydrate ("Hydrate Form 9"), characterized by an XRPD pattern peaks at 10.0, 17.0, and 20.2±0.2 degrees 2θ using Cu Kα radiation.

56. 56. The crystalline form of claim 55, further characterized by XRPD pattern peaks at 6.4, 14.3, 14.9, 17.8, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

57. 57. The crystalline form of claim 56, further characterized by XRPD pattern peaks at 8.8, 10.9, 12.7, 14.8, 15.5, 16.8, 18.1, 18.8, 22.3, and 23.4±0.2 degrees 2θ using Cu Kα radiation.

58. 58. The crystalline form of any one of claims 55 to 57, having an XRPD pattern substantially as shown in Figure 42.

59. 56. The crystalline form of claim 55, having an endothermic transition at 231°C to 237°C as measured by differential scanning calorimetry.

60. 60. The crystalline form of claim 59, wherein the endothermic transition is at 234°C ± 3°C.

61. 56. The crystalline form of claim 55, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 44.

62. A crystalline form of AMG 397 as a hydrate ("Hydrate Form 10"), characterized by XRPD pattern peaks at 10.1, 20.2, 20.3±0.2 degrees 2θ using Cu Kα radiation.

63. 63. The crystalline form of claim 62, further characterized by XRPD pattern peaks at 14.4, 14.9, 17.1, 17.9, and 18.3±0.2 degrees 2θ using Cu Kα radiation.

64. 64. The crystalline form of claim 63, further characterized by XRPD pattern peaks at 6.4, 6.6, 8.5, 10.7, 12.8, 15.4, 16.3, 16.7, 19.4, 19.8, 21.1, 22.3, 23.2, 25.7, 26.5, and 26.9±0.2 degrees 2θ using Cu Kα radiation.

65. 65. The crystalline form of any one of claims 62-64, having an XRPD pattern substantially as shown in Figure 45.

66. 63. The crystalline form of claim 62, having an endothermic transition at 230°C to 236°C as measured by differential scanning calorimetry.

67. 67. The crystalline form of claim 66, wherein the endothermic transition is at 233°C ± 3°C.

68. 63. The crystalline form of claim 62, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 47.

69. 63. A pharmaceutical formulation comprising the crystalline form of any one of claims 1, 9, 17, 25, 33, 40, 47, 55, and 62, and a pharmaceutically acceptable excipient.

70. 10. A method for treating a subject suffering from cancer, wherein the method comprises administering to the subject a therapeutically effective amount of the crystalline form of any one of claims 1, 9, 17, 25, 33, 40, 47, 55, and 62.

71. 71. The method of claim 70, wherein the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

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