Crystalline Salt and Solvate Forms of Murizatoclax (AMG397)

Abstract

(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[1,19etheno-16l6-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG397): Disclosed herein are salts and solvate forms of TIFF2025505142000089.tif35170, including crystalline salts and solvate forms thereof. Methods of making the salts and solvate forms, and methods of treating diseases and disorders with the salts and solvate forms, are also disclosed.

Description

[Technical field]

[0001] The present disclosure provides (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,10,13,16,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,44,53,45,46,47,48,49,54,55,56,57,58,60,61,72,73,74,75,76,77,78,99,10,13,14,15,16,18,19,20,21,22,23,24,25,38,39,46,47,54,48,49,55,56,57,60,72,73,74,75,76,77,78,99,10,13,15,16,17,25,38,39,48,49,54,55,56,57,60,73,74,75,75,76,77,78,99,11E,14S,15R This relates to salt and solvate forms, such as crystalline salt and solvate forms, of 4,15 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 (AMG397). [Background technology]

[0002] 2. Description of Related Art The compound (4S,7aR,9aR,10R,11E,14S,15R)-6'-chloro-10-methoxy-14,15dimethyl-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[1,19etheno-16l6-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG397) is useful as an inhibitor of myeloid cell leukemia 1 ("Mcl-1"): [ka]

[0003] One common characteristic of human cancers is overexpression of Mcl-1, which prevents cancer cells from undergoing programmed cell death (apoptosis) and allows them 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), which upon activation form homo-oligomers in the outer mitochondrial membrane, leading to pore formation and release of mitochondrial contents, a step in the induction of apoptosis. 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] US Patent No. 10,300,075, the entirety of which is incorporated herein by reference, discloses AMG397 as an Mcl-1 inhibitor and provides a method for its preparation.However, alternative forms of AMG397 with improved properties are desirable, particularly for the clinical use of AMG397. [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] Salt forms and solvate forms of AMG397, including crystalline salt forms and solvate forms thereof, are provided herein, wherein AMG397 has the structure [ka] has.

[0008] Also provided herein is a crystalline form of AMG397 as a trifluoroethanol solvate, characterized by an XRPD pattern peaks at 17.5, 19.2, 19.4, and 21.7±0.2 degrees 2θ using CuKα radiation.

[0009] Also provided herein is a crystalline form of AMG397 as a hexafluoroisopropanol solvate, characterized by an XRPD pattern peaks at 11.4, 18.6, and 18.8±0.2 degrees 2θ using CuKα radiation.

[0010] Also provided herein is a crystalline form of AMG397 as a 1-propanol solvate, characterized by an XRPD pattern peaks at 13.3, 15.1, and 18.5±0.2 degrees 2θ using CuKα radiation.

[0011] Also provided herein is a crystalline form of AMG397 as an isopropanol solvate, characterized by an XRPD pattern peaks at 6.1, 7.1, and 10.0±0.2 degrees 2θ using CuKα radiation.

[0012] Also provided herein is a crystalline form of AMG397 as an isopropanol solvate, characterized by an XRPD pattern peaks at 13.3, 15.1, and 18.6±0.2 degrees 2θ using CuKα radiation.

[0013] Also provided herein is a crystalline form of AMG397 as an acetonitrile solvate, characterized by an XRPD pattern peaks at 10.2, 17.0, and 20.5±0.2 degrees 2θ using CuKα radiation.

[0014] 13.63, 19.22, 20.40, 24.22, 25.69, 26.57, 27.75, 29.81, 30.40, 31.28, 36.57, 38.34, 40.10, 43.04, 49.51, 50.10, 51.86, 54.51, 56.28, 57.16, 57.75 , 60.10, 62.16, 65.39, 77.75, 85.10, 115.39, 123.63, 125.10, 128.04, 131.27, 133.04, 133.92, 135.98, 139.80, 141.27, 143.04, 151.86 and 173.92 ± 0.5 ppm solids. 13 Also provided herein is a crystalline form of AMG397 as an acetic acid solvate, characterized by C NMR peaks.

[0015] Also provided herein is a crystalline form of AMG397 as the hydrochloride salt, characterized by an XRPD pattern peaks at 12.9, 16.2, and 17.9±0.2 degrees 2θ using CuKα radiation.

[0016] Also provided herein is an amorphous form of AMG397 as the sodium salt, having an XRPD pattern substantially as shown in FIG.

[0017] Also provided herein is a crystalline form of AMG397 as the potassium salt, characterized by an XRPD pattern peaks at 12.8, 13.4, and 17.2±0.2 degrees 2θ using CuKα radiation.

[0018] Also provided herein is a crystalline form of AMG397 as the potassium salt (ethyl acetate solvate), characterized by an XRPD pattern peaks at 2.7, 11.7, and 12.2±0.2 degrees 2θ using CuKα radiation.

[0019] Also provided herein is a crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 9.3, 13.9, and 19.2±0.2 degrees 2θ using CuKα radiation.

[0020] Also provided herein is a crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 11.7, 17.1, and 20.1±0.2 degrees 2θ using CuKα radiation.

[0021] Also provided herein is a crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 12.3, 17.7, 18.4, and 20.6±0.2 degrees 2θ using CuKα radiation.

[0022] 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8, 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8 and 168.8 ± 0.5 ppm 13 Also provided herein is a crystalline form of AMG397 as the phosphate salt, characterized by C NMR peaks.

[0023] Also provided herein is a crystalline form of AMG397 as the fumarate acetone sobate, characterized by an XRPD pattern peaks at 17.6, 18.2, and 18.4±0.2 degrees 2θ using CuKα radiation.

[0024] Also provided herein is a crystalline form of AMG397 as the fumarate salt, characterized by an XRPD pattern peaks at 11.9, 17.9, and 18.1±0.2 degrees 2θ using CuKα radiation.

[0025] Also provided herein is a crystalline form of AMG397 as the citrate salt, characterized by an XRPD pattern peaks at 10.6, 17.6, and 18.3±0.2 degrees 2θ using CuKα radiation.

[0026] Also provided herein is a crystalline form of AMG397 as the citrate salt, characterized by an XRPD pattern peaks at 17.7, 18.4, and 18.5±0.2 degrees 2θ using CuKα radiation.

[0027] Also provided herein is a crystalline form of AMG397 as the lactate salt, characterized by an XRPD pattern peaks at 12.1, 17.8, and 18.3±0.2 degrees 2θ using CuKα radiation.

[0028] Also provided herein is a crystalline form of AMG397 as the succinate salt, characterized by an XRPD pattern peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation.

[0029] Also provided herein is a crystalline form of AMG397 as the ammonium salt, characterized by an XRPD pattern peaks at 6.2, 10.3, and 17.2±0.2 degrees 2θ using CuKα radiation.

[0030] Also provided herein is a crystalline form of AMG397 as the besylate salt, characterized by an XRPD pattern peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation.

[0031] Also provided herein is a crystalline form of AMG397 as the tosylate salt, characterized by an XRPD pattern peaks at 18.2, 18.4, and 20.5±0.2 degrees 2θ using CuKα radiation.

[0032] Also provided herein is a crystalline form of AMG397 as the maleate salt, characterized by an XRPD pattern peaks at 18.2, 18.9, and 19.9±0.2 degrees 2θ using CuKα radiation.

[0033] Also provided herein is a crystalline form of AMG397 as the maleate salt, characterized by an XRPD pattern peaks at 10.6, 18.6, and 20.3±0.2 degrees 2θ using CuKα radiation.

[0034] Also provided herein is a crystalline form of AMG397 as the malonate salt, characterized by an XRPD pattern peaks at 12.2, 18.8, and 20.4±0.2 degrees 2θ using CuKα radiation.

[0035] Also provided herein is a crystalline form of AMG397 as the malonate salt, characterized by an XRPD pattern peaks at 10.6, 18.5, and 20.2±0.2 degrees 2θ using CuKα radiation.

[0036] Also provided herein is a crystalline form of AMG397 as the tartrate salt, characterized by an XRPD pattern peaks at 18.2, 18.6, and 20.2±0.2 degrees 2θ using CuKα radiation.

[0037] Also provided herein is a crystalline form of AMG397 as a tris(hydroxymethyl)aminomethane salt acetone solvate, characterized by an XRPD pattern peaks at 10.0, 16.8, and 20.0±0.2 degrees 2θ using CuKα radiation.

[0038] Also provided herein is a crystalline form of AMG397 as the iodide salt, characterized by an XRPD pattern peaks at 17.0, 18.0, and 18.1±0.2 degrees 2θ using CuKα radiation.

[0039] Also provided herein are pharmaceutical formulations comprising the salts and solvate forms of AMG397 described herein, such as crystalline salts and solvate forms thereof, and a pharma- ceutically acceptable excipient.

[0040] Also provided herein are methods of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation comprising salt and solvate forms of AMG397, such as the crystalline salt and solvate forms described herein, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0041] [Figure 1]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline trifluoroethanol solvate form of AMG397. [Diagram 2] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline hexafluoroisopropanol solvate form of AMG397. [Diagram 3] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline 1-propanol solvate form of AMG397. [Figure 4] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline 1-propanol solvate form of AMG397, exhibiting a Tm of 234°C. [Diagram 5] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline 1-propanol solvate form of AMG397, exhibiting a weight loss of 5.6% between 38 and 190° C. before melting / decomposition. [Figure 6] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline isopropanol solvate Form 1 of AMG397. [Figure 7] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline isopropanol solvate Form 1 of AMG397 exhibiting a Tm of 247°C. [Figure 8] FIG. 1 shows a thermogravimetric analysis ("TGA") trace of crystalline isopropanol solvate Form 1 of AMG397 showing a 0.5% weight loss from 39-120° C. before melting / decomposition. [Figure 9] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline isopropanol solvate Form 2 of AMG397. [Figure 10] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline isopropanol solvate Form 2 of AMG397 exhibiting Tm of 83°C and 239°C. [Figure 11] FIG. 1 shows a thermogravimetric analysis ("TGA") trace of crystalline isopropanol solvate Form 2 of AMG397 showing a 19.0% weight loss from 37-111° C. before melting / decomposition. [Figure 12] 1 shows the X-ray powder diffraction ("XRPD") pattern of a crystalline acetonitrile solvate form of AMG397. [Figure 13] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline acetic acid solvate form of AMG397. [Figure 14] 1 shows a differential scanning calorimetry ("DSC") thermograph of crystalline acetic acid solvate Form 2 of AMG397 exhibiting a Tm of 95°C and 155°C. [Figure 15] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline acetic acid solvate form of AMG397, showing a 3.1% weight loss up to 150° C., and a further 10.4% weight loss up to 250° C. before melting / decomposition. [Figure 16] 1 shows the solid state 13C NMR of the crystalline acetic acid solvate form of AMG397. [Figure 17] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline hydrochloride salt Form 1 of AMG397. [Figure 18] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline hydrochloride salt Form 1 of AMG397 exhibiting a Tm of 267°C. [Figure 19] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline hydrochloride salt Form 1 of AMG 397, showing a 9.5% weight loss from 35-275°C, and a 5.3% weight loss from 35-250°C before melting / decomposition. [Figure 20] 1 shows the moisture sorption profile (DVS) of the crystalline hydrochloride salt Form 1 of AMG397, showing a weight gain of approximately 0.7% at 95% relative humidity. [Figure 21] 1 shows the X-ray powder diffraction ("XRPD") pattern of the amorphous sodium salt form of AMG397. [Figure 22] 1 shows a differential scanning calorimetry ("DSC") thermograph of the amorphous sodium salt form of AMG397 showing a Tm of 216°C with reverse heat flow. [Figure 23] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline hydrochloride salt form of AMG397, showing a 4.9% weight loss up to 210°C. [Figure 24] FIG. 1 shows the moisture sorption profile (DVS) of the amorphous sodium salt of AMG397, which exhibits approximately 11.4% weight gain at 95% relative humidity and no morphology change after testing. [Diagram 25] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline potassium salt Form 1 of AMG397. [Figure 26] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline potassium salt Form 1 of AMG397 exhibiting Tms of 161 and 227°C. [Figure 27] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline potassium salt Form 2 of AMG397 (ethyl acetate solvate). [Figure 28] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline potassium salt Form 2 of AMG397 (ethyl acetate solvate), showing a Tm of 67 and 149°C. [Figure 29] FIG. 2 shows a thermogravimetric analysis ("TGA") trace of the crystalline potassium salt Form 2 of AMG397 (ethyl acetate solvate) showing 23.8% weight loss up to 200° C. [Diagram 30] 1 shows an overlay of the X-ray powder diffraction ("XRPD") patterns of the crystalline potassium salt forms 1 and 2 of AMG397. [Diagram 31] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline sulfate salt Form 1 of AMG397. [Diagram 32] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline sulfate salt Form 1 of AMG397 exhibiting a Tm of 191°C. [Diagram 33] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline sulfate salt Form 2 of AMG397. [Diagram 34] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline sulfate salt Form 3 of AMG397. [Diagram 35] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline sulfate salt Form 3 of AMG397 exhibiting a Tm of 218°C. [Diagram 36] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline sulfate salt Form 3 of AMG397, showing a 5.6% weight loss up to 150° C., and a further 4.8% weight loss up to 250° C. before melting / decomposition. [Figure 37]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline phosphate salt Form 1 of AMG397. [Figure 38] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline phosphate salt Form 1 of AMG397 exhibiting a Tm of 210°C. [Figure 39] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline phosphate salt Form 1 of AMG397, showing a 2.3% weight loss up to 200°C, and a further 4.2% weight loss up to 240°C. [Diagram 40] FIG. 1 shows the moisture sorption profile (DVS) of the crystalline phosphate salt Form 1 of AMG397, showing approximately 13% weight gain at 95% relative humidity. [Diagram 41] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline fumarate salt Form 1 of AMG397. [Diagram 42] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline fumarate salt Form 1 of AMG397, exhibiting a Tm of 232°C. [Diagram 43] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline fumarate salt Form 1 of AMG397, showing a 21.3% weight loss up to 271°C. [Diagram 44] 1 shows the moisture sorption profile (DVS) of the crystalline fumarate salt Form 1 of AMG397, showing a weight gain of approximately 3.5% at 95% relative humidity and a weight loss at 0% relative humidity associated with morphology change. [Diagram 45] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline fumarate salt Form 2 of AMG397. [Figure 46] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline fumarate salt Form 2 of AMG397, exhibiting a Tm of 243°C. [Figure 47] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline fumarate salt Form 2 of AMG397, showing an 8% weight loss up to 150°C, and a further 9.3% weight loss between 200-275°C. [Figure 48] 1 shows an overlay of X-ray powder diffraction ("XRPD") patterns of crystalline fumarate salt Forms 1 and 2 of AMG397. [Figure 49] 1 shows the X-ray powder diffraction ("XRPD") pattern of crystalline citrate salt Form 1 of AMG397. [Figure 50] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline citrate salt Form 1 of AMG397 exhibiting a Tm of 214°C. [Figure 51] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline citrate salt Form 1 of AMG397, showing a 7.1% weight loss at 190°C and a further 16.9% weight loss at 245°C. [Figure 52] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline citrate salt form dihydrate of AMG397. [Diagram 53] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline citrate salt form dihydrate of AMG397, showing a Tm of 206°C. [Figure 54] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline citrate salt form dihydrate of AMG397, showing a 1.6% weight loss up to 178°C, and a further 13.5% weight loss up to 250°C. [Figure 55] FIG. 1 shows the moisture sorption profile (DVS) of the crystalline citrate salt form dihydrate of AMG397, showing a weight gain of approximately 1.8% at 40% relative humidity, indicative of a monohydrate, and a weight loss from 40% to 0% relative humidity. [Figure 56] 1 shows an overlay of X-ray powder diffraction ("XRPD") patterns for crystalline citrate salt Forms 1 and dihydrate of AMG397. [Figure 57] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline lactate salt Form 1 of AMG397. [Figure 58] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline lactate salt Form 1 of AMG397, exhibiting a Tm of 219°C. [Figure 59] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline lactate salt Form 1 of AMG397, showing a 4.7% weight loss up to 150°C, and a further 12.7% weight loss up to 250°C. [Figure 60]1 shows the moisture sorption profile (DVS) of the crystalline lactate salt Form 1 of AMG397, showing 0% weight gain at 95% relative humidity and weight loss at 0% relative humidity associated with morphology change. [Figure 61] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline succinate salt Form 1 of AMG397. [Figure 62] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline succinate salt Form 1 of AMG397 exhibiting a Tm of 210°C. [Figure 63] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline succinate salt Form 1 of AMG397, exhibiting a 1.1% weight loss at 115°C and a further 15.9% weight loss at 235°C. [Figure 64] 1 shows the moisture sorption profile (DVS) of the crystalline succinate salt Form 1 of AMG397 showing a 5.1% weight gain with 95% relative humidity. [Figure 65] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline ammonium salt Form 1 of AMG397. [Figure 66] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline ammonium salt Form 1 of AMG397 exhibiting a Tm of 227°C. [Figure 67] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline ammonium salt Form 1 of AMG397, exhibiting a weight loss of 5.7% at 170°C and a further weight loss of 3.3% at 255°C. [Figure 68] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline besylate salt form monohydrate of AMG397. [Figure 69] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline besylate salt form monohydrate of AMG397, showing Tms of 57 and 234°C. [Figure 70] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline besylate salt form monohydrate of AMG397, showing a weight loss of 4.1% up to 75°C, and a further weight loss of 4.6% up to 260°C. [Figure 71]FIG. 2 shows the moisture sorption profile (DVS) of the crystalline besylate salt form 1 hydrate of AMG397, showing a weight gain of 8.4% with 95% relative humidity without morphology change. [Figure 72] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline tosylate salt Form 1 of AMG397. [Figure 73] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline tosylate salt Form 1 of AMG397 exhibiting Tm of 40 and 226°C. [Figure 74] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline tosylate salt Form 1 of AMG397, showing a weight loss of 1.6% at 75°C and a further weight loss of 3.9% at 250°C. [Figure 75] 1 shows the moisture sorption profile (DVS) of the crystalline besylate salt form 1 hydrate of AMG397, showing a 4.7% weight gain at 95% relative humidity with no morphology change. [Figure 76] FIG. 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline maleate salt Form 1 of AMG397 (a family of isostructural solvates from acetone, MeCN, DCM, DMF / ACN, DMF / EtOH, and THF). [Figure 77] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline maleate salt Form 1 of AMG397 exhibiting a Tm of 222°C. [Figure 78] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline maleate salt Form 1 of AMG397, showing an 11.9% weight loss up to 250°C. [Figure 79] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline maleate salt Form 2 of AMG397. [Figure 80] FIG. 1 shows the moisture sorption profile (DVS) of the crystalline maleate salt Form 2 of AMG397, showing a 7.7% weight gain with 95% relative humidity without any morphological change. [Figure 81] 1 shows an overlay of X-ray powder diffraction ("XRPD") patterns of crystalline maleate salt Forms 1 and 2 of AMG397. [Figure 82]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline malonate salt Form 1 of AMG397. [Figure 83] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline malonate salt Form 1 of AMG397 exhibiting a Tm of 161°C and 187°C. [Figure 84] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline malonate salt Form 1 of AMG397, showing a 17.5% weight loss up to 250° C. [Figure 85] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline malonate salt Form 2 of AMG397. [Figure 86] 1 shows an overlay of X-ray powder diffraction ("XRPD") patterns of crystalline malonate salt Forms 1 and 2 of AMG397. [Figure 87] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline tartrate salt Form 1 of AMG397 (a family of isostructural solvates from acetone, MeCN, DCM, EtOH, MeOH and water). [Figure 88] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline tartrate salt Form 1 of AMG397, exhibiting a Tm of 227°C. [Figure 89] 1 shows a thermogravimetric analysis ("TGA") trace of the crystalline tartrate salt Form 1 of AMG397, showing a 23.0% weight loss up to 255°C. [Figure 90] 1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 acetone solvate of AMG397. [Figure 91] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 acetone solvate of AMG397, showing a Tm of 59°C and 134°C. [Figure 92] 1 shows a thermogravimetric analysis ("TGA") trace of crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 acetone solvate of AMG397 exhibiting a weight loss of 7.9% at 150° C. [Figure 93]1 shows the X-ray powder diffraction ("XRPD") pattern of the crystalline iodide salt Form 1 of AMG397. [Figure 94] 1 shows a differential scanning calorimetry ("DSC") thermograph of the crystalline iodide salt Form 1 of AMG397 exhibiting a Tm of 231°C. [Figure 95] 1 shows the single crystal X-ray crystal structure of the crystalline DMSO solvate of AMG397. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Disclosed herein are salt and solvate forms of (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[1,19etheno-1616-cyclobuta[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecyne-4,1'-naphthalene]-16,16,18(7H,17H)-trione (AMG397), including crystalline salt and solvate forms thereof: [ka] AMG397 anhydrous Form 4 is a thermodynamically stable form. The crystalline forms described herein have unique physical properties that may be advantageous for new formulations of AMG397.

[0043] Also provided herein are pharmaceutical formulations of the salt and solvate forms of AMG397, and methods of treating a subject suffering from cancer, comprising administering to the subject a pharmaceutical formulation of the salt or solvate forms disclosed herein.

[0044] 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 AMG397.

[0045] Further provided herein are crystalline salt and solvate forms of AMG397, 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 a crystalline salt or solvate form disclosed herein.

[0046] The compounds disclosed herein may be identified herein either by 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.

[0047] 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.

[0048] As used herein, dashed and bold bonds (i.e., [ka] Chemical structures containing one or more stereocenters, designated by a single solid line symbol, are meant to depict the absolute stereochemistry of the stereocenters present in the chemical structure. As used herein, bonds represented by simple line symbols do not depict 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 (e.g., diastereomers, enantiomers) of the compound and mixtures thereof. Structures bearing a single solid or dashed line and at least one additional simple line encompass a single enantiomeric series of all possible diastereomers.

[0049] 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.

[0050] "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 treatment, such as, for example, cancer.

[0051] A "salt" is an ionic compound formed by treating AMG397 with an acid or base. Any salt consistent with the overall stability and usefulness of the compound of AMG397 can be provided using conventional methods. Suitable salts include, but are not limited to, salts of acidic or basic groups that may be present in the compounds provided herein. Under certain acidic conditions, the compounds can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharma- ceutically acceptable salts of such basic compounds include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, gliaryl arsanilate, hexylresorcinate, hydrabamine, hydrochloride, ethyl ester ... It forms salts with pharmacologically acceptable anions, including xinaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate (methylenesulfonate), methylsulfate, muserate, napsylate, nitrate, nitrate, nitrate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide, and pamoate. Under certain basic conditions, the compound can form base salts with various pharmacologically acceptable cations. Non-limiting examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts, and tetraalkylammonium salts. General information regarding pharma- ceutically acceptable salts can be found in Stahl PH, and Wermuth CG, eds., Handbook of Pharmaceutical Salts:Properties, Selection and Use, 2002, Wiley-VCH / VHCA Weinheim / Zuerich.

[0052] 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 myosin activation. A therapeutically effective amount can be ascertained experimentally, e.g., by assaying blood levels of a chemical, or theoretically, or by calculating bioavailability.

[0053] The term "solvate" refers to a chemical entity formed by the interaction of a solvate with a compound. Crystalline solvates of AMG397 used in the formulations herein are specifically contemplated. Solvents that can form crystalline solvate forms of AMG397 include, but are not limited to, ethanol. In some cases, the solvate has 0.5 to 2 solvent molecules per AMG397 molecule.

[0054] Salt and solvate forms Trifluoroethanol solvate form: The crystalline trifluoroethanol solvate form of AMG397 may be obtained as described in the Examples and may be characterized by an X-ray powder diffraction pattern with peaks at 17.5, 19.2, 19.4, and 21.7±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 14.6, 17.2, 18.4, 18.5, 18.8, 20.0, 20.2, 20.4, 21.0, 21.2, and 21.5±0.2 degrees 2θ using CuKα radiation, and / or at 6.7, 10.3, 12.5, 13.5, 13.8, 17.7, 17.8, 18.1, 21.9, 22.3, 22.4, and 22.9±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline trifluoroethanol solvate 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 field of XRPD that the relative peak heights in a spectrum are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0055] Hexafluoroisopropanol Solvate: The crystalline hexafluoroisopropanol solvate can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 11.4, 18.6, and 18.8±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 8.5, 12.8, 17.1, 17.6, 21.1, 22.4, and 23.1±0.2 degrees 2θ using CuKα radiation, and / or at 6.1, 13.6, 15.3, 15.7, 16.2, 16.4, 16.5, 17.4, 17.8, 18.0, 18.1, 19.4, 20.6, 21.5, 21.7, 22.2, and 25.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, hydrate Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 2, 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 a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0056] 1-Propanol Solvate: The crystalline 1-propanol solvate can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 13.3, 15.1, and 18.5±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 8.1, 9.7, 15.7, 16.4, 17.2, and 17.7±0.2 degrees 2θ using CuKα radiation, and / or at 12.0, 12.7, 14.2, 14.8, 17.1, 18.2, 19.1, 19.5, 20.7, 21.2, 21.6, 21.7, 22.1, 22.3, 22.4, 22.8, 23.5, 23.8, 23.9, and 25.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline 1-propanol solvate has an X-ray powder diffraction pattern substantially as shown in Figure 3, 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 are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0057] A differential scanning calorimetry (DSC) thermogram was obtained for the crystalline 1-propanol solvate as described in the Examples. The DSC curve shows an endothermic transition at 234° C.±3° C. Thus, in some embodiments, the crystalline 1-propanol solvate can be characterized by a DSC thermogram having a transition endotherm with an onset temperature of 231° C.-237° C. For example, in some embodiments, the crystalline 1-propanol solvate is characterized by DSC as shown in FIG. 4.

[0058] The crystalline 1-propanol solvate can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline 1-propanol solvate can be characterized by a weight loss in the range of about 5.6% with an onset temperature of 38° C. to 190° C. In some embodiments, the crystalline 1-propanol solvate has a thermogravimetric analysis substantially as shown in FIG. 5, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0059] Isopropanol Solvate Form 1: Crystalline isopropanol solvate Form 1 was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at 6.1, 7.1, and 10.0±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 18.5, 19.0, 19.7, and 20.4±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 10.5, 13.6, 14.5, 15.0, 15.3, 15.9, 16.2, 16.6, 16.7, 16.9, 17.7, 17.9, 18.4, 19.5, 20.7, 21.6, 23.1, and 25.7±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline isopropanol solvate Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 6, 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 are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0060] Differential scanning calorimetry (DSC) thermograms were obtained for crystalline isopropanol solvate Form 1 as described in the Examples. The DSC curve shows an endothermic transition at 247° C.±3° C. Thus, in some embodiments, crystalline isopropanol solvate Form 1 can be characterized by a DSC thermograph having a transition endotherm with an onset temperature between 244° C. and 250° C. For example, in some embodiments, crystalline isopropanol solvate Form 1 is characterized by DSC as shown in FIG. 7.

[0061] Crystalline isopropanol solvate Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline isopropanol solvate Form 1 can be characterized by a weight loss in the range of about 0.5% with an onset temperature of 39° C. to 120° C. In some embodiments, crystalline isopropanol solvate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 8, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0062] Isopropanol Solvate Form 2: Crystalline isopropanol solvate Form 2 was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 13.3, 15.1, and 18.6±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 8.1, 9.7, 16.4, and 17.7±0.2 degrees 2θ using CuKα radiation, and / or 12.0, 12.6, 14.2, 14.8, 15.7, 17.1, 17.2, 18.2, 19.1, 19.5, 21.5, 21.6, 22.3, 22.4, and 23.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline isopropanol solvate Form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 9, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative peak heights in a spectrum are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0063] Differential scanning calorimetry (DSC) thermograms were obtained for crystalline isopropanol solvate Form 1 as described in the Examples. The DSC curve shows endothermic transitions at 83° C.±3° C. and 239° C.±3° C. Thus, in some embodiments, crystalline isopropanol solvate Form 2 can be characterized by a DSC thermogram having transition endotherms with onsets between 80° C. and 86° C. and between 236° C. and 242° C. For example, in some embodiments, crystalline isopropanol solvate Form 2 is characterized by DSC as shown in FIG.

[0064] Crystalline isopropanol solvate Form 2 may be characterized by thermogravimetric analysis (TGA). Thus, crystalline isopropanol solvate Form 2 may be characterized by a weight loss in the range of about 19.0% with an onset temperature of 37° C. to 111° C. In some embodiments, crystalline isopropanol solvate Form 2 has a thermogravimetric analysis substantially as shown in FIG. 11, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0065] Acetonitrile solvate: The crystalline acetonitrile solvate can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 10.2, 17.0, and 20.5±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 6.0, 13.0, 14.3, 15.2, 18.6, and 23.0±0.2 degrees 2θ using CuKα radiation, and / or at 10.9, 15.6, 17.2, 18.2, 19.2, 21.0, 21.4, 22.1, 22.3, 22.5, 23.4, 24.8, 25.2, 25.6, 26.1, 26.5, 26.7, and 26.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline acetonitrile solvate has an X-ray powder diffraction pattern substantially as shown in Figure 12, 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 are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0066] Acetic acid solvate: The crystalline acetic acid solvate has the following average molecular weights: 13.63, 19.22, 20.40, 24.22, 25.69, 26.57, 27.75, 29.81, 30.40, 31.28, 36.57, 38.34, 40.10, 43.04, 49.51, 50.10, 51.86, 54.51, 56.28, 57. 16, 57.75, 60.10, 62.16, 65.39, 77.75, 85.10, 115.39, 123.63, 125.10, 128.04, 131.27, 133.04, 133.92, 135.98, 139.80, 141.27, 143.04, 151.86, and 173.92±0.5 ppm. 13 In some embodiments, the crystalline acetic acid solvate can be characterized by C NMR. 13 C NMR, where "substantially" means that the reported peaks may vary by ±0.5 ppm.

[0067] The crystalline acetic acid solvate can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at 11.1, 17.1, 18.2, and 19.1±0.2° 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.7, 10.9, 11.5, 13.7, 14.3, 18.8, 20.1, and 24.8±0.2° 2θ using CuKα radiation, and / or additional peaks at 8.4, 12.4, 12.7, 15.6, 16.5, 17.6, 19.3, 22.2, 23.6, 24.0, 24.6, and 29.0±0.2° 2θ using CuKα radiation. In some embodiments, the crystalline acetic acid solvate has an X-ray powder diffraction pattern substantially as shown in Figure 13, where "substantially" means that the reported peaks may vary by ±0.2°. It is well known in the field of XRPD that the relative 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.

[0068] Differential scanning calorimetry (DSC) thermograms were obtained for the crystalline acetic acid solvate as described in the Examples. The DSC curve shows endothermic transitions at 95° C.±3° C. and 155° C.±3° C. Thus, in some embodiments, hydrate Form 2 can be characterized by a DSC thermogram having transition endotherms with onsets between 92° C. and 98° C. and between 152° C. and 158° C. For example, in some embodiments, the crystalline acetic acid solvate is characterized by DSC as shown in FIG. 14.

[0069] The crystalline acetic acid solvate can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline acetic acid solvate can be characterized by a weight loss in the range of about 0% to about 3.1% to about 150° C., with an additional weight loss in the range of about 0% to about 10.4% to about 250° C. In some embodiments, the crystalline acetic acid solvate has a thermogravimetric analysis substantially as shown in FIG. 15, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0070] Hydrochloride Salt Form 1: Crystalline hydrochloride salt Form 1 can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 12.9, 16.2, and 17.9±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 11.7, 12.0, 15.9, 19.8, and 20.5±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 10.7, 13.5, 14.4, 14.6, 15.5, 18.1, 22.8, 23.7, 24.6, 25.1, and 26.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline hydrochloride salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 17, 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 a number of 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 was obtained for crystalline hydrochloride salt Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 267° C.±3° C. Thus, in some embodiments, crystalline hydrochloride salt 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 264° C. and 270° C. For example, in some embodiments, crystalline hydrochloride salt 1 is characterized by DSC as shown in FIG.

[0072] Crystalline hydrochloride salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline hydrochloride salt Form 1 can be characterized by a weight loss ranging from about 0% to about 9.5% from 35° C. to 275° C., and a weight loss ranging from about 0% to about 5.3% to about 250° C. In some embodiments, crystalline hydrochloride salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 19, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0073] The crystalline hydrochloride salt Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, the crystalline hydrochloride salt Form 1 is characterized by a moisture sorption profile as shown in Figure 20, which shows a weight gain of 0.7% with 95% RH.

[0074] Sodium Salt Form 1: Amorphous sodium salt Form 1 can be characterized by an X-ray powder diffraction pattern obtained using CuKα radiation. In some embodiments, amorphous sodium salt Form 1 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 are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0075] As described in the Examples, a differential scanning calorimetry (DSC) thermogram was obtained for amorphous sodium salt Form 1. The DSC curve shows an endothermic transition at 216° C.±3° C. Thus, in some embodiments, amorphous sodium salt 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 213° C. and 219° C. For example, in some embodiments, amorphous sodium salt 1 is characterized by DSC as shown in FIG.

[0076] Amorphous sodium salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, amorphous sodium salt Form 1 can be characterized by a weight loss ranging from about 0% to about 4.9% to 210° C. In some embodiments, amorphous sodium salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 23, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0077] Amorphous sodium salt Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, amorphous sodium salt Form 1 is characterized by a moisture sorption profile as shown in Figure 24, which exhibits an 11.4% weight gain at 95% RH and no morphology change.

[0078] Potassium Salt Form 1: Crystalline potassium salt Form 1 can be obtained as shown in the Examples and characterized by an X-ray powder diffraction pattern having peaks at 12.8, 13.4, and 17.2±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 11.0, 11.4, 14.5, 15.7, and 19.2±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline potassium salt Form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 25, 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 are dependent on numerous factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0079] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline potassium salt Form 1, as described in the Examples. The DSC curve shows endothermic transitions at 161° C.±3° C. and 227° C.±3° C. Thus, in some embodiments, crystalline potassium salt 1 can be characterized by a DSC thermogram having transition endotherms with onsets between 158° C.-164° C. and 224° C.-230° C. For example, in some embodiments, crystalline potassium salt 1 is characterized by DSC as shown in FIG. 26.

[0080] Potassium Salt Form 2 (Ethyl Acetate Solvate): Crystalline potassium salt Form 2 (Ethyl Acetate Solvate) can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 2.7, 11.7, and 12.2±0.2 degrees 2θ using CuKα radiation, and optionally 20.5, 20.9, 21.1, 21.6, and 22.9±0.2 degrees 2θ using CuKα radiation. and / or additional peaks at 11.2, 15.1, 15.3, 15.4, 16.1, 16.3, 16.4, 16.6, 16.8, 16.9, 17.3, 17.5, 17.9, 18.5, 18.9, 19.2, 19.5, 19.7, 21.7, 22.2, 22.5, 22.7, 23.3, 23.5, 23.9, and 24.4 ± 0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline potassium salt Form 2 (ethyl acetate solvate) has an X-ray powder diffraction pattern substantially as shown in Figure 27, where "substantially" means that the reported peaks may vary by ± 0.2 degrees. It is well known in the field 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.

[0081] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline potassium salt Form 2 (ethyl acetate solvate) as described in the Examples. The DSC curve shows endothermic transitions at 67° C.±3° C. and 149° C.±3° C. Thus, in some embodiments, crystalline potassium salt 2 (ethyl acetate solvate) can be characterized by a DSC thermogram having transition endotherms with onsets between 64° C. and 70° C. and between 146° C. and 152° C. For example, in some embodiments, crystalline potassium salt 2 (ethyl acetate solvate) is characterized by DSC as shown in FIG. 28.

[0082] The crystalline potassium salt Form 2 (ethyl acetate solvate) may be characterized by thermogravimetric analysis (TGA). Thus, the crystalline potassium salt Form 2 (ethyl acetate solvate) may be characterized by a weight loss ranging from about 0% to about 23.8% to 200° C. In some embodiments, the crystalline potassium salt Form 2 (ethyl acetate solvate) has a thermogravimetric analysis substantially as shown in FIG. 29, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0083] Sulfate Salt Form 1: Crystalline Sulfate Salt Form 1 can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 9.3, 13.9, and 19.2±0.2° 2θ using CuKα radiation, and optionally further characterized by additional peaks at 8.7, 11.5, 17.6, and 21.9±0.2° 2θ using CuKα radiation. In some embodiments, crystalline Sulfate Salt Form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 31, 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 are dependent on numerous factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0084] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline sulfate salt Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 191° C.±3° C. Thus, in some embodiments, crystalline potassium salt 2 can be characterized by a DSC thermogram having a transition endotherm with an onset between 188° C. and 194° C. For example, in some embodiments, crystalline potassium salt 2 is characterized by DSC as shown in FIG.

[0085] Sulfate Salt Form 2: Crystalline Sulfate Salt Form 2 can be characterized by an X-ray powder diffraction pattern obtained as described in the Examples, having peaks at 11.7, 17.1, and 20.1±0.2° 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.8, 15.9, and 24.1±0.2° 2θ using CuKα radiation. In some embodiments, crystalline Sulfate Salt Form 2 has an X-ray powder diffraction pattern substantially as shown in FIG. 33, 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 are dependent on numerous factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0086] Sulfate Salt Form 3: Crystalline Sulfate Salt Form 3 can be obtained as shown in the Examples and characterized by an X-ray powder diffraction pattern having peaks at 12.3, 17.7, 18.4, and 20.6±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 11.2, 14.0, 19.0, and 23.1±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 13.0, 15.3, 15.8, 16.7, 19.0, 21.6, 23.9, and 24.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline Sulfate Salt Form 3 has an X-ray powder diffraction pattern substantially as shown in FIG. 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0087] A differential scanning calorimetry (DSC) thermogram was obtained for the crystalline sulfate salt Form 3, as described in the Examples. The DSC curve shows an endothermic transition at 218° C.±3° C. Thus, in some embodiments, the crystalline potassium salt 3 can be characterized by a DSC thermogram having a transition endotherm with an onset between 215° C. and 221° C. For example, in some embodiments, the crystalline potassium salt 3 is characterized by DSC as shown in FIG.

[0088] Crystalline Sulfate Form 3 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Sulfate Form 3 can be characterized by a weight loss in the range of about 0% to about 5.6% to 150° C., with an additional weight loss in the range of about 0% to about 4.8% to 250° C. In some embodiments, crystalline Sulfate Form 3 has a thermogravimetric analysis substantially as shown in FIG. 36, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0089] Phosphate Form 1: Phosphate Form 1 is obtained as described in the Examples and has peaks at 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8, 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8, and 168.8±0.5 ppm. 13 It can be characterized by C NMR.

[0090] Phosphate Form 1: Crystalline phosphate Form 1 may be obtained as shown in the Examples and characterized by an X-ray powder diffraction pattern having peaks at 17.7, 18.6, and 18.7±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.3, 14.0, and 20.3±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 11.1, 11.2, 12.4, 16.0, 16.1, 16.7, 16.8, 19.3, 20.7, 21.9, 22.9, 23.0, 24.7, and 24.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline phosphate Form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 37, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0091] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline phosphate Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 210° C.±3° C. Thus, in some embodiments, crystalline phosphate Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 207° C. and 213° C. For example, in some embodiments, crystalline phosphate Form 1 is characterized by DSC as shown in FIG. 38.

[0092] Crystalline phosphate Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline phosphate Form 1 can be characterized by a weight loss in the range of about 0% to about 2.3% to 100° C., with an additional weight loss in the range of about 0% to about 4.2% to 240° C. In some embodiments, crystalline phosphate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 39, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0093] Crystalline phosphate Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, crystalline phosphate Form 1 is characterized by the moisture sorption profile shown in Figure 40, which shows a 13% weight gain with 95% RH.

[0094] Fumarate Form 1: Fumarate Form 1 may be obtained as shown in the Examples and may be characterized by an X-ray powder diffraction pattern with peaks at 17.6, 18.2, and 18.4±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 5.3, 10.4, 12.2, 13.9, 15.8, and 24.0±0.2 degrees 2θ using CuKα radiation, and / or at 9.7, 11.0, 12.9, 14.9, 15.5, 16.3, 16.9, 17.9, 19.2, 20.2, 20.9, 21.6, 22.8, 24.7, and 26.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline Fumarate Salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 41, 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 are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0095] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline fumarate salt Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 232° C.±3° C. Thus, in some embodiments, crystalline fumarate salt Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 229° C. and 235° C. For example, in some embodiments, crystalline fumarate salt Form 1 is characterized by DSC as shown in FIG.

[0096] Crystalline Fumarate Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Fumarate Form 1 can be characterized by a weight loss ranging from about 0% to about 21.3% to 271° C. In some embodiments, crystalline Fumarate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 43, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0097] Crystalline fumarate Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, crystalline fumarate Form 1 is characterized by a moisture sorption profile as shown in Figure 44, which shows a 3.5% weight gain with 95% RH and a weight loss at 0% RH accompanied by a morphology change.

[0098] Fumarate Form 2 (Acetone Solvate): Fumarate Form 2 (Acetone Solvate) was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 11.9, 17.9, and 18.1±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.7, 13.6, 15.7, 18.6, 18.8, 19.6, and 21.5±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 10.3, 14.9, 16.3, 16.5, 20.0, 22.2, 22.6, 13.3, 13.9, 24.5, 25.5, and 28.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline fumarate salt Form 2 (acetone solvate) 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 field of XRPD that the relative peak heights in a spectrum are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0099] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline fumarate salt Form 2 (acetone solvate) as described in the Examples. The DSC curve shows an endothermic transition at 243° C.±3° C. Thus, in some embodiments, crystalline fumarate salt Form 2 (acetone solvate) can be characterized by a DSC thermogram having a transition endotherm with an onset between 240° C. and 246° C. For example, in some embodiments, crystalline fumarate salt Form 2 (acetone solvate) is characterized by DSC as shown in FIG. 46.

[0100] Crystalline Fumarate Form 2 (acetone solvate) can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Fumarate Form 2 (acetone solvate) can be characterized by a weight loss ranging from about 0% to about 8% to 150°C, with an additional weight loss ranging from about 0% to about 9.3% between 200°C and 275°C. In some embodiments, crystalline Fumarate Form 2 (acetone solvate) has a thermogravimetric analysis substantially as shown in Figure 47, where "substantially" means that the reported TGA characteristics can vary by ±5°C.

[0101] Citrate Form 1: Citrate Form 1 can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 10.6, 17.6, and 18.3±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.1, 13.9, 16.0, 19.2, and 21.9±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 6.1, 11.0, 12.8, 15.2, 16.9, 19.5, 20.0, 20.5, 21.1, 22.9, 24.4, 24.7, 25.9, and 28.7±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline Citrate Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 49, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0102] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline Citrate Form 1 as described in the Examples. The DSC curve shows an endothermic transition at 214° C.±3° C. Thus, in some embodiments, crystalline Citrate Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 211° C. and 217° C. For example, in some embodiments, crystalline Citrate Form 1 is characterized by DSC as shown in FIG.

[0103] Crystalline Citrate Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Citrate Form 1 can be characterized by a weight loss in the range of about 0% to about 7.1% to 190° C., with an additional weight loss in the range of about 0% to about 16.9% to 245° C. In some embodiments, crystalline Citrate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 51, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0104] Citrate Salt Form 2 (Hydrate): Citrate Salt Form 2 (Hydrate) can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 17.7, 18.4, and 18.5±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 14.0, 16.0, 20.1, and 21.9±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 10.7, 11.1, 12.2, 12.9, 15.2, 19.3, 20.6, 22.9, 24.4, and 24.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline Citrate Salt Form 2 (Hydrate) has an X-ray powder diffraction pattern substantially as shown in Figure 52, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0105] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline citrate salt form 2 (hydrate) as described in the Examples. The DSC curve shows an endothermic transition at 206° C.±3° C. Thus, in some embodiments, crystalline citrate salt form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 203° C. and 209° C. For example, in some embodiments, crystalline citrate salt form 2 (hydrate) is characterized by DSC as shown in FIG. 53.

[0106] Crystalline Citrate Form 2 (hydrate) can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Citrate Form 2 (hydrate) can be characterized by a weight loss in the range of about 0% to about 1.6% to 178°C, with an additional weight loss in the range of about 0% to about 13.5% to 250°C. In some embodiments, crystalline Citrate Form 2 (hydrate) has a thermogravimetric analysis substantially as shown in Figure 54, where "substantially" means that the reported TGA characteristics can vary by ±5°C.

[0107] Crystalline Citrate Form 2 (hydrate) can be characterized by a moisture sorption profile. For example, in some embodiments, crystalline Citrate Form 2 (hydrate) is characterized by a moisture sorption profile as shown in Figure 55, which exhibits a 1.8% weight gain with 40% RH and a weight loss from 40% to 0% RH, indicative of a monohydrate.

[0108] Lactate Salt Form 1: Lactate Salt Form 1 was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at 12.1, 17.8, and 18.3±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.5, 10.9, 13.8, 17.5, and 20.0±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 5.9, 12.8, 15.9, 16.2, 19.1, 20.4, 21.7, 23.9, 24.6, and 25.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline Lactate Salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 57, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0109] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline lactate salt Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 219° C.±3° C. Thus, in some embodiments, crystalline lactate salt Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset of 216° C.-222° C. For example, in some embodiments, crystalline lactate salt Form 1 is characterized by DSC as shown in FIG.

[0110] Crystalline Lactate Salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline Lactate Salt Form 1 can be characterized by a weight loss in the range of about 0% to about 4.7% to 150° C., and an additional weight loss in the range of about 0% to about 12.7% to 250° C. In some embodiments, crystalline Lactate Salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 59, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0111] Succinate Form 1: Succinate Form 1 was obtained as shown in the Examples and may be characterized by an X-ray powder diffraction pattern with peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.2, 13.9, 18.0, 20.3, and 24.5±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 5.2, 10.4, 10.7, 11.1, 12.9, 15.2, 15.8, 16.7, 19.1, 21.6, 22.2, 22.8, 23.9, 26.2, 28.3, and 29.2±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline succinate salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 61, 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 are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0112] As described in the Examples, a differential scanning calorimetry (DSC) thermogram was obtained for crystalline succinate Form 1. The DSC curve shows an endothermic transition at 210° C.±3° C. Thus, in some embodiments, crystalline succinate Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 207° C. and 213° C. For example, in some embodiments, crystalline succinate Form 1 is characterized by DSC as shown in FIG.

[0113] The crystalline succinate salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline succinate salt Form 1 can be characterized by a weight loss in the range of about 0% to about 1.1% to 115° C., with an additional weight loss in the range of about 0% to about 15.9% to 235° C. In some embodiments, the crystalline succinate salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 63, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0114] The crystalline succinate salt Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, the crystalline succinate salt Form 1 is characterized by the moisture sorption profile shown in Figure 64, which shows a 5.1% weight gain at 95% RH.

[0115] Ammonium Salt Form 1: Ammonium salt Form 1 can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 6.2, 10.3, and 17.2±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 4.0, 4.7, 17.3, 17.9, 19.8, and 20.3±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 13.0, 14.4, 15.1, 15.5, 15.9, 16.2, 16.4, 17.7, 18.6, 19.7, and 22.8±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline ammonium salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 65, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0116] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline ammonium salt Form 1, as described in the Examples. The DSC curve shows an endothermic transition at 227° C.±3° C. Thus, in some embodiments, crystalline ammonium salt Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 224° C. and 230° C. For example, in some embodiments, crystalline ammonium salt Form 1 is characterized by DSC as shown in FIG.

[0117] The crystalline ammonium salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline ammonium salt Form 1 can be characterized by a weight loss in the range of about 0% to about 5.7% to 170° C., with an additional weight loss in the range of about 0% to about 3.3% to 255° C. In some embodiments, the crystalline ammonium salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 67, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0118] Besylate Form 1 (hydrate): Besylate Form 1 (hydrate) can be obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 14.0, 17.7, and 20.4±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 11.2, 12.4, 13.8, 14.1, 15.9, 16.1, 18.0, 19.3, 20.8, 21.7, 22.9, 23.9, and 24.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline besylate Form 1 (hydrate) has an X-ray powder diffraction pattern substantially as shown in Figure 68, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0119] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline besylate Form 1 (hydrate) as described in the Examples. The DSC curve shows endothermic transitions at 57° C.±3° C. and 234° C.±3° C. Thus, in some embodiments, crystalline besylate Form 1 (hydrate) can be characterized by a DSC thermogram having transition endotherms with onsets between 54° C. and 60° C. and between 231° C. and 237° C. For example, in some embodiments, crystalline besylate Form 1 (hydrate) is characterized by DSC as shown in FIG.

[0120] The crystalline besylate salt Form 1 (hydrate) can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline besylate salt Form 1 (hydrate) can be characterized by a weight loss in the range of about 0% to about 4.1% to 75° C., with an additional weight loss in the range of about 0% to about 4.6% to 260° C. In some embodiments, the crystalline besylate salt Form 1 (hydrate) has a thermogravimetric analysis substantially as shown in FIG. 70, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0121] The crystalline besylate salt Form 1 (hydrate) can be characterized by a moisture sorption profile. For example, in some embodiments, the crystalline besylate salt Form 1 (hydrate) is characterized by a moisture sorption profile as shown in Figure 71, which shows a weight gain of 8.4% with 95% RH without morphology change.

[0122] Tosylate Form 1: Tosylate Form 1 was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at 18.2, 18.4, and 20.5±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.2, 12.3, 17.6, 18.9, and 19.1±0.2 degrees 2θ using CuKα radiation, and / or at 4.5, 5.2, 13.0, 13.8, 14.0, 15.2, 15.8, 16.2, 16.4, 19.8, 20.0, 21.4, 22.9, 23.4, 23.6, 23.8, 24.3, 24.6, 25.1, and 27.1±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline tosylate salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 72, 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 are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0123] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline tosylate salt Form 1, as described in the Examples. The DSC curve shows endothermic transitions at 40° C.±3° C. and 226° C.±3° C. Thus, in some embodiments, crystalline tosylate salt Form 1 can be characterized by a DSC thermogram having transition endotherms with onsets between 37° C.-43° C. and 223° C.-229° C. For example, in some embodiments, crystalline tosylate salt Form 1 is characterized by DSC as shown in FIG. 73.

[0124] Crystalline tosylate salt Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline tosylate salt Form 1 can be characterized by a weight loss in the range of about 0% to about 1.6% to 75° C., with an additional weight loss in the range of about 0% to about 3.9% to 250° C. In some embodiments, crystalline tosylate salt Form 1 has a thermogravimetric analysis substantially as shown in FIG. 74, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0125] Crystalline tosylate Form 1 can be characterized by a moisture sorption profile. For example, in some embodiments, crystalline tosylate Form 1 is characterized by a moisture sorption profile as shown in Figure 75, which shows a 4.7% weight gain with 95% RH without morphology change.

[0126] Maleate Salt Form 1 (family of isostructural solvates): Maleate Salt Form 1 (family of isostructural solvates) can be obtained as shown in the Examples and characterized by an X-ray powder diffraction pattern with peaks at 18.2, 18.9, and 19.9±0.2° 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.4, 10.9, 12.0, and 21.5±0.2° 2θ using CuKα radiation, and / or additional peaks at 10.3, 13.8, 15.8, 17.9, 19.2, and 24.2±0.2° 2θ using CuKα radiation. In some embodiments, crystalline Maleate Salt Form 1 (family of isostructural solvates) has an X-ray powder diffraction pattern substantially as shown in Figure 76, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0127] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline maleate salt Form 1 (a family of isostructural solvates) as described in the Examples. The DSC curve shows an endothermic transition at 222° C.±3° C. Thus, in some embodiments, crystalline maleate salt Form 1 (a family of isostructural solvates) can be characterized by a DSC thermogram having a transition endotherm with an onset between 219° C. and 225° C. For example, in some embodiments, crystalline maleate salt Form 1 (a family of isostructural solvates) is characterized by DSC as shown in FIG. 77.

[0128] The crystalline maleate salt Form 1 (family of isostructural solvates) can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline maleate salt Form 1 (family of isostructural solvates) can be characterized by a weight loss ranging from about 0% to about 11.9% to 250° C. In some embodiments, the crystalline maleate salt Form 1 (family of isostructural solvates) has a thermogravimetric analysis substantially as shown in FIG. 78, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0129] Maleate Form 2: Maleate Form 2 may be obtained as shown in the Examples and may be characterized by an X-ray powder diffraction pattern having peaks at 10.6, 18.6, and 20.3±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.8, 12.3, 15.2, 15.9, and 16.7±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 9.8, 11.1, 13.9, 14.1, 18.0, 18.4, 19.2, 19.4, 20.8, 22.3, 23.0, 23.6, 24.6, and 28.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline maleate Form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 79, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0130] Crystalline maleate Form 2 can be characterized by a moisture sorption profile. For example, in some embodiments, crystalline maleate Form 2 is characterized by a moisture sorption profile as shown in Figure 80, which shows a 7.7% weight gain with 95% RH without morphological change.

[0131] Malonate Form 1: Malonate Form 1 was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern having peaks at 12.2, 18.8, and 20.4±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 10.3, 11.1, 17.9, 18.3, and 19.1±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 10.7, 13.9, 14.0, 15.8, 16.5, 18.4, 19.5, 19.7, 21.6, 21.7, 22.8, and 24.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, crystalline Malonate Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 82, 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 a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0132] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline malonate salt Form 1, as described in the Examples. The DSC curve shows endothermic transitions at 161° C.±3° C. and 187° C.±3° C. Thus, in some embodiments, crystalline tosylate salt Form 1 can be characterized by a DSC thermogram having transition endotherms with onsets between 158° C.-164° C. and 184° C.-190° C. For example, in some embodiments, crystalline malonate salt Form 1 is characterized by DSC as shown in FIG. 83.

[0133] Crystalline malonate Form 1 can be characterized by thermogravimetric analysis (TGA). Thus, crystalline malonate Form 1 can be characterized by a weight loss ranging from about 0% to about 17.5% to 250° C. In some embodiments, crystalline malonate Form 1 has a thermogravimetric analysis substantially as shown in FIG. 84, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0134] Malonate Form 2: Malonate Form 2 may be obtained as shown in the Examples and characterized by an X-ray powder diffraction pattern with peaks at 10.6, 18.5, and 20.2±0.2° 2θ using CuKα radiation, and optionally further characterized by additional peaks at 11.0, 14.0, and 17.9±0.2° 2θ using CuKα radiation, and / or additional peaks at 11.1, 12.3, 15.3, 16.1, 16.8, 17.0, 18.6, 19.4, and 22.2±0.2° 2θ using CuKα radiation. In some embodiments, crystalline Malonate Form 2 has an X-ray powder diffraction pattern substantially as shown in Figure 85, 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 are dependent on numerous factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0135] Tartrate Salt Form 1 (Family of Isostructural Solvates): Tartrate Salt Form 1 (Family of Isostructural Solvates) was obtained as described in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 18.2, 18.6, and 20.2±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.1, 17.8, 19.0, and 21.5±0.2 degrees 2θ using CuKα radiation, and / or at 10.6, 11.0, 12.8, 13.8, 15.1, 15.8, 16.4, 16.6, 17.4, 19.3, 19.5, 20.6, 22.1, 22.6, 23.5, and 24.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline tartrate salt Form 1 (a family of isostructural solvates) has an X-ray powder diffraction pattern substantially as shown in Figure 87, 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 are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0136] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline tartrate salt Form 1 (a family of isostructural solvates) as described in the Examples. The DSC curve shows an endothermic transition at 227° C.±3° C. Thus, in some embodiments, crystalline tartrate salt Form 1 (a family of isostructural solvates) can be characterized by a DSC thermogram having a transition endotherm with an onset between 224° C. and 230° C. For example, in some embodiments, crystalline tartrate salt Form 1 (a family of isostructural solvates) is characterized by DSC as shown in FIG.

[0137] The crystalline tartrate salt Form 1 (family of isostructural solvates) can be characterized by thermogravimetric analysis (TGA). Thus, the crystalline tartrate salt Form 1 (family of isostructural solvates) can be characterized by a weight loss in the range of about 0% to about 23.0% to 255° C. In some embodiments, the crystalline tartrate salt Form 1 (family of isostructural solvates) has a thermogravimetric analysis substantially as shown in FIG. 89, where "substantially" means that the reported TGA characteristics can vary by ±5° C.

[0138] Tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate): Crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) was obtained as shown in the Examples and can be characterized by an X-ray powder diffraction pattern with peaks at 10.0, 16.8, and 20.0±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 12.7, 14.1, and 18.2±0.2 degrees 2θ using CuKα radiation, and / or at 6.1, 14.9, 15.3, 16.0, 17.3, 17.6, 18.0, 19.0, 19.1, 19.4, 20.6, 22.1, 22.5, 22.7, 22.9, 26.3, and 26.4±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) has an X-ray powder diffraction pattern substantially as shown in Figure 90, 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 are dependent on a number of factors, such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0139] Differential scanning calorimetry (DSC) thermograms were obtained for crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) as described in the Examples. The DSC curve shows endothermic transitions at 59° C.±3° C. and 134° C.±3° C. Thus, in some embodiments, crystalline tris(hydroxymethyl)aminomethane (tris) salt 1 (acetone solvate) can be characterized by a DSC thermograph having transition endotherms with onsets between 56° C. and 62° C. and between 131° C. and 137° C. For example, in some embodiments, crystalline tris(hydroxymethyl)aminomethane (tris) salt 1 (acetone solvate) is characterized by DSC as shown in FIG.

[0140] The crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) may be characterized by thermogravimetric analysis (TGA). Thus, the crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) may be characterized by a weight loss ranging from about 0% to about 7.9% to 150° C. In some embodiments, the crystalline tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) has a thermogravimetric analysis substantially as shown in FIG. 92, where "substantially" means that the reported TGA characteristics may vary by ±5° C.

[0141] Iodide Salt Form 1: Iodide Salt Form 1 may be obtained as shown in the Examples and may be characterized by an X-ray powder diffraction pattern having peaks at 17.0, 18.0, and 18.1±0.2 degrees 2θ using CuKα radiation, and optionally further characterized by additional peaks at 8.3, 11.0, 18.6, 18.8, 19.1, 20.0, 22.1, 23.5, and 24.7±0.2 degrees 2θ using CuKα radiation, and / or additional peaks at 6.2, 10.6, 10.8, 12.4, 13.0, 14.1, 15.5, 17.6, 22.5, 24.1, 28.6, 28.8, 29.0, and 29.5±0.2 degrees 2θ using CuKα radiation. In some embodiments, the crystalline iodide salt Form 1 has an X-ray powder diffraction pattern substantially as shown in Figure 93, 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 are dependent on a number of factors such as sample preparation and instrument geometry, while the peak positions are relatively insensitive to experimental details.

[0142] A differential scanning calorimetry (DSC) thermogram was obtained for crystalline iodide salt Form 1 as described in the Examples. The DSC curve shows an endothermic transition at 231° C.±3° C. Thus, in some embodiments, crystalline iodide salt Form 1 can be characterized by a DSC thermogram having a transition endotherm with an onset between 228° C. and 234° C. For example, in some embodiments, crystalline iodide salt Form 1 is characterized by DSC as shown in FIG. 94.

[0143] DMSO solvate: The DMSO solvate may be characterized by a single crystal structure substantially as shown in Figure 95 or as described in the Examples.

[0144] Pharmaceutical preparations Provided herein is a pharmaceutical formulation comprising a salt or solvate of AMG397 disclosed herein and a pharma- ceutically acceptable excipient.

[0145] 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," ​​published August 1997, 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.

[0146] "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. Typically, 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.

[0147] 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 sweetening agents, flavoring agents, coloring agents and preservatives. Such components are generally present in admixture within the tablet.

[0148] Examples of solubilizing agents include, but are not limited to, ionic surfactants (including both ionic and non-ionic surfactants) such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 188 or 207), and macrogols.

[0149] 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.

[0150] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, croscarmellose sodium, and the like.

[0151] 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.

[0152] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, starch, and the like.

[0153] 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.

[0154] 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 weight % of the tablet mean the weight % of the total tablet, i.e., including the coating.

[0155] The pharmaceutical compositions disclosed herein may further comprise a surfactant. As used herein, a surfactant may be cationic, anionic or non-ionic. In some embodiments, the pharmaceutical formulation may comprise a non-ionic surfactant. In some embodiments, the surfactant may comprise a polysorbate, a poloxamer, or a combination thereof. In some embodiments, the surfactant may comprise polysorbate 20, polysorbate 60, polysorbate 80, or a combination thereof.

[0156] How to treat 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 salt or solvate form of AMG397 disclosed herein, optionally as a pharmaceutical formulation disclosed herein, in some embodiments, the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

[0157] Preparation of Salt and Solvate 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 amorphous, crude, or other crystalline forms of AMG397. In some embodiments, AMG397 is combined with a solvent to form the desired crystalline form, for example, as described in the examples below. In some embodiments, AMG397 is dissolved in a solvent or combined with a solvent to form a slurry. In some embodiments, AMG397 is combined with a solvent and the solution or slurry thus formed is aged to form the crystalline form. In some embodiments, the solution or slurry is heated prior to aging or crystal formation.

[0158] Other embodiments It should be understood that the foregoing description, while being read in conjunction with the detailed description thereof, is intended to be illustrative and not limiting of the scope of the present disclosure, as defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. EXAMPLES

[0159] The following examples are offered for illustrative purposes and are not intended to limit the scope of the invention.

[0160] Materials and Methods Unless stated, commercially available reagents are used as received without further purification.

[0161] The synthesis of the starting material (AMG397) for the following method 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.

[0162] 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 fine focus source. An elliptical tilted multilayer mirror was used to focus the Cu Kα X-ray radiation through the sample onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the position of the observed Si(111) peak matched the NIST certified position. The samples were sandwiched between 3 mm thick films and analyzed in transmission geometry. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize divergence from axial spread. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.2.2 b or software v.5.5.

[0163] 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° using CuKα radiation (1.541874 Å) at 45 kV and 40 mA.

[0164] XRPD indexing was performed using the proprietary SSCI software TRIADS™ disclosed in US Pat. No. 8,576,985.

[0165] Differential Scanning Calorimetry: Differential scanning calorimetry (DSC) was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Tau lag adjustments are made with indium, tin, and zinc. Temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin, and zinc. Adjustments are then verified with octane, phenyl salicylate, indium, tin, and zinc. Samples were placed into sealed aluminum DSC pans and weights were accurately recorded. The instrument was pierced through the lid of the pan and then inserted into the DSC cell for analysis. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell.

[0166] Differential scanning calorimetry (DSC) analysis was performed using a TA Instruments Discovery Series calorimeter in aluminum pans under dry nitrogen at 50 ml / min from 25 to 250–350 °C at 10 °C / min.

[0167] Thermal Analysis: Thermogravimetric analysis (TGA) and TGA / DSC combo analysis were performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature and enthalpy adjustments were made with indium, tin and zinc, then verified with indium. Balance was verified with calcium oxalate. Samples were placed in open aluminum pans. The pans were sealed, the lids pierced, and then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on a reference platform. The furnace was heated under nitrogen.

[0168] Thermogravimetric analysis (TGA) was performed using a TA Instruments Discovery Series analyzer in platinum pans from ambient temperature to 250–350 °C at 10 °C / min under dry nitrogen at 25 ml / min.

[0169] Moisture Sorption: Moisture sorption data was collected using a VTI SGA 100 Symmetric Vapor Sorption Analyzer. Sample sizes of approximately 5-10 mg were used on platinum pans. Hygroscopicity was evaluated from 5 to 95% RH in 5% RH increments. Data was collected for adsorption and desorption cycles. Equilibrium criteria was set at 0.001% weight change in 10 minutes, with a maximum equilibration time of 180 minutes.

[0170] 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 SSCI using an Agilent DD2-400 spectrometer using deuterated DMSO or methanol.

[0171] 13 C SSNMR data was obtained at 600 MHz ( 1 All experiments were performed on a Bruker DSX spectrometer operating at 1H. A 4 mm H / F / X spinning probe operating at a spinning frequency of 14 kHz was used for all experiments. CPMAS with the TOSS program was used with a recycle delay of 10 seconds. 1 H 90° pulse and 8μs 13 A C 180° pulse was used. Separation was performed using a spinal64 sequence. 4096 transients were acquired for signal averaging. Data were processed with Topspin 3.0 software.

[0172] Example 1: AMG397 trifluoroethanol solvate Crystalline AMG397 trifluoroethanol solvate was prepared by charging AMG397 with a solution of L-arginine in trifluoroethanol (1:1) to form a solution. Upon stirring at room temperature for 3 days, a suspension formed. The isolated solid was then collected to give AMG397 trifluoroethanol solvate, which was characterized as shown in the table below.

[0173]

Table 1

[0174]

Table 2

[0175]

Table 3

[0176] 1 H NMR データ 1 H NMR(400MHz,DMSO-d6)δ ppm 0.78-1.04(m,2H)1.16(br d,J=12.31Hz,2H)1.29-1.51(m,2H)1.51-1.71(m,3H)1.71-1.82(m,1H)1.85(br s,1H)2.00(br d,J=12.95Hz,1H)2.12-2.18(m,1H)2.19-2.29(m,1H)2.29-2.47(m,2H)2.53-2.85(m,1H)2.63-2.85(m ,1H)2.86-3.01(m,1H)3.12-3.30(m,2H)3.45-3.62(m,1H)3.77-4.07(m,7H)5.31-5.51(m,1H)5.59(br s,1H)6.05(t,J=6.66Hz,3H)6.72-6.90(m,1H)6.90-7.11(m,2H)7.11-7.21(m,1H)7.27(br dd,J=8.50,2.32Hz,1H)7.67(d,J=8.52Hz,1H).

[0177]

Table 4

[0178] Example 2: AMG397 ヘキサフルオロイソプロパノール solvent mixture Crystalline AMG397 hexafluoroisopropanol (HFIPA) solvate was formed by charging AMG397 and L-arginine (1:1) with hexafluoroisopropanol and stirring the slurry at room temperature for 2 days. Alternatively, a crystalline solvate was prepared by charging AMG397 and L-lysine (1:1) with hexafluoroisopropanol and stirring at 55° C. The isolated solid was AMG397 hexafluoroisopropanol solvate and was characterized as shown in the table below.

[0179] [Table 5]

[0180] [Table 6]

[0181] [Table 7]

[0182] [Table 8]

[0183] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.86-0.97(m,3H)1.10-1.19(m,3H)1.22-1.45(m,4H)1.47-1.71(m,6H)1.75-1.91(m,3H)1.9 4-2.11(m,3H)2.13-2.44(m,6H)2.53-2.85(m,1H)2.53-2.85(m,4H)2.87-3.00(m,1H)2.94(br dd,J=14.85,10.36Hz,1H)3.01-3.16(m,1H)3.02-3.20(m,1H)3.25-3.48(m,3H)3.27-3.45( m,1H)3.49-3.63(m,2H)3.62-3.74(m,1H)3.63-3.77(m,1H)3.80-3.92(m,1H)3.91-4.07(m,2 H)3.92-4.05(m,2H)5.05-5.24(m,1H)5.05-5.24(m,1H)5.15(dt,J=13.04,6.30Hz,5H)5.42 -5.53(m,1H)5.42-5.53(m,1H)5.44-5.54(m,1H)5.55-5.69(m,1H)5.56-5.70(m,1H)5.57-5. 69(m,1H)6.75-6.84(m,1H)6.77-6.86(m,1H)6.77-6.86(m,1H)6.96-7.06(m,1H)6.97-7.05 (m,1H)6.98-7.05(m,1H)7.12-7.23(m,2H)7.13-7.22(m,2H)7.13-7.22(m,2H)7.13-7.22(m, 2H)7.14-7.22(m,2H)7.22-7.31(m,1H)7.23-7.30(m,1H)7.24-7.30(m,1H)7.24-7.31(m,1H )7.69(s,1H)7.61-7.73(m,1H)7.64-7.74(m,1H)7.96-8.21(m,1H)7.98-8.16(m,1H)8.07(br s,5H).

[0184]

Table 9

[0185] Example 3: AMG397 1-プロパノール solvent mixture Crystalline AMG397 1-propanol (1-PrOH) solvate was formed by charging AMG397 with 1-propanol and stirring the slurry for 2 days at 55° C. The isolated solid was AMG397 1-propanol solvate and was characterized as shown in the table below.

[0186] [Table 10]

[0187] [Table 11]

[0188] [Table 12]

[0189] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.79-0.89(m,1H)0.92(br d,J=6.41Hz,2H)0.97-1.12(m,1H)1.19(br s,2H)1.30-1.50(m,3H)1.57-1.71(m,2H)1.71-1.92(m,3H)2.01(br d,J=13.46Hz,2H)2.13-2.30(m,2H)2.30-2.49(m,2H)2.53-2.65(m,2H)2.66-2.83(m,2H)2.8 7-3.02(m,2H)3.02-3.15(m,1H)3.16-3.30(m,3H)3.34-3.42(m,3H)3.52-3.76(m,2H)3.99(br d,J=9.40Hz,3H)4.35(t,J=5.24Hz,1H)5.35-5.51(m,1H)5.54-5.70(m,1H)6.74-6.88(m,1H)7.00( dd,J=8.12,1.71Hz,1H)7.18(d,J=2.35Hz,1H)7.28(dd,J=8.55,2.35Hz,1H)7.68(d,J=8.55Hz,1H).

[0190] [Table 13]

[0191] Example 4: AMG397 Isopropanol Solvate Form 1 Crystalline AMG397 isopropanol (IPA) solvate Form 1 was formed by charging AMG397 and Ca(OAc)2, Mg(OAc)2 or NaOAc (1:1) with IPA and stirring the slurry at room temperature for 3-6 days. The isolated solid was AMG397 isopropanol solvate Form 1 and was characterized as shown in the table below.

[0192] [Table 14]

[0193] [Table 15]

[0194] [Table 16]

[0195] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.81-0.98(m,3H)1.04(d,J=6.18Hz,3H)1.12-1.20(m,2H)1.21-1.28(m,2H)1.28-1.47(m,3H)1.47-1. 72(m,4H)1.73-1.82(m,1H)1.82-1.88(m,1H)1.88-1.95(m,1H)1.95-2.05(m,2H)2.12-2.29(m,3H)2.2 9-2.38(m,1H)2.39-2.48(m,1H)2.52-2.65(m,2H)2.65-2.79(m,2H)2.86-3.01(m,2H)3.01-3.17(m,2H) )3.17-3.25(m,3H)3.38-3.64(m,3H)3.65-3.90(m,5H)3.91-4.06(m,3H)4.34(d,J=4.26Hz,2H)5.44(br d,J=15.77Hz,2H)5.61(br d,J=16.62Hz,2H)6.80(br d,J=7.67Hz,2H)6.90-7.09(m,2H)7.09-7.21(m,2H)7.27(dd,J=8.52,2.34Hz,1H)7.67(d,J=8.52Hz,1H).

[0196] [Table 17]

[0197] Example 5: AMG397 Isopropanol Solvate Form 2 Crystalline AMG397 isopropanol (IPA) solvate Form 2 was formed by charging AMG397 and Mg(OAc)2 (2:1) with IPA and stirring the slurry for 2 days at 77° C. The isolated solid was AMG397 isopropanol solvate Form 2 and was characterized as shown in the table below.

[0198] [Table 18]

[0199] [Table 19]

[0200] [Table 20]

[0201] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.83-0.95(m,1H)1.00-1.08(m,8H)1.10-1.26(m,2H)1.26-1.53(m,2H)1.54-1.71(m,2H)1.71-1.88(m,2H)1.88-1.93(m,1H)2.00(br d,J=12.79Hz,1H)2.10-2.28(m,2H)2.28-2.36(m,1H)2.37-2.46(m,1H)2.52-2.86(m,3H)2.87-2.99(m ,1H)2.99-3.12(m,1H)3.16-3.28(m,2H)3.49-3.61(m,1H)3.69-3.82(m,2H)3.82-3.91(m,1H)3.98(br d,J=10.23Hz,1H)4.33(d,J=4.05Hz,7H)5.36-5.51(m,1H)5.53-5.72(m,1H)6.71-6.88(m,1H)6.93-7.21(m,4H)7.26(br d,J=8.52Hz,3H)7.67(br d,J=8.74Hz,1H).

[0202] [Table 21]

[0203] Example 6: AMG397 Acetonitrile Solvate Crystalline AMG397 acetonitrile (MeCN) solvate was formed by charging AMG397 with MeCN to form a suspension, then charging a solution of L-lactic acid in MeCN (1:1) and stirring the suspension at room temperature for 6 days. The isolated solid was AMG397 acetonitrile solvate and was characterized as shown in the table below.

[0204]

Table 22

[0205]

Table 23

[0206]

Table 24

[0207] 1 1H NMR data 1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (s, 1H) 0.75 (br d, J = 6.55 Hz, 1H) 0.91 (br d, J = 6.65 Hz, 2H) 1.17 (br d, J = 6.11 Hz, 2H) 1.27 - 1.46 (m, 2H) 1.47 - 1.72 (m, 3H) 1.74 - 1.90 (m, 2H) 1.98 - 2.11 (m, 6H) 2.18 - 2.40 (m, 3H) 2.42 - 2.48 (m, 1H) 2.52 - 2.74 (m, 2H) 2.76 - 2.83 (m, 1H) 2.93 (br dd, J = 14.77, 10.47 Hz, 2H) 3.01 - 3.13 (m, 1H) 3.13 - 3.20 (m, 1H) 3.25 - 3.44 (m, 4H) 3.55 (br d, J = 14.23 Hz, 1H) 3.71 (br s, 1H) 3.86 (br d, J = 14.53 Hz, 1H) 3.91 - 4.07 (m, 1H) 4.14 (s, 1H) 5.44 (br d, J = 16.04 Hz, 1H) 5.52 - 5.73 (m, 1H) 6.80 (br d, J = 8.02 Hz, 1H) 7.00 (dd, J = 8.07, 1.66 Hz, 1H) 7.17 (d, J = 2.35 Hz, 1H) 7.27 (dd, J = 8.49, 2.27 Hz, 1H) 7.67 (d, J = 8.51 Hz, 1H) 8.62 (s, 1H).

[0208]

Table 25

[0209] Example 7: AMG397 Acetic Acid Solvate Crystalline AMG397 acetic acid solvate was formed as follows: AMG397 was combined with ethanol and aqueous sodium hydroxide. Aqueous acetic acid was added and the resulting slurry was aged. The product was collected by filtration. The isolated solid was AMG397 acetic acid solvate, which was characterized as shown in the table below.

[0210] [Table 26]

[0211] [Table 27]

[0212] [Table 28]

[0213] Example 8: AMG397 Hydrochloride Form 1 Crystalline AMG397 hydrochloride Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with HCl in EtOH stirred at room temperature for 2 hours followed by 1 hour at 75° C. Alternatively, it was prepared by a 1:1 (mol / mol, API / acid) salt reaction with HCl in dioxane stirred at room temperature for 6 days. The isolated solid was AMG397 hydrochloride Form 1, which was characterized as shown in the table below.

[0214] [Table 29]

[0215] [Table 30]

[0216] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.96(br d,J=6.18Hz,5H)1.27-1.52(m,7H)1.53-1.72(m,3H)1.79(br d,J=10.28Hz,4H)1.82-1.91(m,2H)1.92-2.15(m,4H)2.15-2.27(m,1H)2.27-2.37(m,2H)2.37-2.47(m,2H)2 .52-2.63(m,2H)2.64-2.87(m,3H)2.88-3.10(m,3H)3.10-3.30(m,6H)3.57(s,10H)3.79-4.07(m,9H)5.34(br d,J=16.09Hz,2H)5.58(br d,J=15.50Hz,3H)6.66-6.95(m,4H)7.01(br dd,J=8.12,1.57Hz,3H)7.07-7.15(m,2H)7.18(d,J=2.18Hz,2H)7.27(dd,J=8.52,2.18Hz,2H)7.66(d,J=8.58Hz,1H)9.67(br s,3H)11.87(s,2H).

[0217] [Table 31]

[0218] Example 9: AMG397 Amorphous Sodium Salt Form 1 AMG397 amorphous sodium salt Form 1 was formed by extracting AMG397 from a 100 mg drug product tablet using a solvent exchange into Me-THF and ethanol, followed by the addition of NaOH to form the sodium salt. The wet cake was vacuum dried under a stream of N2 to obtain the sodium salt.

[0219] Example 10: AMG397 Potassium Salt Form 1 Crystalline AMG397 potassium salt Form 1 was formed by a 1:1 (mol / mol, API / base) salt reaction with KOMe in 1:1 DMF / HO stirred for 8 hours at 55° C. The isolated solid was AMG397 potassium salt Form 1, which was characterized as shown in the table below.

[0220] [Table 32]

[0221] Example 11: AMG397 Potassium Salt Form 2 (Ethyl Acetate Solvate) Crystalline AMG397 potassium salt Form 2 (ethyl acetate solvate) was formed by a 1:1 (mol / mol, API / base) salt reaction with KOH in EtOAc stirred at room temperature for 2 days. The isolated solid was AMG397 potassium salt Form 2 (ethyl acetate solvate) and was characterized as shown in the table below.

[0222] [Table 33]

[0223] [Table 34]

[0224] [Table 35]

[0225] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.79-0.96(m,3H)0.96-1.13(m,3H)1.13-1.25(m,2H)1.29-1.50(m,3H)1.50-1.59(m,2H)1.64(br d,J=14.70Hz,1H)1.71-1.81(m,1H)1.82-2.04(m,5H)2.06-2.26(m,3H)2.2 7-2.47(m,3H)2.53-2.64(m,1H)2.65-2.84(m,2H)2.85-2.98(m,1H)3.03(br d,J=7.03Hz,1H)3.13-3.28(m,3H)3.47-3.56(m,1H)3.80-4.06(m,3H)5.14-5.59(m,3H)5.67(dt,J=16.84,4.79Hz, 2H)6.71(d,J=8.10Hz,1H)6.98(dd,J=8.10,1.49Hz,1H)7.08-7.19(m,1H)7.19-7.34(m,2H)7.69(d,J=8.52Hz,1H).

[0226] [Table 36]

[0227] Example 12: AMG397 Sulfate Form 1 Crystalline AMG397 sulfate Form 1 was formed by a 1:1 (mol / mol, API / base) salt reaction with HSOIn EtOH / H0 9:1 stirred for 8 hours at 55° C. The isolated solid was AMG397 sulfate Form 1, which was characterized as shown in the table below.

[0228] [Table 37]

[0229] Example 13: AMG397 Sulfate Form 2 Crystalline AMG397 sulfate Form 2 was formed by a 1:1 (mol / mol, API / base) salt reaction with HSO in DMF / H0 1:1 stirred for 8 hours at 55° C. The isolated solid was AMG397 sulfate Form 2, which was characterized as shown in the table below.

[0230] [Table 38]

[0231] Example 14: AMG397 Sulfate Form 3 Crystalline AMG397 sulfate Form 3 was formed by a 1:1 (mol / mol, API / acid) salt reaction with H2SO4 in EtOH stirred for 8 hours at 55° C. The isolated solid was AMG397 sulfate Form 3, which was characterized as shown in the table below.

[0232] [Table 39]

[0233] Example 15: AMG397 Phosphate Form 1 Crystalline AMG397 phosphate Form 1 was formed by a 1:1 (mol / mol, API / base) salt reaction with H3PO4 in EtOH / THF 1:1 with evaporative cooling. The isolated solid was AMG397 phosphate Form 1 and was characterized as shown in the table below.

[0234] [Table 40]

[0235] [Table 41]

[0236] [Table 42]

[0237] [Table 43]

[0238] [Table 44]

[0239] [Table 45]

[0240] Example 16: AMG397 Fumarate Form 1 Crystalline AMG397 fumarate Form 1 was formed by a 1:2 (mol / mol, API / acid) salt reaction with fumaric acid in EtOAc with mixing at room temperature for 3 days. The isolated solid was AMG397 fumarate Form 1, which was characterized as shown in the table below.

[0241] [Table 46]

[0242] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.91(br d,J=6.65Hz,3H)1.06-1.21(m,3H)1.21-1.48(m,3H)1.49-1.71(m,4H)1.74-1.88(m,2H)1.95-2.13(m,2H)2.13-2.39(m,3H)2.39 -2.48(m,1H)2.52-2.79(m,3H)2.80-2.99(m,2H)3.01-3.17(m,1H)3.17-3.25(m,2H)3.47-3.65(m,2H)3.66-3.79(m,1H)3.86(br d,J=14.23Hz,1H)3.91-4.10(m,2H)5.32-5.52(m,1H)5.61(br d,J=16.24Hz,1H)6.51-6.71(m,2H)6.81(br d,J=7.97Hz,1H)6.91-7.12(m,1H)7.12-7.21(m,1H)7.27(dd,J=8.53,2.27Hz,1H)7.67(d,J=8.56Hz,1H).

[0243] Example 17: AMG397 Fumarate Salt Form 2 (Acetone Solvate) AMG397 Fumarate Form 2 (acetone solvate) was formed by a 1:1 (mol / mol, API / acid) salt reaction with fumaric acid in acetone mixed at room temperature for 3 days. The isolated solid was AMG397 Fumarate Form 2 (acetone solvate) and was characterized as shown in the table below.

[0244] [Table 47]

[0245] [Table 48]

[0246] [Table 49]

[0247] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.92(d,J=6.70Hz,3H)1.15-1.44(m,5H)1.49-1.71(m,4H)1.71-1.95(m,3H)1.96-2.18(m,5H)2 .18-2.34(m,2H)2.39-2.48(m,2H)2.53-2.78(m,3H)2.87-3.14(m,3H)3.14-3.22(m,1H)3.56(br d,J=13.99Hz,4H)3.65-3.78(m,3H)3.86(br d,J=14.33Hz,4H)3.91-4.18(m,7H)5.33-5.51(m,3H)5.61(dt,J=16.24,5.11Hz,3H)6.61(s,3H)6.81(d ,J=8.12Hz,3H)6.91-7.12(m,3H)7.12-7.21(m,3H)7.27(dd,J=8.49,2.27Hz,3H)7.67(d,J=8.51Hz,1H).

[0248] [Table 50]

[0249] Example 18: AMG397 Citrate Form 1 AMG397 Citrate Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with citric acid in EtOAc mixed at room temperature for 3 days. The isolated solid was AMG397 Citrate Form 1, which was characterized as shown in the table below.

[0250] [Table 51]

[0251] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.92-0.99(m,2H)1.22-1.31(m,2H)1.32-1.51(m,3H)1.55-1.68(m,2H)1.70-1.89(m,4H)2.02-2.11(m,12H)2.15 -2.36(m,2H)2.37-2.47(m,1H)2.55-2.64(m,4H)2.65-2.73(m,3H)2.75-2.87(m,2H)2.89-3.03(m,2H)3.08-3.22 (m,3H)3.29-3.45(m,5H)3.53-3.63(m,1H)3.80-3.92(m,2H)3.94-4.11(m,2H)5.31-5.42(m,1H)5.52-5.68(m,1H) )6.83-6.91(m,1H)6.97-7.04(m,1H)7.09-7.15(m,1H)7.15-7.21(m,1H)7.22-7.32(m,1H)7.66(d,J=8.56Hz,1H).

[0252] [Table 52]

[0253] Example 19: AMG397 Citrate Salt Form 2 (Hydrate) AMG397 citrate salt Form 2 (hydrate) was formed by a 1:1 (mol / mol, API / acid) salt reaction with citric acid in EtOAc mixed at room temperature for 3 days. The isolated solid was AMG397 citrate salt Form 2 (hydrate) and was characterized as shown in the table below.

[0254] [Table 53]

[0255] Example 20: AMG397 Lactate Salt Form 1 AMG397 lactate Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with lactic acid in EtOAc mixed at room temperature for 3 days. The isolated solid was AMG397 lactate Form 1, which was characterized as shown in the table below.

[0256] [Table 54]

[0257] 1 H NMR data 1 H NMR(500MHz,CHLOROFORM-d)δ ppm 0.76-0.99(m,3H)1.06(d,J=6.23Hz,4H)1.18-1.34(m,3H)1.34-1.55(m,8H)1.55-1.61 (m,1H)1.64-1.71(m,2H)1.75-1.89(m,3H)1.89-2.01(m,3H)2.01-2.24(m,6H)2.32(br d,J=14.27Hz,1H)2.39-2.51(m,1H)2.51-2.65(m,3H)2.65-2.83(m,6H)2.92(br dd,J=14.92,9.47Hz,2H)3.04-3.19(m,1H)3.19-3.33(m,2H)3.33-3.38(m,2H)3.41(br d,J=10.12Hz,1H)3.51(br d,J=9.34Hz,1H)3.73(br d,J=14.27Hz,1H)4.00-4.19(m,5H)5.34(br d,J=16.09Hz,1H)5.61-5.74(m,1H)6.84-7.01(m,2H)7.01-7.15(m,1H)7.15-7.26(m,1H)7.29-7.53(m,8H)7.72(d,J=8.56Hz,1H).

[0258] Example 21: AMG397 Succinate Form 1 AMG397 succinate Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with lactic acid in EtOAc mixed at room temperature for 3 days. The isolated solid was AMG397 succinate Form 1, which was characterized as shown in the table below.

[0259] [Table 55]

[0260] 1 H NMR data 1 H NMR(500MHz,CHLOROFORM-d)δ ppm 0.77-0.99(m,2H)0.99-1.15(m,3H)1.15-1.33(m,2H)1.33-1.44(m,2H)1.45-1.67(m,6H)1.68-1.78(m,1H)1.83(br d,J=13.75Hz,2H)1.89-2.00(m,2H)2.01-2.17(m,2H)2.22(br dd,J=15.05,6.23Hz,1H)2.28-2.49(m,1H)2.49-2.65(m,3H)2.70-2.85(m,3H)2.92(br dd,J=14.92,9.73Hz,1H)3.05-3.19(m,1H)3.19-3.31(m,1H)3.36(s,2H)3.49(br d,J=11.42Hz,1H)3.73(br d,J=14.53Hz,1H)4.00-4.20(m,3H)5.33(br d,J=16.87Hz,1H)5.51-5.74(m,1H)6.87-6.99(m,1H)7.01-7.15(m,1H)7.20(dd,J=8.56,2.34Hz,1H)7.48(s,1H)7.72(d,J=8.56Hz,1H).

[0261] Example 22: AMG397 Besylate Form 1 (Hydrate) AMG397 besylate Form 1 (hydrate) was formed by a 1:1 (mol / mol, API / base) salt reaction with BSA in EtOH heat cycled for 1 hour to 60° C. The isolated solid was AMG397 besylate Form 1 (hydrate) and was characterized as shown in the table below.

[0262] [Table 56]

[0263] [Table 57]

[0264] Example 23: AMG397 Tosylate Form 1 AMG397 tosylate Form 1 was formed by a 1:1 (mol / mol, API / base) salt reaction with TSA in EtOH heat cycled for 1 hour to 60° C. The isolated solid was AMG397 tosylate Form 1, which was characterized as shown in the table below.

[0265] [Table 58]

[0266] [Table 59]

[0267] Example 24: AMG397 Maleate Form 1 (Family of Isostructural Solvates) AMG397 maleate salt Form 1 (family of isostructural solvates) was formed by 1:1 (mol / mol, API / acid) salt reaction with maleic acid in acetone mixed at room temperature for 1 day. Family of isostructural solvates from acetone, MeCN, DCM, DMF / ACN, DMF / EtOH and THF. The isolated solid was AMG397 maleate salt Form 1 (family of isostructural solvates) and was characterized as shown in the table below.

[0268] [Table 60]

[0269] [Table 61]

[0270] 1 H NMR data 1H NMR(400MHz,DMSO-d6)δ ppm 0.96(br d,J=6.02Hz,2H)1.22-1.54(m,4H)1.54-1.71(m,2H)1.71-1.88(m,3H)1.91-2.13(m,2H)2.15-2.37(m ,2H)2.37-2.48(m,1H)2.52-2.65(m,1H)2.65-2.86(m,2H)2.88-3.12(m,2H)3.12-3.28(m,4H)3.58(br d,J=13.96Hz,3H)3.81-4.08(m,7H)5.23-5.46(m,3H)5.58(br d,J=15.77Hz,2H)6.02(s,2H)6.76-6.95(m,2H)6.95-7.08(m,2H)7.08-7.15(m,1H)7.18( d,J=2.24Hz,1H)7.27(dd,J=8.52,2.29Hz,2H)7.66(d,J=8.52Hz,1H)8.97(s,2H)11.88(br s,1H).

[0271] [Table 62]

[0272] Example 25: AMG397 Maleate Form 2 AMG397 maleate Form 2 was formed by a 1:1 (mol / mol, API / acid) salt reaction with maleic acid in EtOH heat cycled to 60° C. for 1 hour. Alternatively, maleate Form 2 was prepared by stressing maleate Form 1 at 40° C. / 75% relative humidity for 10 days. The isolated solid was AMG397 maleate Form 2 and was characterized as shown in the table below.

[0273] [Table 63]

[0274] [Table 64]

[0275] [Table 65]

[0276] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.96(br d,J=5.97Hz,3H)1.23-1.52(m,4H)1.54-1.70(m,2H)1.70-1.90(m,3H)1.91-2.13(m,2H)2.14-2.37(m ,2H)2.37-2.47(m,1H)2.53-2.63(m,1H)2.64-2.86(m,2H)2.87-3.07(m,2H)3.07-3.27(m,4H)3.58(br d,J=14.07Hz,1H)3.73-3.95(m,2H)3.95-4.24(m,2H)5.35(br d,J=15.77Hz,1H)5.58(br d,J=15.98Hz,1H)6.02(s,1H)6.79-6.95(m,1H)7.01(dd,J=8.10,1.70Hz,1H)7.07-7.15( m,1H)7.18(d,J=2.13Hz,1H)7.27(dd,J=8.52,2.34Hz,1H)7.66(d,J=8.52Hz,1H)8.97(br s,1H)11.87(br s,2H).

[0277] [Table 66]

[0278] Example 26: AMG397 Malonate Form 1 AMG397 Malonate Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with malonic acid in MeCN with mixing for 1 day at room temperature. The isolated solid was AMG397 Malonate Form 1, which was characterized as shown in the table below.

[0279] [Table 67]

[0280] [Table 68]

[0281] [Table 69]

[0282] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(br d,J=6.13Hz,2H)1.20-1.30(m,3H)1.30-1.51(m,3H)1.52-1.58(m,1H)1.59-1.87(m,6H)1.92-2.13(m,3H)2.19(br d,J=12.95Hz,2H)2.25-2.36(m,1H)2.36-2.48(m,2H)2.54-2.66(m,1H)2.66-2.87(m,4H)2.87-3.04(m ,3H)3.05-3.23(m,4H)3.49-3.71(m,4H)3.72-3.92(m,4H)3.92-4.13(m,4H)5.24-5.49(m,2H)5.59(br d,J=15.93Hz,2H)6.79-6.94(m,2H)6.94-7.10(m,2H)7.10-7.22(m,2H)7.27(dd,J=8.50,2.26Hz,2H)7.66(d,J=8.52Hz,1H).

[0283] [Table 70]

[0284] Example 27: AMG397 Malonate Form 2 AMG397 malonate form 2 was formed by stressing malonate form 1 at 40° C. / 75% relative humidity for 10 days. The isolated solid was AMG397 malonate form 2, which was characterized as shown in the table below.

[0285] [Table 71]

[0286] [Table 72]

[0287] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.94(br d,J=5.97Hz,2H)1.20-1.30(m,2H)1.30-1.51(m,2H)1.59-1.87(m,5H)1.92-2.12(m,2H)2.19(br d,J=13.00Hz,2H)2.25-2.48(m,2H)2.54-2.65(m,1H)2.66-2.86(m,4H)2.87-3.04(m,3H)3.05-3.23(m,4H)3.57(br d,J=14.49Hz,7H)3.86(br d,J=14.49Hz,5H)3.92-4.21(m,5H)5.23-5.49(m,3H)5.59(br d,J=15.77Hz,3H)6.86(br d,J=8.10Hz,2H)7.00(dd,J=8.10,1.70Hz,2H)7.08-7.22(m,3H)7.27(dd,J=8.52,2.34Hz,2H)7.66(d,J=8.52Hz,1H).

[0288] [Table 73]

[0289] Example 28: AMG397 Tartrate Salt Form 1 (Family of Isostructural Solvates) AMG397 tartrate salt Form 1 (family of isostructural solvates) was formed by 1:1 (mol / mol, API / acid) salt reaction with tartaric acid in acetone mixed at room temperature for 3 days. Family of isostructural solvates from acetone, MeCN, DCM, EtOH, MeOH and water. The isolated solid was AMG397 tartrate salt Form 1, characterized as shown in the table below.

[0290]

Table 74

[0291]

Table 75

[0292] 1 H NMR データ 1 H NMR(400MHz,DMSO-d6)δ ppm 0.93(br d,J=6.55Hz,3H)1.21(br d,J=6.70Hz,6H)1.63(br s,4H)1.74-1.89(m,2H)1.90-2.04(m,1H)2.09(s,9H)2.12-2.25(m,2H)2.28-2.48(m,3H)2.54-2.62(m ,1H)2.63-2.79(m,2H)2.87-3.00(m,2H)3.02-3.22(m,3H)3.49-3.62(m,1H)3.72-3.91(m,2H)3.99(br d,J=9.39Hz,5H)4.19(s,6H)5.34-5.46(m,1H)5.54-5.66(m,1H)6.79-6.87(m,1H)6.99(br d,J=1.71Hz,2H)7.07-7.31(m,6H)7.67(d,J=8.56Hz,1H).

[0293]

Table 76

[0294] Example 29: AMG397 Toruス(ヒドロキシメチル) aminoメタン(トリス) form 1 (アセトン solvent compound) AMG397 tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) was formed by a 1:1 (mol / mol, API / base) salt reaction with tromethamine in acetone mixed at room temperature for 8 days. The isolated solid was AMG397 tris(hydroxymethyl)aminomethane (tris) salt Form 1 (acetone solvate) and was characterized as shown in the table below.

[0295] [Table 77]

[0296] [Table 78]

[0297] [Table 79]

[0298] 1 H NMR data 1 H NMR(400MHz,DMSO-d6)δ ppm 0.79-0.97(m,5H)0.97-1.16(m,5H)1.16-1.40(m,5H)1.57(br s,6H)1.71-1.79(m,1H)1.81-2.04(m,6H)2.09(s,10H)2.12-2.28(m,3H)2.39(br d,J=14.38Hz,2H)2.54-2.63(m,2H)2.64-2.95(m,4H)2.97-3.09(m,1H)3.15-3.30(m,4H)3.34-3.48(m,13H)3.53(br d,J=13.55Hz,9H)3.94(br d,J=10.56Hz,10H)5.06(br s,10H)5.43-5.56(m,1H)5.59-5.73(m,1H)6.62-6.85(m,5H)6.85-7.08(m,6H)7.08-7.19(m,4H)7.19-7.39(m,7H)7.69(d,J=8.56Hz,1H).

[0299] [Table 80]

[0300] Example 30: AMG397 Iodide Salt Form 1 AMG397 iodide salt Form 1 was formed by a 1:1 (mol / mol, API / acid) salt reaction with hydroiodic acid in EtOH at room temperature by precipitation. The isolated solid was AMG397 iodide salt Form 1, characterized as shown in the table below.

[0301] [Table 81]

[0302] [Table 82]

[0303] Example 31: AMG397 DMSO solvate AMG397 DMSO solvate was formed by charging AMG397 with hot DMSO to form a solution, which was then cooled to room temperature. The isolated solid was AMG397 DMSO solvate, which was characterized as shown in the table below.

[0304] [Table 83]

[0305] The above description is given for clarity of understanding only, 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.

[0306] 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.

[0307] Throughout this specification, when a composition is described as comprising components or materials, it is also contemplated that the composition may consist essentially of, or consist of, any combination of the recited components or materials, unless otherwise stated. Similarly, when a method is described as comprising particular steps, it is also contemplated that the method may consist essentially of, or consist of, any combination of the recited 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.

[0308] 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 can be carried out in the order of events recited or in any other order which is logically possible.

[0309] The implementation of the methods disclosed herein and their individual steps can be performed manually and / or with or utilizing automation provided by electronic devices. Although the methods have been described with respect to specific embodiments, one of ordinary skill in the art will readily appreciate that other methods 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.

[0310] 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 indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual 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 indicated. No language herein should be construed as indicating any non-claimed element as essential to the practice of the disclosure herein.

[0311] 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.

[0312] Embodiment The above disclosure may be better understood through the following embodiments.

[0313] Embodiment 1. A crystalline form of AMG397 as a trifluoroethanol solvate, characterized by an XRPD pattern peaks at 17.5, 19.2, 19.4, and 21.7±0.2 degrees 2θ using CuKα radiation.

[0314] Embodiment 2. The crystalline form of embodiment 1, further characterized by an XRPD pattern peaks at 14.6, 17.2, 18.4, 18.5, 18.8, 20.0, 20.2, 20.4, 21.0, 21.2, and 21.5±0.2 degrees 2θ using CuKα radiation.

[0315] Embodiment 3. The crystalline form of embodiment 2, further characterized by an XRPD pattern peaks at 6.7, 10.3, 12.5, 13.5, 13.8, 17.7, 17.8, 18.1, 21.9, 22.3, 22.4, and 22.9±0.2 degrees 2θ using CuKα radiation.

[0316] Embodiment 4. The crystalline form of any one of embodiments 1-3, having an XRPD pattern substantially as shown in FIG.

[0317] Embodiment 5. A crystalline form of AMG397 as a hexafluoroisopropanol solvate, characterized by an XRPD pattern peaks at 11.4, 18.6, and 18.8±0.2 degrees 2θ using CuKα radiation.

[0318] Embodiment 6. The crystalline form of embodiment 5, further characterized by an XRPD pattern peaks at 8.5, 12.8, 17.1, 17.6, 21.1, 22.4, and 23.1±0.2 degrees 2θ using CuKα radiation.

[0319] Embodiment 7. The crystalline form of embodiment 6, further characterized by an XRPD pattern peaks at 6.1, 13.6, 15.3, 15.7, 16.2, 16.4, 16.5, 17.4, 17.8, 18.0, 18.1, 19.4, 20.6, 21.5, 21.7, 22.2, and 25.4±0.2 degrees 2θ using CuKα radiation.

[0320] Embodiment 8. The crystalline form of any one of embodiments 5-7, having an XRPD pattern substantially as shown in FIG. 2.

[0321] Embodiment 9. A crystalline form of AMG397 as a 1-propanol solvate, characterized by an XRPD pattern peaks at 13.3, 15.1, and 18.5±0.2 degrees 2θ using CuKα radiation.

[0322] Embodiment 10. The crystalline form of embodiment 9, further characterized by an XRPD pattern peaks at 8.1, 9.7, 15.7, 16.4, 17.2, and 17.7±0.2 degrees 2θ using CuKα radiation.

[0323] Embodiment 11. The crystalline form of embodiment 10, further characterized by an XRPD pattern peaks at 12.0, 12.7, 14.2, 14.8, 17.1, 18.2, 19.1, 19.5, 20.7, 21.2, 21.6, 21.7, 22.1, 22.3, 22.4, 22.8, 23.5, 23.8, 23.9, and 25.5±0.2° 2θ using CuKα radiation.

[0324] Embodiment 12. The crystalline form of any one of embodiments 9 to 11, having an XRPD pattern substantially as shown in FIG.

[0325] Embodiment 13. The crystalline form of any one of embodiments 9 to 12, having an endothermic transition at 231° C. to 237° C. as measured by differential scanning calorimetry.

[0326] Embodiment 14. The crystalline form of embodiment 13, wherein the endothermic transition is 234° C.±3° C.

[0327] Embodiment 15. The crystalline form of any one of embodiments 9-14, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 5.

[0328] Embodiment 16. A crystalline form of AMG397 as an isopropanol solvate, characterized by an XRPD pattern peaks at 6.1, 7.1, and 10.0±0.2 degrees 2θ using CuKα radiation.

[0329] Embodiment 17. The crystalline form of embodiment 16, further characterized by an XRPD pattern peaks at 18.5, 19.0, 19.7, and 20.4±0.2 degrees 2θ using CuKα radiation.

[0330] Embodiment 18. The crystalline form of embodiment 17, further characterized by an XRPD pattern peaks at 10.5, 13.6, 14.5, 15.0, 15.3, 15.9, 16.2, 16.6, 16.7, 16.9, 17.7, 17.9, 18.4, 19.5, 20.7, 21.6, 23.1, and 25.7±0.2° 2θ using CuKα radiation.

[0331] Embodiment 19. The crystalline form of any one of embodiments 16-18, having an XRPD pattern substantially as shown in FIG.

[0332] Embodiment 20. The crystalline form of any one of embodiments 16-19, having an endothermic transition at 244° C. to 250° C. as measured by differential scanning calorimetry.

[0333] Embodiment 21. The crystalline form of embodiment 20, wherein the endothermic transition is 247° C.±3° C.

[0334] EMBODIMENT 22. 22. The crystalline form of any one of embodiments 16-21, having a thermogravimetric analysis ("TGA") substantially as shown in FIG.

[0335] Embodiment 23. A crystalline form of AMG397 as an isopropanol solvate, characterized by an XRPD pattern peaks at 13.3, 15.1, and 18.6±0.2 degrees 2θ using CuKα radiation.

[0336] Embodiment 24. The crystalline form of embodiment 23, further characterized by an XRPD pattern peaks at 8.1, 9.7, 16.4, and 17.7±0.2 degrees 2θ using CuKα radiation.

[0337] Embodiment 25. The crystalline form of embodiment 24, further characterized by an XRPD pattern peaks at 12.0, 12.6, 14.2, 14.8, 15.7, 17.1, 17.2, 18.2, 19.1, 19.5, 21.5, 21.6, 22.3, 22.4, and 23.8±0.2° 2θ using CuKα radiation.

[0338] Embodiment 26. The crystalline form of any one of embodiments 23-25, having an XRPD pattern substantially as shown in FIG.

[0339] Embodiment 27. A crystalline form according to any one of embodiments 23 to 26, having endothermic transitions at 80°C to 86°C and 236°C to 242°C as measured by differential scanning calorimetry.

[0340] Embodiment 28. The crystalline form of embodiment 27, wherein the endothermic transitions are 83°C ± 3°C and 239°C ± 3°C.

[0341] Embodiment 29. The crystalline form of any one of embodiments 23-28, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 11.

[0342] Embodiment 30. A crystalline form of AMG397 as an acetonitrile solvate, characterized by an XRPD pattern peaks at 10.2, 17.0, and 20.5±0.2 degrees 2θ using CuKα radiation.

[0343] Embodiment 31. The crystalline form of embodiment 30, further characterized by an XRPD pattern peaks at 6.0, 13.0, 14.3, 15.2, 18.6, and 23.0±0.2 degrees 2θ using CuKα radiation.

[0344] Embodiment 32. The crystalline form of embodiment 31, further characterized by an XRPD pattern peaks at 10.9, 15.6, 17.2, 18.2, 19.2, 21.0, 21.4, 22.1, 22.3, 22.5, 23.4, 24.8, 25.2, 25.6, 26.1, 26.5, 26.7, and 26.8±0.2 degrees 2θ using CuKα radiation.

[0345] Embodiment 33. The crystalline form of any one of embodiments 30-32, having an XRPD pattern substantially as shown in FIG. 12.

[0346] In the embodiments 34.13.63, 19.22, 20.40, 24.22, 25.69, 26.57, 27.75, 29.81, 30.40, 31.28, 36.57, 38.34, 40.10, 43.04, 49.51, 50.10, 51.86, 54.51, 56.28, 57.16, 57 .75, 60.10, 62.16, 65.39, 77.75, 85.10, 115.39, 123.63, 125.10, 128.04, 131.27, 133.04, 133.92, 135.98, 139.80, 141.27, 143.04, 151.86 and 173.92 ± 0.5 ppm solids 13 The crystalline form of AMG397 as an acetic acid solvate, characterized by C NMR peaks.

[0347] Embodiment 35. The crystalline form of embodiment 34, further characterized by an XRPD pattern peaks at 11.1, 17.1, 18.2, and 19.1±0.2 degrees 2θ using CuKα radiation.

[0348] Embodiment 36. The crystalline form of embodiment 35, further characterized by an XRPD pattern peaks at 10.7, 10.9, 11.5, 13.7, 14.3, 18.8, 20.1, and 24.8±0.2 degrees 2θ using CuKα radiation.

[0349] Embodiment 37. The crystalline form of embodiment 36, further characterized by an XRPD pattern peaks at 8.4, 12.4, 12.7, 15.6, 16.5, 17.6, 19.3, 22.2, 23.6, 24.0, 24.6, and 29.0±0.2° 2θ using CuKα radiation.

[0350] Embodiment 38. The crystalline form of any one of embodiments 34 to 37, having an XRPD pattern substantially as shown in FIG. 13.

[0351] Embodiment 39. The crystalline form of any one of embodiments 34 to 38, having endothermic transitions at 92°C to 98°C and 152°C to 158°C as measured by differential scanning calorimetry.

[0352] Embodiment 40. The crystalline form of embodiment 39, wherein the endothermic transitions are at 95°C ± 3°C and 155°C ± 3°C.

[0353] Embodiment 41. The crystalline form of any one of embodiments 34-40, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 15.

[0354] Embodiment 42. A crystalline form of AMG397 as the hydrochloride salt, characterized by an XRPD pattern peaks at 12.9, 16.2, and 17.9±0.2 degrees 2θ using CuKα radiation.

[0355] Embodiment 43. The crystalline form of embodiment 42, further characterized by an XRPD pattern peaks at 11.7, 12.0, 15.9, 19.8, and 20.5±0.2° 2θ using CuKα radiation.

[0356] Embodiment 44. The crystalline form of embodiment 43, further characterized by an XRPD pattern peaks at 10.7, 13.5, 14.4, 14.6, 15.5, 18.1, 22.8, 23.7, 24.6, 25.1, and 26.5±0.2 degrees 2θ using CuKα radiation.

[0357] Embodiment 45. The crystalline form of any one of embodiments 42-44, having an XRPD pattern substantially as shown in FIG. 17.

[0358] Embodiment 46. The crystalline form of any one of embodiments 42 to 45, having an endothermic transition at 264° C. to 270° C. as measured by differential scanning calorimetry.

[0359] Embodiment 47. The crystalline form of embodiment 46, wherein the endothermic transition is 267° C.±3° C.

[0360] Embodiment 48. The crystalline form of any one of embodiments 42-47, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 19.

[0361] Embodiment 49. An amorphous form of AMG397 as the sodium salt, having an XRPD pattern substantially as shown in FIG. 21.

[0362] Embodiment 50. The amorphous form of embodiment 49, having an endothermic transition at 213° C. to 219° C. as measured by differential scanning calorimetry.

[0363] Embodiment 51. The amorphous form of embodiment 50, wherein the endothermic transition is 216°C ± 3°C.

[0364] Embodiment 52. The amorphous form of any one of embodiments 49-51, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 23.

[0365] Embodiment 53. A crystalline form of AMG397 as the potassium salt, characterized by an XRPD pattern peaks at 12.8, 13.4, and 17.2±0.2 degrees 2θ using CuKα radiation.

[0366] Embodiment 54. The crystalline form of embodiment 53, further characterized by an XRPD pattern peaks at 11.0, 11.4, 14.5, 15.7, and 19.2±0.2 degrees 2θ using CuKα radiation.

[0367] Embodiment 55. The crystalline form of embodiment 53 or 54, having an XRPD pattern substantially as shown in FIG. 25.

[0368] Embodiment 56. A crystalline form according to any one of embodiments 53 to 55, having endothermic transitions at 158°C to 164°C and 224°C to 230°C as measured by differential scanning calorimetry.

[0369] Embodiment 57. The crystalline form of embodiment 56, wherein the endothermic transitions are 161°C ± 3°C and 227°C ± 3°C.

[0370] Embodiment 58. A crystalline form of AMG397 as the potassium salt (ethyl acetate solvate), characterized by an XRPD pattern peaks at 2.7, 11.7, and 12.2±0.2 degrees 2θ using CuKα radiation.

[0371] Embodiment 59. The crystalline form of embodiment 58, further characterized by an XRPD pattern peaks at 20.5, 20.9, 21.1, 21.6, and 22.9±0.2° 2θ using CuKα radiation.

[0372] Embodiment 60. The crystalline form of embodiment 59, further characterized by an XRPD pattern peaks at 11.2, 15.1, 15.3, 15.4, 16.1, 16.3, 16.4, 16.6, 16.8, 16.9, 17.3, 17.5, 17.9, 18.5, 18.9, 19.2, 19.5, 19.7, 21.7, 22.2, 22.5, 22.7, 23.3, 23.5, 23.9, and 24.4±0.2 degrees 2θ using CuKα radiation.

[0373] Embodiment 61. The crystalline form of any one of embodiments 58-60, having an XRPD pattern substantially as shown in FIG. 27.

[0374] Embodiment 62. The crystalline form of any one of embodiments 58-61, having endothermic transitions at 64°C to 70°C and 146°C to 152°C, as measured by differential scanning calorimetry.

[0375] Embodiment 63. The crystalline form of embodiment 62, wherein the endothermic transitions are 67°C ± 3°C and 149°C ± 3°C.

[0376] Embodiment 64. The crystalline form of any one of embodiments 58-63, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 29.

[0377] Embodiment 65. A crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 9.3, 13.9, and 19.2±0.2° 2θ using CuKα radiation.

[0378] Embodiment 66. The crystalline form of embodiment 65, further characterized by an XRPD pattern peaks of 8.7, 11.5, 17.6, and 21.9±0.2° 2θ using CuKα radiation.

[0379] Embodiment 67. The crystalline form of embodiment 65 or 66, having an XRPD pattern substantially as shown in FIG. 31.

[0380] Embodiment 68. The crystalline form of any one of embodiments 65-67, having an endothermic transition at 188°C to 194°C as measured by differential scanning calorimetry.

[0381] Embodiment 69. The crystalline form of embodiment 68, wherein the endothermic transition is 191° C.±3° C.

[0382] Embodiment 70. A crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 11.7, 17.1, and 20.1±0.2 degrees 2θ using CuKα radiation.

[0383] Embodiment 71. The crystalline form of embodiment 70, further characterized by an XRPD pattern peaks at 12.8, 15.9, and 24.1±0.2° 2θ using CuKα radiation.

[0384] Embodiment 72. The crystalline form of embodiment 70 or 71 having an XRPD pattern substantially as shown in FIG. 33.

[0385] Embodiment 73. A crystalline form of AMG397 as the sulfate salt, characterized by an XRPD pattern peaks at 12.3, 17.7, 18.4, and 20.6±0.2 degrees 2θ using CuKα radiation.

[0386] Embodiment 74. The crystalline form of embodiment 73, further characterized by an XRPD pattern peaks at 11.2, 14.0, 19.0, and 23.1±0.2° 2θ using CuKα radiation.

[0387] Embodiment 75. The crystalline form of embodiment 74, further characterized by an XRPD pattern peaks at 13.0, 15.3, 15.8, 16.7, 19.0, 21.6, 13.9, and 24.8±0.2° 2θ using CuKα radiation.

[0388] Embodiment 76. The crystalline form of any one of embodiments 73-75, having an XRPD pattern substantially as shown in FIG. 34.

[0389] Embodiment 77. The crystalline form of any one of embodiments 73 to 76, having an endothermic transition at 215°C to 221°C as measured by differential scanning calorimetry.

[0390] Embodiment 78. The crystalline form of embodiment 77, wherein the endothermic transition is 218° C.±3° C.

[0391] Embodiment 79. The crystalline form of any one of embodiments 73-78, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 36.

[0392] In the embodiments 80.5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8, 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8 and 168.8 ± 0.5 ppm 13 Crystalline form of AMG397 as the phosphate salt, characterized by C NMR peaks.

[0393] Embodiment 81. The crystalline form of embodiment 80, further characterized by an XRPD pattern peaks at 17.7, 18.6, and 18.7±0.2 degrees 2θ using CuKα radiation.

[0394] Embodiment 82. The crystalline form of embodiment 81, further characterized by an XRPD pattern peaks at 12.3, 14.0, and 20.3±0.2° 2θ using CuKα radiation.

[0395] Embodiment 83. The crystalline form of embodiment 82, further characterized by an XRPD pattern peaks at 11.1, 11.2, 12.4, 16.0, 16.1, 16.7, 16.8, 19.3, 20.7, 21.9, 22.9, 23.0, 24.7, and 24.8±0.2° 2θ using CuKα radiation.

[0396] Embodiment 84. The crystalline form of any one of embodiments 80-83, having an XRPD pattern substantially as shown in FIG. 37.

[0397] Embodiment 85. The crystalline form of any one of embodiments 80 to 84, having an endothermic transition at 207°C to 213°C as measured by differential scanning calorimetry.

[0398] Embodiment 86. The crystalline form of embodiment 85, wherein the endothermic transition is 210° C.±3° C.

[0399] Embodiment 87. The crystalline form of any one of embodiments 80-86, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 39.

[0400] Embodiment 88. A crystalline form of AMG397 as a fumarate acetone solvate, characterized by an XRPD pattern peaks at 17.6, 18.2, and 18.4±0.2 degrees 2θ using CuKα radiation.

[0401] Embodiment 89. The crystalline form of embodiment 88, further characterized by an XRPD pattern peaks at 5.3, 10.4, 12.2, 13.9, 15.8, and 24.0±0.2° 2θ using CuKα radiation.

[0402] Embodiment 90. The crystalline form of embodiment 89, further characterized by an XRPD pattern peaks at 9.7, 11.0, 12.9, 14.9, 15.5, 16.3, 16.9, 17.9, 19.2, 20.2, 20.9, 21.6, 22.8, 24.7, and 26.1±0.2° 2θ using CuKα radiation.

[0403] Embodiment 91. The crystalline form of any one of embodiments 88-90, having an XRPD pattern substantially as shown in FIG. 41.

[0404] Embodiment 92. The crystalline form of any one of embodiments 88-91, having an endothermic transition at 229° C. to 235° C. as measured by differential scanning calorimetry.

[0405] Embodiment 93. The crystalline form of embodiment 92, wherein the endothermic transition is 232° C.±3° C.

[0406] Embodiment 94. The crystalline form of any one of embodiments 88-93, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 43.

[0407] Embodiment 95. A crystalline form of AMG397 as the fumarate salt, characterized by an XRPD pattern peaks at 11.9, 17.9, and 18.1±0.2 degrees 2θ using CuKα radiation.

[0408] Embodiment 96. The crystalline form of embodiment 95, further characterized by an XRPD pattern peaks at 10.7, 13.6, 15.7, 18.6, 18.8, 19.6, and 21.5±0.2° 2θ using CuKα radiation.

[0409] Embodiment 97. The crystalline form of embodiment 96, further characterized by an XRPD pattern peaks at 10.3, 14.9, 16.3, 16.5, 20.0, 22.2, 22.6, 13.3, 13.9, 24.5, 25.5, and 28.1±0.2 degrees 2θ using CuKα radiation.

[0410] Embodiment 98. The crystalline form of any one of embodiments 95-97, having an XRPD pattern substantially as shown in FIG. 45.

[0411] Embodiment 99. The crystalline form of any one of embodiments 95-98, having an endothermic transition at 240° C. to 246° C. as measured by differential scanning calorimetry.

[0412] Embodiment 100. The crystalline form of embodiment 99, wherein the endothermic transition is 243° C.±3° C.

[0413] Embodiment 101. The crystalline form of any one of embodiments 95-100, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 47.

[0414] Embodiment 102. A crystalline form of AMG397 as the Citrate Salt, characterized by an XRPD pattern peaks at 10.6, 17.6, and 18.3±0.2 degrees 2θ using CuKα radiation.

[0415] Embodiment 103. The crystalline form of embodiment 102, further characterized by an XRPD pattern peaks at 12.1, 13.9, 16.0, 19.2, and 21.9±0.2 degrees 2θ using CuKα radiation.

[0416] Embodiment 104. The crystalline form of embodiment 103, further characterized by an XRPD pattern peaks at 6.1, 11.0, 12.8, 15.2, 16.9, 19.5, 20.0, 20.5, 21.1, 22.9, 24.4, 24.7, 25.9 and 28.7±0.2° 2θ using CuKα radiation.

[0417] Embodiment 105. The crystalline form of any one of embodiments 102-104, having an XRPD pattern substantially as shown in FIG. 49.

[0418] Embodiment 106. The crystalline form of any one of embodiments 102 to 105, having an endothermic transition at 211° C. to 217° C. as measured by differential scanning calorimetry.

[0419] Embodiment 107. The crystalline form of embodiment 106, wherein the endothermic transition is 214°C ± 3°C.

[0420] Embodiment 108. The crystalline form of any one of embodiments 102-107, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 51.

[0421] Embodiment 109. A crystalline form of AMG397 as the Citrate Salt, characterized by an XRPD pattern peaks of 17.7, 18.4, and 18.5±0.2° 2θ using CuKα radiation.

[0422] Embodiment 110. The crystalline form of embodiment 109, further characterized by an XRPD pattern peaks at 14.0, 16.0, 20.1, and 21.9±0.2 degrees 2θ using CuKα radiation.

[0423] Embodiment 111. The crystalline form of embodiment 110, further characterized by an XRPD pattern peaks at 10.7, 11.1, 12.2, 12.9, 15.2, 19.3, 20.6, 22.9, 24.4, and 24.8±0.2° 2θ using CuKα radiation.

[0424] Embodiment 112. The crystalline form of any one of embodiments 109-111, having an XRPD pattern substantially as shown in FIG. 52.

[0425] Embodiment 113. The crystalline form of any one of embodiments 109 to 112, having an endothermic transition at 203°C to 209°C as measured by differential scanning calorimetry.

[0426] Embodiment 114. The crystalline form of embodiment 113, wherein the endothermic transition is 206° C.±3° C.

[0427] Embodiment 115. The crystalline form of any one of embodiments 109-114, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 54.

[0428] Embodiment 116. A crystalline form of AMG397 as the Lactate Salt, characterized by an XRPD pattern peaks of 12.1, 17.8, and 18.3±0.2° 2θ using CuKα radiation.

[0429] Embodiment 117. The crystalline form of embodiment 116, further characterized by an XRPD pattern peaks at 10.5, 10.9, 13.8, 17.5, and 20.0±0.2° 2θ using CuKα radiation.

[0430] Embodiment 118. The crystalline form of embodiment 117, further characterized by an XRPD pattern peaks at 5.9, 12.8, 15.9, 16.2, 19.1, 20.4, 21.7, 23.9, 24.6, and 25.1±0.2° 2θ using CuKα radiation.

[0431] Embodiment 119. The crystalline form of any one of embodiments 116-118, having an XRPD pattern substantially as shown in FIG. 57.

[0432] Embodiment 120. The crystalline form of any one of embodiments 116 to 119, having an endothermic transition at 216°C to 222°C as measured by differential scanning calorimetry.

[0433] Embodiment 121. The crystalline form of embodiment 120, wherein the endothermic transition is 219°C ± 3°C.

[0434] Embodiment 122. The crystalline form of any one of embodiments 116-121, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 59.

[0435] Embodiment 123. A crystalline form of AMG397 as the succinate salt, characterized by an XRPD pattern peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation.

[0436] Embodiment 124. The crystalline form of embodiment 123, further characterized by an XRPD pattern peaks at 12.2, 13.9, 18.0, 20.3, and 24.5±0.2° 2θ using CuKα radiation.

[0437] Embodiment 125. The crystalline form of embodiment 124, further characterized by an XRPD pattern peaks at 5.2, 10.4, 10.7, 11.1, 12.9, 15.2, 15.8, 16.7, 19.1, 21.6, 22.2, 22.8, 23.9, 26.2, 28.3, and 29.2±0.2 degrees 2θ using CuKα radiation.

[0438] Embodiment 126. The crystalline form of any one of embodiments 123-125, having an XRPD pattern substantially as shown in FIG. 61.

[0439] Embodiment 127. The crystalline form of any one of embodiments 123 to 126, having an endothermic transition at 207°C to 213°C as measured by differential scanning calorimetry.

[0440] Embodiment 128. The crystalline form of embodiment 127, wherein the endothermic transition is 210°C ± 3°C.

[0441] Embodiment 129. The crystalline form of any one of embodiments 123-128, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 63.

[0442] Embodiment 130. A crystalline form of AMG397 as the ammonium salt, characterized by an XRPD pattern peaks at 6.2, 10.3, and 17.2±0.2 degrees 2θ using CuKα radiation.

[0443] Embodiment 131. The crystalline form of embodiment 130, further characterized by an XRPD pattern peaks at 4.0, 4.7, 17.3, 17.9, 19.8, and 20.3±0.2° 2θ using CuKα radiation.

[0444] Embodiment 132. The crystalline form of embodiment 131, further characterized by an XRPD pattern peaks at 13.0, 14.4, 15.1, 15.5, 15.9, 16.2, 16.4, 17.7, 18.6, 19.7, and 22.8±0.2° 2θ using CuKα radiation.

[0445] Embodiment 133. The crystalline form of any one of embodiments 130-132, having an XRPD pattern substantially as shown in FIG. 65.

[0446] Embodiment 134. The crystalline form of any one of embodiments 130 to 133, having an endothermic transition at 224°C to 230°C as measured by differential scanning calorimetry.

[0447] Embodiment 135. The crystalline form of embodiment 134, wherein the endothermic transition is 227°C ± 3°C.

[0448] Embodiment 136. The crystalline form of any one of embodiments 130-135, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 67.

[0449] Embodiment 137. A crystalline form of AMG397 as the besylate salt, characterized by an XRPD pattern peaks at 17.6, 18.4, and 18.7±0.2 degrees 2θ using CuKα radiation.

[0450] Embodiment 138. The crystalline form of embodiment 137, further characterized by an XRPD pattern peaks at 14.0, 17.7, and 20.4±0.2° 2θ using CuKα radiation.

[0451] Embodiment 139. The crystalline form of embodiment 138, further characterized by an XRPD pattern peaks at 11.2, 12.4, 13.8, 14.1, 15.9, 16.1, 18.0, 19.3, 20.8, 21.7, 22.9, 23.9 and 24.5±0.2° 2θ using CuKα radiation.

[0452] Embodiment 140. The crystalline form of any one of embodiments 137-139, having an XRPD pattern substantially as shown in FIG. 68.

[0453] Embodiment 141. The crystalline form of any one of embodiments 137 to 140, having endothermic transitions at 54°C to 60°C and 231°C to 237°C, as measured by differential scanning calorimetry.

[0454] Embodiment 142. The crystalline form of embodiment 141, wherein the endothermic transitions are 57°C ± 3°C and 234°C ± 3°C.

[0455] Embodiment 143. The crystalline form of any one of embodiments 137-142, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 70.

[0456] Embodiment 144. A crystalline form of AMG397 as the tosylate salt, characterized by an XRPD pattern peaks at 18.2, 18.4, and 20.5±0.2 degrees 2θ using CuKα radiation.

[0457] Embodiment 145. The crystalline form of embodiment 144, further characterized by an XRPD pattern peaks at 12.2, 12.3, 17.6, 18.9, and 19.1±0.2 degrees 2θ using CuKα radiation.

[0458] Embodiment 146. The crystalline form of embodiment 145, further characterized by an XRPD pattern peaks at 4.5, 5.2, 13.0, 13.8, 14.0, 15.2, 15.8, 16.2, 16.4, 19.8, 20.0, 21.4, 22.9, 23.4, 23.6, 23.8, 24.3, 24.6, 25.1, and 27.1±0.2° 2θ using CuKα radiation.

[0459] Embodiment 147. The crystalline form of any one of embodiments 144-146, having an XRPD pattern substantially as shown in FIG. 72.

[0460] Embodiment 148. The crystalline form of any one of embodiments 144 to 147, having endothermic transitions at 37°C to 43°C and 223°C to 229°C, as measured by differential scanning calorimetry.

[0461] Embodiment 149. The crystalline form of embodiment 148, wherein the endothermic transitions are 40°C ± 3°C and 226°C ± 3°C.

[0462] Embodiment 150. The crystalline form of any one of embodiments 144-149, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 74.

[0463] Embodiment 151. A crystalline form of AMG397 as the maleate salt, characterized by an XRPD pattern peaks at 18.2, 18.9, and 19.9±0.2 degrees 2θ using CuKα radiation.

[0464] Embodiment 152. The crystalline form of embodiment 151, further characterized by an XRPD pattern peaks at 10.4, 10.9, 12.0, and 21.5±0.2 degrees 2θ using CuKα radiation.

[0465] Embodiment 153. The crystalline form of embodiment 152, further characterized by an XRPD pattern peaks at 10.3, 13.8, 15.8, 17.9, 19.2, and 24.2±0.2 degrees 2θ using CuKα radiation.

[0466] Embodiment 154. The crystalline form of any one of embodiments 151-153, having an XRPD pattern substantially as shown in FIG. 76.

[0467] Embodiment 155. The crystalline form of any one of embodiments 151 to 154, having an endothermic transition at 219°C to 225°C as measured by differential scanning calorimetry.

[0468] Embodiment 156. The crystalline form of embodiment 155, wherein the endothermic transition is 222°C ± 3°C.

[0469] Embodiment 157. The crystalline form of any one of embodiments 151-156, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 78.

[0470] Embodiment 158. A crystalline form of AMG397 as the maleate salt, characterized by an XRPD pattern peaks at 10.6, 18.6, and 20.3±0.2 degrees 2θ using CuKα radiation.

[0471] Embodiment 159. The crystalline form of embodiment 158, further characterized by an XRPD pattern peaks at 10.8, 12.3, 15.2, 15.9, and 16.7±0.2 degrees 2θ using CuKα radiation.

[0472] Embodiment 160. The crystalline form of embodiment 159, further characterized by an XRPD pattern peaks at 9.8, 11.1, 13.9, 14.1, 18.0, 18.4, 19.2, 19.4, 20.8, 22.3, 23.0, 23.6, 24.6, and 28.4±0.2° 2θ using CuKα radiation.

[0473] Embodiment 161. The crystalline form of any one of embodiments 158-160, having an XRPD pattern substantially as shown in FIG. 79.

[0474] Embodiment 162. A crystalline form of AMG397 as the malonate salt, characterized by an XRPD pattern peaks at 12.2, 18.8, and 20.4±0.2 degrees 2θ using CuKα radiation.

[0475] Embodiment 163. The crystalline form of embodiment 162, further characterized by an XRPD pattern peaks at 10.3, 11.1, 17.9, 18.3, and 19.1±0.2 degrees 2θ using CuKα radiation.

[0476] Embodiment 164. The crystalline form of embodiment 163, further characterized by an XRPD pattern peaks at 10.7, 13.9, 14.0, 15.8, 16.5, 18.4, 19.5, 19.7 21.6, 21.7, 22.8 and 24.5±0.2° 2θ using CuKα radiation.

[0477] Embodiment 165. The crystalline form of any one of embodiments 162-164, having an XRPD pattern substantially as shown in FIG. 82.

[0478] Embodiment 166. The crystalline form of any one of embodiments 162 to 165, having endothermic transitions at 158°C to 164°C and 184°C to 190°C, as measured by differential scanning calorimetry.

[0479] Embodiment 167. The crystalline form of embodiment 166, wherein the endothermic transitions are 161°C ± 3°C and 187°C ± 3°C.

[0480] Embodiment 168. The crystalline form of any one of embodiments 162-167, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 84.

[0481] Embodiment 169. A crystalline form of AMG397 as the malonate salt, characterized by an XRPD pattern peaks at 10.6, 18.5, and 20.2±0.2 degrees 2θ using CuKα radiation.

[0482] Embodiment 170. The crystalline form of embodiment 169, further characterized by an XRPD pattern peaks at 11.0, 14.0, and 17.9±0.2° 2θ using CuKα radiation.

[0483] Embodiment 171. The crystalline form of embodiment 170, further characterized by an XRPD pattern peaks at 11.1, 12.3, 15.3, 16.1, 16.8, 17.0, 18.6, 19.4, and 22.2±0.2° 2θ using CuKα radiation.

[0484] Embodiment 172. The crystalline form of any one of embodiments 169-171, having an XRPD pattern substantially as shown in FIG. 85.

[0485] Embodiment 173. A crystalline form of AMG397 as the tartrate salt, characterized by an XRPD pattern peaks at 18.2, 18.6 and 20.2±0.2 degrees 2θ using CuKα radiation.

[0486] Embodiment 174. The crystalline form of embodiment 173, further characterized by an XRPD pattern peaks at 12.1, 17.8, 19.0, and 21.5±0.2° 2θ using CuKα radiation.

[0487] Embodiment 175. The crystalline form of embodiment 174, further characterized by an XRPD pattern peaks at 10.6, 11.0, 12.8, 13.8, 15.1, 15.8, 16.4, 16.6, 17.4, 19.3, 19.5, 20.6, 22.1, 22.6, 23.5 and 24.4±0.2° 2θ using CuKα radiation.

[0488] Embodiment 176. The crystalline form of any one of embodiments 173-175, having an XRPD pattern substantially as shown in FIG. 87.

[0489] Embodiment 177. The crystalline form of any one of embodiments 173 to 176, having an endothermic transition at 224°C to 230°C as measured by differential scanning calorimetry.

[0490] Embodiment 178. The crystalline form of embodiment 177, wherein the endothermic transition is 227°C ± 3°C.

[0491] Embodiment 179. The crystalline form of any one of embodiments 173-178, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 89.

[0492] Embodiment 180. A crystalline form of AMG397 as a tris(hydroxymethyl)aminomethane salt acetone solvate, characterized by an XRPD pattern peaks at 10.0, 16.8, and 20.0±0.2 degrees 2θ using CuKα radiation.

[0493] Embodiment 181. The crystalline form of embodiment 180, further characterized by an XRPD pattern peaks at 12.7, 14.1, and 18.2±0.2 degrees 2θ using CuKα radiation.

[0494] Embodiment 182. The crystalline form of embodiment 181, further characterized by an XRPD pattern peaks at 6.1, 14.9, 15.3, 16.0, 17.3, 17.6, 18.0, 19.0, 19.1, 19.4, 20.6, 22.1, 22.5, 22.7, 22.9, 26.3, and 26.4±0.2° 2θ using CuKα radiation.

[0495] Embodiment 183. The crystalline form of any one of embodiments 180-182, having an XRPD pattern substantially as shown in FIG. 90.

[0496] Embodiment 184. The crystalline form of any one of embodiments 180 to 183, having endothermic transitions at 56°C to 62°C and 131°C to 137°C, as measured by differential scanning calorimetry.

[0497] Embodiment 185. The crystalline form of embodiment 184, wherein the endothermic transitions are 59°C ± 3°C and 134°C ± 3°C.

[0498] Embodiment 186. The crystalline form of any one of embodiments 180-185, having a thermogravimetric analysis ("TGA") substantially as shown in FIG. 92.

[0499] Embodiment 187. A crystalline form of AMG397 as the iodide salt, characterized by an XRPD pattern peaks at 17.0, 18.0, and 18.1±0.2 degrees 2θ using CuKα radiation.

[0500] Embodiment 188. The crystalline form of embodiment 187, further characterized by an XRPD pattern peaks at 8.3, 11.0, 18.6, 18.8, 19.1, 20.0, 22.1, 23.5, and 24.7±0.2° 2θ using CuKα radiation.

[0501] Embodiment 189. The crystalline form of embodiment 188, further characterized by an XRPD pattern peaks at 6.2, 10.6, 10.8, 12.4, 13.0, 14.1, 15.5, 17.6, 22.5, 24.1, 28.6, 28.8, 29.0, and 29.5±0.2° 2θ using CuKα radiation.

[0502] Embodiment 190. The crystalline form of any one of embodiments 187-189, having an XRPD pattern substantially as shown in FIG. 93.

[0503] Embodiment 191. The crystalline form of any one of embodiments 187 to 190, having an endothermic transition at 228°C to 234°C as measured by differential scanning calorimetry.

[0504] Embodiment 192. The crystalline form of embodiment 191, wherein the endothermic transition is 231° C.±3° C.

[0505] Embodiment 193. A pharmaceutical formulation comprising a crystalline form according to any one of embodiments 1 to 192 and a pharma- ceutically acceptable excipient.

[0506] Embodiment 194. 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 192 or a pharmaceutical formulation according to embodiment 193.

[0507] Embodiment 195. The method of embodiment 194, wherein the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

Claims

1. A crystalline form of AMG397 as a trifluoroethanol solvate, characterized by XRPD pattern peaks at 17.5, 19.2, 19.4 and 21.7±0.2° 2θ using CuKα radiation.

2. 10. The crystalline form of claim 1, further characterized by XRPD pattern peaks at 14.6, 17.2, 18.4, 18.5, 18.8, 20.0, 20.2, 20.4, 21.0, 21.2, and 21.5±0.2 degrees 2θ using CuKα radiation.

3. 3. The crystalline form of claim 2, further characterized by XRPD pattern peaks at 6.7, 10.3, 12.5, 13.5, 13.8, 17.7, 17.8, 18.1, 21.9, 22.3, 22.4, and 22.9±0.2 degrees 2θ using CuKα radiation.

4. 4. The crystalline form of any one of claims 1 to 3, having an XRPD pattern substantially as shown in Figure 1.

5. A crystalline form of AMG397 as a hexafluoroisopropanol solvate, characterized by XRPD pattern peaks at 11.4, 18.6, and 18.8±0.2° 2θ using CuKα radiation.

6. 6. The crystalline form of claim 5, further characterized by XRPD pattern peaks at 8.5, 12.8, 17.1, 17.6, 21.1, 22.4, and 23.1±0.2 degrees 2θ using CuKα radiation.

7. 7. The crystalline form of claim 6, further characterized by XRPD pattern peaks at 6.1, 13.6, 15.3, 15.7, 16.2, 16.4, 16.5, 17.4, 17.8, 18.0, 18.1, 19.4, 20.6, 21.5, 21.7, 22.2, and 25.4±0.2 degrees 2θ using CuKα radiation.

8. 8. The crystalline form of any one of claims 5 to 7, having an XRPD pattern substantially as shown in Figure 2.

9. A crystalline form of AMG397 as a 1-propanol solvate, characterized by XRPD pattern peaks at 13.3, 15.1, and 18.5±0.2° 2θ using CuKα radiation.

10. 10. The crystalline form of claim 9, further characterized by XRPD pattern peaks at 8.1, 9.7, 15.7, 16.4, 17.2, and 17.7±0.2 degrees 2θ using CuKα radiation.

11. 11. The crystalline form of claim 10, further characterized by XRPD pattern peaks at 12.0, 12.7, 14.2, 14.8, 17.1, 18.2, 19.1, 19.5, 20.7, 21.2, 21.6, 21.7, 22.1, 22.3, 22.4, 22.8, 23.5, 23.8, 23.9, and 25.5±0.2 degrees 2θ using CuKα radiation.

12. 12. The crystalline form of any one of claims 9 to 11, having an XRPD pattern substantially as shown in Figure 3.

13. 10. The crystalline form of claim 9, having an endothermic transition at 231°C to 237°C as measured by differential scanning calorimetry.

14. 14. The crystalline form of claim 13, wherein the endothermic transition is at 234°C ± 3°C.

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

16. A crystalline form of AMG397 as an isopropanol solvate, characterized by XRPD pattern peaks at 6.1, 7.1, and 10.0±0.2° 2θ using CuKα radiation.

17. 17. The crystalline form of claim 16, further characterized by XRPD pattern peaks at 18.5, 19.0, 19.7, and 20.4±0.2 degrees 2θ using CuKα radiation.

18. 18. The crystalline form of claim 17, further characterized by XRPD pattern peaks at 10.5, 13.6, 14.5, 15.0, 15.3, 15.9, 16.2, 16.6, 16.7, 16.9, 17.7, 17.9, 18.4, 19.5, 20.7, 21.6, 23.1, and 25.7±0.2 degrees 2θ using CuKα radiation.

19. 19. The crystalline form of any one of claims 16 to 18, having an XRPD pattern substantially as shown in Figure 6.

20. 17. The crystalline form of claim 16, having an endothermic transition at 244°C to 250°C as measured by differential scanning calorimetry.

21. 21. The crystalline form of claim 20, wherein the endothermic transition is at 247°C ± 3°C.

22. 17. The crystalline form of claim 16, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 8.

23. A crystalline form of AMG397 as an isopropanol solvate, characterized by XRPD pattern peaks at 13.3, 15.1, and 18.6±0.2° 2θ using CuKα radiation.

24. 24. The crystalline form of claim 23, further characterized by XRPD pattern peaks at 8.1, 9.7, 16.4, and 17.7±0.2 degrees 2θ using CuKα radiation.

25. 25. The crystalline form of claim 24, further characterized by XRPD pattern peaks at 12.0, 12.6, 14.2, 14.8, 15.7, 17.1, 17.2, 18.2, 19.1, 19.5, 21.5, 21.6, 22.3, 22.4, and 23.8±0.2 degrees 2θ using CuKα radiation.

26. 26. The crystalline form of any one of claims 23 to 25, having an XRPD pattern substantially as shown in Figure 9.

27. 24. The crystalline form of claim 23, having endothermic transitions at 80°C to 86°C and 236°C to 242°C as measured by differential scanning calorimetry.

28. 28. The crystalline form of claim 27, wherein the endothermic transitions are at 83°C ± 3°C and 239°C ± 3°C.

29. 24. The crystalline form of claim 23, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 11.

30. A crystalline form of AMG397 as an acetonitrile solvate, characterized by XRPD pattern peaks at 10.2, 17.0, and 20.5±0.2° 2θ using CuKα radiation.

31. 31. The crystalline form of claim 30, further characterized by XRPD pattern peaks at 6.0, 13.0, 14.3, 15.2, 18.6, and 23.0±0.2 degrees 2θ using CuKα radiation.

32. 32. The crystalline form of claim 31 , further characterized by XRPD pattern peaks at 10.9, 15.6, 17.2, 18.2, 19.2, 21.0, 21.4, 22.1, 22.3, 22.5, 23.4, 24.8, 25.2, 25.6, 26.1, 26.5, 26.7, and 26.8±0.2 degrees 2θ using CuKα radiation.

33. 33. The crystalline form of any one of claims 30 to 32, having an XRPD pattern substantially as shown in Figure 12.

34. 13.63, 19.22, 20.40, 24.22, 25.69, 26.57, 27.75, 29.81, 30.40, 31.28, 36.57, 38.34, 40.10, 43.04, 49.51, 50.10, 51.86, 54.51, 56.28, 57.16, 57.75 , 60.10, 62.16, 65.39, 77.75, 85.10, 115.39, 123.63, 125.10, 128.04, 131.27, 133.04, 133.92, 135.98, 139.80, 141.27, 143.04, 151.86 and 173.92 ± 0.5 ppm solids １３ A crystalline form of AMG397 as an acetic acid solvate, characterized by a C NMR peak.

35. 35. The crystalline form of claim 34, further characterized by XRPD pattern peaks at 11.1, 17.1, 18.2, and 19.1±0.2 degrees 2θ using CuKα radiation.

36. 36. The crystalline form of claim 35, further characterized by XRPD pattern peaks at 10.7, 10.9, 11.5, 13.7, 14.3, 18.8, 20.1, and 24.8±0.2 degrees 2θ using CuKα radiation.

37. 37. The crystalline form of claim 36, further characterized by XRPD pattern peaks at 8.4, 12.4, 12.7, 15.6, 16.5, 17.6, 19.3, 22.2, 23.6, 24.0, 24.6, and 29.0±0.2 degrees 2θ using CuKα radiation.

38. 38. The crystalline form of any one of claims 34 to 37, having an XRPD pattern substantially as shown in Figure 13.

39. 35. The crystalline form of claim 34, having endothermic transitions at 92°C to 98°C and 152°C to 158°C as measured by differential scanning calorimetry.

40. 40. The crystalline form of claim 39, wherein the endothermic transitions are at 95°C ± 3°C and 155°C ± 3°C.

41. 35. The crystalline form of claim 34, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 15.

42. A crystalline form of AMG397 as the hydrochloride salt, characterized by XRPD pattern peaks at 12.9, 16.2, and 17.9±0.2° 2θ using CuKα radiation.

43. 43. The crystalline form of claim 42, further characterized by XRPD pattern peaks at 11.7, 12.0, 15.9, 19.8, and 20.5±0.2 degrees 2θ using CuKα radiation.

44. 44. The crystalline form of claim 43, further characterized by XRPD pattern peaks at 10.7, 13.5, 14.4, 14.6, 15.5, 18.1, 22.8, 23.7, 24.6, 25.1, and 26.5±0.2 degrees 2θ using CuKα radiation.

45. 45. The crystalline form of any one of claims 42 to 44, having an XRPD pattern substantially as shown in Figure 17.

46. 43. The crystalline form of claim 42, having an endothermic transition at 264°C to 270°C as measured by differential scanning calorimetry.

47. 47. The crystalline form of claim 46, wherein the endothermic transition is 267°C ± 3°C.

48. 43. The crystalline form of claim 42, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 19.

49. An amorphous form of AMG397 as the sodium salt, having an XRPD pattern substantially as shown in FIG.

21.

50. 50. The amorphous form of claim 49, having an endothermic transition at 213°C to 219°C as measured by differential scanning calorimetry.

51. 51. The amorphous form of claim 50, wherein the endothermic transition is 216°C ± 3°C.

52. 52. The amorphous form of any one of claims 49-51, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 23.

53. A crystalline form of AMG397 as the potassium salt, characterized by XRPD pattern peaks at 12.8, 13.4 and 17.2±0.2° 2θ using CuKα radiation.

54. 54. The crystalline form of claim 53, further characterized by XRPD pattern peaks at 11.0, 11.4, 14.5, 15.7, and 19.2±0.2 degrees 2θ using CuKα radiation.

55. 55. The crystalline form of claim 53 or 54, having an XRPD pattern substantially as shown in Figure 25.

56. 54. The crystalline form of claim 53, having endothermic transitions at 158°C to 164°C and 224°C to 230°C as measured by differential scanning calorimetry.

57. 57. The crystalline form of claim 56, wherein the endothermic transitions are at 161°C ± 3°C and 227°C ± 3°C.

58. A crystalline form of AMG397 as the potassium salt (ethyl acetate solvate), characterized by XRPD pattern peaks at 2.7, 11.7, and 12.2±0.2° 2θ using CuKα radiation.

59. 59. The crystalline form of claim 58, further characterized by XRPD pattern peaks at 20.5, 20.9, 21.1, 21.6, and 22.9±0.2 degrees 2θ using CuKα radiation.

60. 60. The crystalline form of claim 59, further characterized by XRPD pattern peaks at 11.2, 15.1, 15.3, 15.4, 16.1, 16.3, 16.4, 16.6, 16.8, 16.9, 17.3, 17.5, 17.9, 18.5, 18.9, 19.2, 19.5, 19.7, 21.7, 22.2, 22.5, 22.7, 23.3, 23.5, 23.9, and 24.4±0.2 degrees 2θ using CuKα radiation.

61. 61. The crystalline form of any one of claims 58-60, having an XRPD pattern substantially as shown in Figure 27.

62. 59. The crystalline form of claim 58, having endothermic transitions at 64°C to 70°C and 146°C to 152°C as measured by differential scanning calorimetry.

63. 63. The crystalline form of claim 62, wherein the endothermic transitions are at 67°C ± 3°C and 149°C ± 3°C.

64. 59. The crystalline form of claim 58, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 29.

65. A crystalline form of AMG397 as the sulfate salt, characterized by XRPD pattern peaks at 9.3, 13.9 and 19.2±0.2° 2θ using CuKα radiation.

66. 66. The crystalline form of claim 65, further characterized by XRPD pattern peaks at 8.7, 11.5, 17.6, and 21.9±0.2 degrees 2θ using CuKα radiation.

67. 67. The crystalline form of claim 65 or 66, having an XRPD pattern substantially as shown in Figure 31.

68. 66. The crystalline form of claim 65, having an endothermic transition at 188°C to 194°C as measured by differential scanning calorimetry.

69. 69. The crystalline form of claim 68, wherein the endothermic transition is 191°C ± 3°C.

70. A crystalline form of AMG397 as the sulfate salt, characterized by XRPD pattern peaks at 11.7, 17.1 and 20.1±0.2° 2θ using CuKα radiation.

71. 71. The crystalline form of claim 70, further characterized by XRPD pattern peaks at 12.8, 15.9, and 24.1±0.2 degrees 2θ using CuKα radiation.

72. 72. The crystalline form of claim 70 or 71, having an XRPD pattern substantially as shown in Figure 33.

73. A crystalline form of AMG397 as the sulfate salt, characterized by XRPD pattern peaks at 12.3, 17.7, 18.4 and 20.6±0.2° 2θ using CuKα radiation.

74. 74. The crystalline form of claim 73, further characterized by XRPD pattern peaks at 11.2, 14.0, 19.0, and 23.1±0.2 degrees 2θ using CuKα radiation.

75. 75. The crystalline form of claim 74, further characterized by XRPD pattern peaks at 13.0, 15.3, 15.8, 16.7, 19.0, 21.6, 13.9, and 24.8±0.2 degrees 2θ using CuKα radiation.

76. 76. The crystalline form of any one of claims 73 to 75, having an XRPD pattern substantially as shown in Figure 34.

77. 74. The crystalline form of claim 73, having an endothermic transition at 215°C to 221°C as measured by differential scanning calorimetry.

78. 78. The crystalline form of claim 77, wherein the endothermic transition is 218°C ± 3°C.

79. 74. The crystalline form of claim 73, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 36.

80. 5.8, 15.0, 18.3, 21.2, 22.2, 23.6, 27.6, 27.6, 29.3, 31.7, 31.9, 35.7, 41.3, 43.6, 49.9, 51.7, 53.3, 53.7, 55.8, 57.7, 58.8, 58.9, 59.8, 61.0, 79.6, 80.9, 115.4, 117.3, 119.1, 126.0, 127.9, 128.7, 129.4, 129.5, 130.2, 139.2, 139.8, 139.9, 150.8 and 168.8±0.5 ppm １３ Crystalline form of AMG397 as the phosphate salt, characterized by C NMR peaks.

81. 81. The crystalline form of claim 80, further characterized by XRPD pattern peaks at 17.7, 18.6, and 18.7±0.2 degrees 2θ using CuKα radiation.

82. 82. The crystalline form of claim 81, further characterized by XRPD pattern peaks at 12.3, 14.0, and 20.3±0.2 degrees 2θ using CuKα radiation.

83. 83. The crystalline form of claim 82, further characterized by XRPD pattern peaks at 11.1, 11.2, 12.4, 16.0, 16.1, 16.7, 16.8, 19.3, 20.7, 21.9, 22.9, 23.0, 24.7, and 24.8±0.2 degrees 2θ using CuKα radiation.

84. 84. The crystalline form of any one of claims 80-83, having an XRPD pattern substantially as shown in Figure 37.

85. 81. The crystalline form of claim 80, having an endothermic transition at 207°C to 213°C as measured by differential scanning calorimetry.

86. 86. The crystalline form of claim 85, wherein the endothermic transition is at 210°C ± 3°C.

87. 81. The crystalline form of claim 80, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 39.

88. A crystalline form of AMG397 as a fumarate acetone solvate, characterized by XRPD pattern peaks at 17.6, 18.2, and 18.4±0.2° 2θ using CuKα radiation.

89. 90. The crystalline form of claim 88, further characterized by XRPD pattern peaks at 5.3, 10.4, 12.2, 13.9, 15.8, and 24.0±0.2 degrees 2θ using CuKα radiation.

90. 90. The crystalline form of claim 89, further characterized by XRPD pattern peaks at 9.7, 11.0, 12.9, 14.9, 15.5, 16.3, 16.9, 17.9, 19.2, 20.2, 20.9, 21.6, 22.8, 24.7, and 26.1±0.2 degrees 2θ using CuKα radiation.

91. 91. The crystalline form of any one of claims 88-90, having an XRPD pattern substantially as shown in Figure 41.

92. 89. The crystalline form of claim 88, having an endothermic transition at 229°C to 235°C as measured by differential scanning calorimetry.

93. 93. The crystalline form of claim 92, wherein the endothermic transition is at 232°C ± 3°C.

94. 89. The crystalline form of claim 88, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 43.

95. A crystalline form of AMG397 as the fumarate salt, characterized by XRPD pattern peaks at 11.9, 17.9 and 18.1±0.2° 2θ using CuKα radiation.

96. 96. The crystalline form of claim 95, further characterized by XRPD pattern peaks at 10.7, 13.6, 15.7, 18.6, 18.8, 19.6, and 21.5±0.2 degrees 2θ using CuKα radiation.

97. 97. The crystalline form of claim 96, further characterized by XRPD pattern peaks at 10.3, 14.9, 16.3, 16.5, 20.0, 22.2, 22.6, 13.3, 13.9, 24.5, 25.5, and 28.1±0.2 degrees 2θ using CuKα radiation.

98. 98. The crystalline form of any one of claims 95-97, having an XRPD pattern substantially as shown in Figure 45.

99. 96. The crystalline form of claim 95, having an endothermic transition at 240°C to 246°C as measured by differential scanning calorimetry.

100. 100. The crystalline form of claim 99, wherein the endothermic transition is 243°C ± 3°C.

101. 96. The crystalline form of claim 95, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 47.

102. A crystalline form of AMG397 as the citrate salt, characterized by XRPD pattern peaks at 10.6, 17.6, and 18.3±0.2° 2θ using CuKα radiation.

103. 103. The crystalline form of claim 102, further characterized by XRPD pattern peaks at 12.1, 13.9, 16.0, 19.2, and 21.9±0.2 degrees 2θ using CuKα radiation.

104. 104. The crystalline form of claim 103, further characterized by XRPD pattern peaks at 6.1, 11.0, 12.8, 15.2, 16.9, 19.5, 20.0, 20.5, 21.1, 22.9, 24.4, 24.7, 25.9, and 28.7±0.2 degrees 2θ using CuKα radiation.

105. 105. The crystalline form of any one of claims 102-104, having an XRPD pattern substantially as shown in Figure 49.

106. 103. The crystalline form of claim 102, having an endothermic transition at 211°C to 217°C as measured by differential scanning calorimetry.

107. 107. The crystalline form of claim 106, wherein the endothermic transition is 214°C ± 3°C.

108. 103. The crystalline form of claim 102, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 51.

109. A crystalline form of AMG397 as the citrate salt, characterized by XRPD pattern peaks at 17.7, 18.4 and 18.5±0.2° 2θ using CuKα radiation.

110. 110. The crystalline form of claim 109, further characterized by XRPD pattern peaks at 14.0, 16.0, 20.1, and 21.9±0.2 degrees 2θ using CuKα radiation.

111. 111. The crystalline form of claim 110, further characterized by XRPD pattern peaks at 10.7, 11.1, 12.2, 12.9, 15.2, 19.3, 20.6, 22.9, 24.4, and 24.8±0.2 degrees 2θ using CuKα radiation.

112. 112. The crystalline form of any one of claims 109 to 111, having an XRPD pattern substantially as shown in Figure 52.

113. 110. The crystalline form of claim 109, having an endothermic transition at 203°C to 209°C as measured by differential scanning calorimetry.

114. 114. The crystalline form of claim 113, wherein the endothermic transition is 206°C ± 3°C.

115. 110. The crystalline form of claim 109, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 54.

116. A crystalline form of AMG397 as the lactate salt, characterized by XRPD pattern peaks at 12.1, 17.8, and 18.3±0.2° 2θ using CuKα radiation.

117. 117. The crystalline form of claim 116, further characterized by XRPD pattern peaks at 10.5, 10.9, 13.8, 17.5, and 20.0±0.2 degrees 2θ using CuKα radiation.

118. 118. The crystalline form of claim 117, further characterized by XRPD pattern peaks at 5.9, 12.8, 15.9, 16.2, 19.1, 20.4, 21.7, 23.9, 24.6, and 25.1±0.2 degrees 2θ using CuKα radiation.

119. 119. The crystalline form of any one of claims 116-118, having an XRPD pattern substantially as shown in Figure 57.

120. 117. The crystalline form of claim 116, having an endothermic transition at 216°C to 222°C as measured by differential scanning calorimetry.

121. 121. The crystalline form of claim 120, wherein the endothermic transition is 219°C ± 3°C.

122. 117. The crystalline form of claim 116, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 59.

123. A crystalline form of AMG397 as the succinate salt, characterized by XRPD pattern peaks at 17.6, 18.4 and 18.7±0.2° 2θ using CuKα radiation.

124. 124. The crystalline form of claim 123, further characterized by XRPD pattern peaks at 12.2, 13.9, 18.0, 20.3, and 24.5±0.2 degrees 2θ using CuKα radiation.

125. 125. The crystalline form of claim 124, further characterized by XRPD pattern peaks at 5.2, 10.4, 10.7, 11.1, 12.9, 15.2, 15.8, 16.7, 19.1, 21.6, 22.2, 22.8, 23.9, 26.2, 28.3, and 29.2±0.2 degrees 2θ using CuKα radiation.

126. 126. The crystalline form of any one of claims 123-125, having an XRPD pattern substantially as shown in Figure 61.

127. 124. The crystalline form of claim 123, having an endothermic transition at 207°C to 213°C as measured by differential scanning calorimetry.

128. 128. The crystalline form of claim 127, wherein the endothermic transition is at 210°C ± 3°C.

129. 124. The crystalline form of claim 123, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 63.

130. A crystalline form of AMG397 as the ammonium salt, characterized by XRPD pattern peaks at 6.2, 10.3, and 17.2±0.2° 2θ using CuKα radiation.

131. 131. The crystalline form of claim 130, further characterized by XRPD pattern peaks at 4.0, 4.7, 17.3, 17.9, 19.8, and 20.3±0.2 degrees 2θ using CuKα radiation.

132. 132. The crystalline form of claim 131, further characterized by XRPD pattern peaks at 13.0, 14.4, 15.1, 15.5, 15.9, 16.2, 16.4, 17.7, 18.6, 19.7, and 22.8±0.2 degrees 2θ using CuKα radiation.

133. 133. The crystalline form of any one of claims 130-132, having an XRPD pattern substantially as shown in Figure 65.

134. 131. The crystalline form of claim 130, having an endothermic transition at 224°C to 230°C as measured by differential scanning calorimetry.

135. 135. The crystalline form of claim 134, wherein the endothermic transition is 227°C ± 3°C.

136. 131. The crystalline form of claim 130, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 67.

137. A crystalline form of AMG397 as the besylate salt, characterized by XRPD pattern peaks at 17.6, 18.4 and 18.7±0.2° 2θ using CuKα radiation.

138. 138. The crystalline form of claim 137, further characterized by XRPD pattern peaks at 14.0, 17.7, and 20.4±0.2° 2θ using CuKα radiation.

139. 139. The crystalline form of claim 138, further characterized by XRPD pattern peaks at 11.2, 12.4, 13.8, 14.1, 15.9, 16.1, 18.0, 19.3, 20.8, 21.7, 22.9, 23.9, and 24.5±0.2 degrees 2θ using CuKα radiation.

140. 140. The crystalline form of any one of claims 137-139, having an XRPD pattern substantially as shown in Figure 68.

141. 138. The crystalline form of claim 137, having endothermic transitions at 54°C to 60°C and 231°C to 237°C as measured by differential scanning calorimetry.

142. 142. The crystalline form of claim 141, wherein the endothermic transitions are at 57°C ± 3°C and 234°C ± 3°C.

143. 138. The crystalline form of claim 137, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 70.

144. A crystalline form of AMG397 as the tosylate salt, characterized by XRPD pattern peaks at 18.2, 18.4 and 20.5±0.2° 2θ using CuKα radiation.

145. 145. The crystalline form of claim 144, further characterized by XRPD pattern peaks at 12.2, 12.3, 17.6, 18.9, and 19.1±0.2 degrees 2θ using CuKα radiation.

146. 146. The crystalline form of claim 145, further characterized by XRPD pattern peaks at 4.5, 5.2, 13.0, 13.8, 14.0, 15.2, 15.8, 16.2, 16.4, 19.8, 20.0, 21.4, 22.9, 23.4, 23.6, 23.8, 24.3, 24.6, 25.1, and 27.1±0.2 degrees 2θ using CuKα radiation.

147. 147. The crystalline form of any one of claims 144-146, having an XRPD pattern substantially as shown in Figure 72.

148. 145. The crystalline form of claim 144, having endothermic transitions at 37°C to 43°C and 223°C to 229°C as measured by differential scanning calorimetry.

149. 149. The crystalline form of claim 148, wherein the endothermic transitions are at 40°C ± 3°C and 226°C ± 3°C.

150. 145. The crystalline form of claim 144, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 74.

151. A crystalline form of AMG397 as the maleate salt, characterized by XRPD pattern peaks at 18.2, 18.9, and 19.9±0.2° 2θ using CuKα radiation.

152. 152. The crystalline form of claim 151, further characterized by XRPD pattern peaks at 10.4, 10.9, 12.0, and 21.5±0.2 degrees 2θ using CuKα radiation.

153. 153. The crystalline form of claim 152, further characterized by XRPD pattern peaks at 10.3, 13.8, 15.8, 17.9, 19.2, and 24.2±0.2 degrees 2θ using CuKα radiation.

154. 154. The crystalline form of any one of claims 151-153, having an XRPD pattern substantially as shown in Figure 76.

155. 152. The crystalline form of claim 151, having an endothermic transition at 219°C to 225°C as measured by differential scanning calorimetry.

156. 156. The crystalline form of claim 155, wherein the endothermic transition is 222°C ± 3°C.

157. 152. The crystalline form of claim 151, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 78.

158. A crystalline form of AMG397 as the maleate salt, characterized by XRPD pattern peaks at 10.6, 18.6 and 20.3±0.2° 2θ using CuKα radiation.

159. 159. The crystalline form of claim 158, further characterized by XRPD pattern peaks at 10.8, 12.3, 15.2, 15.9, and 16.7±0.2 degrees 2θ using CuKα radiation.

160. 160. The crystalline form of claim 159, further characterized by XRPD pattern peaks at 9.8, 11.1, 13.9, 14.1, 18.0, 18.4, 19.2, 19.4, 20.8, 22.3, 23.0, 23.6, 24.6, and 28.4±0.2 degrees 2θ using CuKα radiation.

161. 161. The crystalline form of any one of claims 158-160, having an XRPD pattern substantially as shown in Figure 79.

162. A crystalline form of AMG397 as the malonate salt, characterized by XRPD pattern peaks at 12.2, 18.8 and 20.4±0.2° 2θ using CuKα radiation.

163. 163. The crystalline form of claim 162, further characterized by XRPD pattern peaks at 10.3, 11.1, 17.9, 18.3, and 19.1±0.2 degrees 2θ using CuKα radiation.

164. 164. The crystalline form of claim 163, further characterized by XRPD pattern peaks at 10.7, 13.9, 14.0, 15.8, 16.5, 18.4, 19.5, 19.7 21.6, 21.7, 22.8, and 24.5±0.2 degrees 2θ using CuKα radiation.

165. 165. The crystalline form of any one of claims 162-164, having an XRPD pattern substantially as shown in Figure 82.

166. 163. The crystalline form of claim 162, having endothermic transitions at 158°C to 164°C and 184°C to 190°C as measured by differential scanning calorimetry.

167. 167. The crystalline form of claim 166, wherein the endothermic transitions are at 161°C ± 3°C and 187°C ± 3°C.

168. 163. The crystalline form of claim 162, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 84.

169. A crystalline form of AMG397 as the malonate salt, characterized by XRPD pattern peaks at 10.6, 18.5 and 20.2±0.2° 2θ using CuKα radiation.

170. 170. The crystalline form of claim 169, further characterized by XRPD pattern peaks at 11.0, 14.0, and 17.9±0.2° 2θ using CuKα radiation.

171. 171. The crystalline form of claim 170, further characterized by XRPD pattern peaks at 11.1, 12.3, 15.3, 16.1, 16.8, 17.0, 18.6, 19.4, and 22.2±0.2 degrees 2θ using CuKα radiation.

172. 172. The crystalline form of any one of claims 169-171, having an XRPD pattern substantially as shown in Figure 85.

173. A crystalline form of AMG397 as the tartrate salt, characterized by XRPD pattern peaks at 18.2, 18.6 and 20.2±0.2° 2θ using CuKα radiation.

174. 174. The crystalline form of claim 173, further characterized by XRPD pattern peaks at 12.1, 17.8, 19.0, and 21.5±0.2 degrees 2θ using CuKα radiation.

175. 175. The crystalline form of claim 174, further characterized by XRPD pattern peaks at 10.6, 11.0, 12.8, 13.8, 15.1, 15.8, 16.4, 16.6, 17.4, 19.3, 19.5, 20.6, 22.1, 22.6, 23.5, and 24.4±0.2 degrees 2θ using CuKα radiation.

176. 176. The crystalline form of any one of claims 173-175, having an XRPD pattern substantially as shown in Figure 87.

177. 174. The crystalline form of claim 173, having an endothermic transition at 224°C to 230°C as measured by differential scanning calorimetry.

178. 178. The crystalline form of claim 177, wherein the endothermic transition is 227°C ± 3°C.

179. 174. The crystalline form of claim 173, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 89.

180. A crystalline form of AMG397 as a tris(hydroxymethyl)aminomethane salt acetone solvate, characterized by XRPD pattern peaks at 10.0, 16.8, and 20.0±0.2° 2θ using CuKα radiation.

181. 181. The crystalline form of claim 180, further characterized by XRPD pattern peaks at 12.7, 14.1, and 18.2±0.2 degrees 2θ using CuKα radiation.

182. 182. The crystalline form of claim 181, further characterized by XRPD pattern peaks at 6.1, 14.9, 15.3, 16.0, 17.3, 17.6, 18.0, 19.0, 19.1, 19.4, 20.6, 22.1, 22.5, 22.7, 22.9, 26.3, and 26.4±0.2 degrees 2θ using CuKα radiation.

183. 183. The crystalline form of any one of claims 180-182, having an XRPD pattern substantially as shown in Figure 90.

184. 181. The crystalline form of claim 180, having endothermic transitions at 56°C to 62°C and 131°C to 137°C as measured by differential scanning calorimetry.

185. 185. The crystalline form of claim 184, wherein the endothermic transitions are at 59°C ± 3°C and 134°C ± 3°C.

186. 181. The crystalline form of claim 180, having a thermogravimetric analysis ("TGA") substantially as shown in Figure 92.

187. A crystalline form of AMG397 as the iodide salt, characterized by XRPD pattern peaks at 17.0, 18.0, and 18.1±0.2° 2θ using CuKα radiation.

188. 188. The crystalline form of claim 187, further characterized by XRPD pattern peaks at 8.3, 11.0, 18.6, 18.8, 19.1, 20.0, 22.1, 23.5, and 24.7±0.2 degrees 2θ using CuKα radiation.

189. 189. The crystalline form of claim 188, further characterized by XRPD pattern peaks at 6.2, 10.6, 10.8, 12.4, 13.0, 14.1, 15.5, 17.6, 22.5, 24.1, 28.6, 28.8, 29.0, and 29.5±0.2 degrees 2θ using CuKα radiation.

190. 190. The crystalline form of any one of claims 187-189, having an XRPD pattern substantially as shown in Figure 93.

191. 188. The crystalline form of claim 187, having an endothermic transition at 228°C to 234°C as measured by differential scanning calorimetry.

192. 192. The crystalline form of claim 191, wherein the endothermic transition is 231°C ± 3°C.

193. 187. A pharmaceutical formulation comprising the crystalline form of any one of claims 1, 5, 9, 16, 23, 30, 34, 42, 53, 58, 65, 70, 73, 80, 88, 95, 102, 109, 116, 123, 130, 137, 144, 151, 158, 162, 169, 173, 180, and 187 and a pharmaceutically acceptable excipient.

194. 180, 182, 183, 184, 185, 186, 187, 188, 188, 189, 190, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283,

195. The method of claim 194, wherein the cancer is multiple myeloma, non-Hodgkin's lymphoma, or acute myeloid leukemia.

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