(S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide in solid form and its use

Abstract

Providing a solid form of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide and its use. [Solution] This disclosure relates to a) a solid form of hydrobromide of compound 1; b) a pharmaceutical composition comprising one or more solid forms of hydrobromide of compound 1 and, optionally, a pharmaceutically acceptable carrier; c) a method for treating a tumor or cancer by administering one or more solid forms of hydrobromide of compound 1 to a subject requiring it; and d) a method for preparing a solid form of compound 1.

Description

[Technical Field]

[0001] Technical field This disclosure relates to: a) a solid form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide ("Compound 1"); b) a pharmaceutical composition comprising one or more solid forms of hydrobromide of Compound 1 and, optionally, a pharmaceutically acceptable carrier; c) a method for treating a tumor or cancer by administering one or more solid forms of hydrobromide of Compound 1 to a subject requiring it; and d) a method for preparing a solid form of hydrobromide of Compound 1. [Background technology]

[0002] background (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide ("Compound 1") is a gamma-secretase inhibitor that can inhibit Aβ-peptide production.

[0003] Not all gamma-secretase inhibitors possess the characteristics that best contribute to their potential as useful therapeutic agents. Some of these characteristics include high affinity for gamma-secretase, duration of gamma-secretase inactivation, oral bioavailability, tissue distribution, and stability (e.g., ability to be formulated or crystallized, shelf life). Favorable characteristics can lead to improvements in safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, and ease of manufacture.

[0004] Furthermore, the solid state form of the hydrobromide salt of compound 1, the isolation and commercial-scale preparation of the corresponding pharmaceutical formulation having acceptable solid state properties (including chemical stability, thermal stability, solubility, hygroscopicity, and / or particle size), the manufacturability of the compound (including yield, impurity removal during crystallization, filtration properties, drying properties, and milling properties), and formulation feasibility (including stability with respect to pressure or compressive force during tableting) present several challenges.

[0005] Therefore, there is currently a need for one or more solid forms of hydrobromide of compound 1 that have an acceptable balance of these properties and can be used to prepare pharmaceutically acceptable solid dosage forms. [Overview of the Initiative] [Means for solving the problem]

[0006] Summary of the Invention In one embodiment, the disclosure relates to a solid form of the hydrobromide salt of compound 1. In one embodiment, the solid form is the crystalline form of the hydrobromide salt of compound 1. In one embodiment, the solid form is the crystalline form of the dihydrobromide salt of compound 1. In another embodiment, the solid form is the amorphous form of the dihydrobromide salt of compound 1.

[0007] In one embodiment, this disclosure relates to formula (I) [ka] The crystalline form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, as follows: a) Crystal morphology A, characterized by an XRPD pattern with two theta peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees; b) Crystal morphology B, characterized by the XRPD pattern substantially shown in Figure 4; c) Crystal morphology D, characterized by the XRPD pattern substantially shown in Figure 11; d) Crystal morphology E, characterized by the XRPD pattern substantially shown in Figure 14; e) Crystal morphology F, characterized by the XRPD pattern substantially shown in Figure 17; f) Crystal morphology F' characterized by the XRPD pattern substantially shown in Figure 18; g) Crystal morphology G, characterized by the XRPD pattern substantially shown in Figure 21; h) Crystal morphology H characterized by the XRPD pattern substantially shown in Figure 22; i) Crystal morphology H' characterized by the XRPD pattern substantially shown in Figure 23; j) Crystal morphology J, characterized by the XRPD pattern substantially shown in Figure 24; k) Crystal morphology K, characterized by the XRPD pattern substantially shown in Figure 25; l) Crystal morphology L characterized by the XRPD pattern substantially shown in Figure 26; m) Crystal morphology M characterized by the XRPD pattern substantially shown in Figure 29; and n) Crystal morphology N characterized by the XRPD pattern substantially shown in Figure 30 This relates to crystal forms selected from the group consisting of the following.

[0008] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form A of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0009] In one embodiment, crystalline form A is anhydrous.

[0010] In another embodiment, the melting point of crystalline form A is approximately 254°C.

[0011] In another embodiment, Form A is characterized by an XRPD pattern having peaks at 2-theta of 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees. In another embodiment, Form A is characterized by an XRPD pattern having peaks at 2-theta of 8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2 and 29.3±0.2 degrees. In another embodiment, Form A is characterized by an XRPD pattern having peaks at 2-theta of 8.8±0.2, 9.8±0.2, 20.0±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, 29.3±0.2 and 32.5±0.2 degrees.

[0012] In another embodiment, Form A is characterized by an XRPD pattern substantially shown in FIG. 1. In another embodiment, Form A is characterized by a TGA profile substantially shown in FIG. 2. In another embodiment, Form A is characterized by a DSC profile substantially shown in FIG. 3.

[0013] In another embodiment, Form A has a unit cell that is indexed as simple monoclinic.

[0014] In another embodiment, Form A has a unit cell with an a value of about 10.03 Å, a b value of about 7.53 Å, and a c value of about 20.09 Å. In another embodiment, Form A has a unit cell with a volume of about 1518.1 Å ,

[0016] , In another embodiment, Form A has a unit cell having a volume of. [[ID=十七]]

[0015] In another embodiment, Form A is substantially free of other polymorphic forms. In one embodiment, Form A has a polymorph purity of at least 90%. In one embodiment, Form A has a polymorph purity of at least 99%.

[0016] In another embodiment, Form A has one or more of a D[V,0.10] particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90] particle size between about 8 μm and about 600 μm, or a D[4,3] particle size between about 5 μm and about 200 μm.

[0017] In one aspect, the present disclosure relates to crystalline Form B of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having the formula (I)

Chemical formula

[0019] In another embodiment, Form B substantially does not contain other polymorphic forms. In another embodiment, Form B has a polymorph purity of at least ǘ0%. In another embodiment, Form B has a polymorph purity of at least 99%. <所000110>

[0020] In another embodiment, Form B has one or more of a D[V,0.1'0] particle size between about 0.5 μm and about 15 μm, a D[V,0.50] particle size between about 2 μm and about 30 μm, a D[V,0.90] particle size between about 8 μm and about 600 μm, or a D[4,3] particle size between about 5 μm and about 200 μm.

[0021] In one aspect, the present disclosure relates to the formula (II)

Chemical formula

[0022] In one embodiment, form C is a)~d): a) The XRPD pattern substantially shown in Figure 5; b) TGA profile substantially shown in Figure 6; c) DSC profile substantially shown in Figure 7; and d) TG-IR linked spectra substantially shown in a figure selected from the group consisting of Figures 8-10 One or more features are selected from the group consisting of the following.

[0023] In another embodiment, form C has a unit cell that is indexed as a simple orthorhombic system.

[0024] In another embodiment, morphology C has a unit cell with an a value of approximately 7.491 Å, a b value of approximately 10.353 Å, and a c value of approximately 48.790 Å. In yet another embodiment, morphology C has a unit cell with an a value of approximately 3783.9 Å. 3 It has a unit cell having a volume of .

[0025] In another embodiment, the TGA shows that form C loses at least 8% by weight between approximately 60°C and approximately 190°C. In another embodiment, form C shows a DSC thermogram with a first endothermic event at approximately 39°C and a second endothermic event at approximately 152°C.

[0026] In another embodiment, form C substantially does not contain other polymorphic forms. In one embodiment, form C has a polymorphic purity of at least 90%. In one embodiment, form C has a polymorphic purity of at least 99%.

[0027] In another embodiment, form C has one or more of the following D[V,0.10] particle sizes: about 0.5 μm to about 15 μm, D[V,0.50] particle sizes: about 2 μm to about 30 μm, D[V,0.90] particle sizes: about 8 μm to about 600 μm, or D[4,3] particle sizes: about 5 μm to about 200 μm.

[0028] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form D of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0029] In one embodiment, form D is a)~c): a) The XRPD pattern substantially shown in Figure 11; b) TGA profiles substantially shown in Figure 12A or Figure 12B; and c) DSC profile substantially shown on line A or line B in Figure 13 One or more features are selected from the group consisting of the following.

[0030] In another embodiment, morphology D has a unit cell indexed as a simple monoclinic system. In another embodiment, morphology D has a unit cell with an a value of approximately 18.465 Å, a b value of approximately 7.441 Å, and a c value of approximately 23.885 Å. In another embodiment, morphology D has a unit cell of approximately 3250.4 Å 3 It has a unit cell having a volume of .

[0031] In another embodiment, TGA shows that form D undergoes a weight loss of approximately 1.2 to 2.5% by weight between approximately 24°C and approximately 109°C.

[0032] In another embodiment, form D shows a DSC thermogram with an endothermic event at approximately 65°C.

[0033] In another embodiment, form D substantially does not contain other polymorphic forms. In one embodiment, form D has a polymorphic purity of at least 90%. In one embodiment, form D has a polymorphic purity of at least 99%.

[0034] In another embodiment, morphology D has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0035] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form E of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0036] In one embodiment, form E is a)~c): a) The XRPD pattern substantially shown in Figure 14; b) TGA profile substantially shown in Figure 15; and c) DSC profile substantially shown in Figure 16 One or more features are selected from the group consisting of the following.

[0037] In another embodiment, TGA shows that form E loses about 8% by weight between about 28°C and about 120°C.

[0038] In another embodiment, form E shows a DSC thermogram with an endothermic event at approximately 80°C.

[0039] In another embodiment, form E substantially does not contain other polymorphic forms. In one embodiment, form E has a polymorphic purity of at least 90%. In one embodiment, form E has a polymorphic purity of at least 99%.

[0040] In another embodiment, form E has one or more of the following D[V,0.10] particle sizes: about 0.5 μm to about 15 μm, D[V,0.50] particle sizes: about 2 μm to about 30 μm, D[V,0.90] particle sizes: about 8 μm to about 600 μm, or D[4,3] particle sizes: about 5 μm to about 200 μm.

[0041] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form F of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0042] In another embodiment, form F features an XRPD pattern substantially shown in Figure 17.

[0043] In another embodiment, form F substantially does not contain other polymorphic forms. In one embodiment, form F has a polymorphic purity of at least 90%. In one embodiment, form F has a polymorphic purity of at least 99%.

[0044] In another embodiment, morphology F has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0045] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form F' of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0046] In one embodiment, form F' is a)~b): a) XRPD patterns substantially shown in Figure 18; and b) TGA profile substantially shown in Figure 19; and c) DSC profile substantially shown in Figure 20 One or more features are selected from the group consisting of the following.

[0047] In another embodiment, TGA shows that form F' loses about 12.6% by weight between about 24°C and about 90°C, and about 15.6% by weight between about 97°C and about 198°C.

[0048] In another embodiment, form F' substantially contains no other polymorphic forms. In one embodiment, form F' has a polymorphic purity of at least 90%. In one embodiment, form F' has a polymorphic purity of at least 99%.

[0049] In another embodiment, form F' has one or more of the following D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm.

[0050] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form G of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0051] In one embodiment, form G is characterized by an XRPD pattern substantially shown in Figure 21.

[0052] In another embodiment, form G substantially does not contain other polymorphic forms. In one embodiment, form G has a polymorphic purity of at least 90%. In one embodiment, form G has a polymorphic purity of at least 99%.

[0053] In another embodiment, morphology G has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0054] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form H of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0055] In one embodiment, form H is characterized by an XRPD pattern substantially shown in Figure 22.

[0056] In another embodiment, form H substantially contains no other polymorphic forms. In one embodiment, form H has a polymorphic purity of at least 90%. In one embodiment, form H has a polymorphic purity of at least 99%.

[0057] In another embodiment, morphology H has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0058] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form H' of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0059] In one embodiment, form H' is characterized by an XRPD pattern substantially shown in Figure 23.

[0060] In another embodiment, form H' substantially contains no other polymorphic forms. In one embodiment, form H' has a polymorphic purity of at least 90%. In one embodiment, form H' has a polymorphic purity of at least 99%.

[0061] In another embodiment, morphology H' has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0062] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form J of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0063] In one embodiment, form J is characterized by an XRPD pattern substantially shown in Figure 24.

[0064] In another embodiment, form J substantially contains no other polymorphic forms. In one embodiment, form J has a polymorphic purity of at least 90%. In one embodiment, form J has a polymorphic purity of at least 99%.

[0065] In another embodiment, morphology J has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0066] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form K of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0067] In one embodiment, form K is characterized by an XRPD pattern substantially shown in Figure 25.

[0068] In another embodiment, form K substantially does not contain other polymorphic forms. In one embodiment, form K has a polymorphic purity of at least 90%. In one embodiment, form K has a polymorphic purity of at least 99%.

[0069] In another embodiment, morphology K has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0070] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form L of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0071] In one embodiment, form L is a)~c): a) The XRPD pattern substantially shown in Figure 26; b) TGA profile substantially shown in Figure 27; and c) DSC profile substantially shown in Figure 28 One or more features are selected from the group consisting of the following.

[0072] In another embodiment, form L shows a DSC thermogram with an endothermic event at approximately 157°C.

[0073] In another embodiment, form L substantially does not contain other polymorphic forms. In one embodiment, form L has a polymorphic purity of at least 90%. In one embodiment, form L has a polymorphic purity of at least 99%.

[0074] In another embodiment, morphology L has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0075] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form M of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0076] In one embodiment, form M is characterized by an XRPD pattern substantially shown in Figure 29.

[0077] In another embodiment, form M substantially does not contain other polymorphic forms. In one embodiment, form M has a polymorphic purity of at least 90%. In one embodiment, form M has a polymorphic purity of at least 99%.

[0078] In another embodiment, morphology M has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0079] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form N of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0080] In one embodiment, form N is characterized by an XRPD pattern substantially shown in Figure 30.

[0081] In another embodiment, form N substantially does not contain other polymorphic forms. In one embodiment, form N has a polymorphic purity of at least 90%. In one embodiment, form N has a polymorphic purity of at least 99%.

[0082] In another embodiment, morphology N has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0083] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the amorphous form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0084] In one embodiment, the amorphous form of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) is characterized by an XRPD pattern substantially shown in Figure 31.

[0085] In another embodiment, the amorphous form of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) is substantially free of polymorphic forms. In one embodiment, the amorphous form of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) has a polymorphic purity of at least 90%. In one embodiment, the amorphous form of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) has a polymorphic purity of at least 99%.

[0086] In another embodiment, the amorphous morphology has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0087] In one embodiment, the present disclosure relates to a composition comprising a crystalline or amorphous form of a hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having one or more of the following D[V,0.10] particle sizes: D[V,0.50] particle size: D[V,0.9 In one embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is in amorphous form. In one embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is in crystalline form.

[0088] In one embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is of formula (I) [ka] It is a compound of [the compound].

[0089] In another embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1H-imidazole-4-yl)pentanamide is a compound of formula (II). [ka] That is the case.

[0090] In another embodiment, the crystal morphology is selected from the group consisting of morphology A, morphology B, morphology C, morphology D, morphology E, morphology F, morphology F', morphology G, morphology H, morphology H', morphology J, morphology K, morphology L, morphology M, and morphology N. In another embodiment, the crystal morphology is morphology A.

[0091] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising one or more of the forms or compositions discussed above, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises crystalline form A of the compound of formula (I). In one embodiment, the pharmaceutical composition is a tablet. In one embodiment, the pharmaceutical composition comprises about 25 mg to about 400 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. In one embodiment, the pharmaceutical composition contains about 50 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. In one embodiment, the pharmaceutical composition contains about 100 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. In one embodiment, the pharmaceutical composition contains approximately 150 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0092] In one embodiment, the present disclosure relates to a method for treating a tumor or cancer, comprising the step of administering to a subject requiring such treatment one or more of the hydrobromide forms A to N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide discussed above. In one embodiment, a method for treating a tumor or cancer comprises the step of administering to a subject requiring such treatment a crystalline form A of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. In one embodiment, the present disclosure relates to a method for treating a tumor or cancer, comprising the step of administering to a subject requiring such treatment a pharmaceutical composition comprising one or more of the hydrobromide forms A to N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide discussed above, and a pharmaceutically acceptable carrier. In one embodiment, a method for treating a tumor or cancer comprises the step of administering to a subject requiring such treatment a pharmaceutical composition comprising the crystalline form A of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide and a pharmaceutically acceptable carrier. In one embodiment of the method, the tumor is a tendinoid tumor. In one embodiment of the method, the cancer is selected from the group consisting of multiple myeloma, cancer with mutations in the Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. In another embodiment of the method, the cancer is multiple myeloma.In another embodiment, the cancer is a cancer with a mutation in the Notch pathway gene. In another embodiment, the cancer is adenoid cystic carcinoma. In another embodiment, the cancer is T-cell acute lymphoblastic leukemia. In another embodiment, the subject is administered approximately 50 mg to approximately 500 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. In another embodiment, the subject is administered approximately 100 mg to approximately 400 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. In another embodiment, the subject is administered approximately 300 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. In another embodiment, the subject is administered approximately 200 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. In another embodiment, the total daily dose is supplied as two separate doses. In another embodiment, the total daily dose is supplied as two separate doses totaling 150 mg. In another embodiment, the total daily dose is supplied as two separate doses totaling 100 mg.

[0093] In one embodiment, the disclosure relates to the use of one or more of the hydrobromide forms A to N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide hydrobromide for the manufacture of a medicament for treating tumors or cancer. In one embodiment, the disclosure relates to the use of crystalline form A of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide hydrobromide for the manufacture of a medicament for treating tumors or cancer. In one embodiment, the present disclosure relates to the pharmaceutical compositions discussed above for treating tumors or cancers. In one embodiment, the use is for treating tendinoid tumors. In one embodiment, the use is for treating cancers selected from the group consisting of multiple myeloma, cancers with mutations in the Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

[0094] In one embodiment, the disclosure relates to one or more of the hydrobromide forms A to N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide discussed above for use in methods of treating tumors or cancer. In one embodiment, the disclosure relates to the pharmaceutical composition discussed above for use in methods of treating tumors or cancer. In one embodiment, the use is for treating tendinoid tumors. In one embodiment, the use is for treating cancers selected from the group consisting of multiple myeloma, cancers with mutations in the Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. [Brief explanation of the drawing]

[0095] [Figure 1] Figure 1 shows the powder X-ray diffraction pattern ("XRPD") corresponding to crystal morphology A.

[0096] [Figure 2] Figure 2 is a thermogravimetric thermogram ("TGA") corresponding to crystal morphology A.

[0097] [Figure 3] Figure 3 is a differential scanning calorimetry thermogram ("DSC") corresponding to crystal morphology A.

[0098] [Figure 4] Figure 4 shows the XRPD corresponding to crystal morphology B.

[0099] [Figure 5] Figure 5 shows the XRPD corresponding to crystal morphology C.

[0100] [Figure 6] Figure 6 shows the TGA corresponding to crystal morphology C.

[0101] [Figure 7] Figure 7 shows the DSC corresponding to crystal morphology C.

[0102] [Figure 8] Figures 8-10 show thermogravimetric infrared (TG-IR) analysis results corresponding to crystal morphology C. [Figure 9] Figures 8-10 show thermogravimetric infrared (TG-IR) analysis results corresponding to crystal morphology C. [Figure 10] Figures 8-10 show thermogravimetric infrared (TG-IR) analysis results corresponding to crystal morphology C.

[0103] [Figure 11] Figure 11 shows the XRPD corresponding to crystal morphology D.

[0104] [Figure 12A]Figure 12A shows the TGA corresponding to the as-prepared crystal morphology D.

[0105] [Figure 12B] Figure 12B shows the TGA corresponding to crystal morphology D when vacuum-dried at 75°C.

[0106] [Figure 13] Figure 13 shows DSCs corresponding to crystal morphology D. Line A is the DSC of morphology D as prepared. Line B is the DSC of morphology D after vacuum drying at 75°C.

[0107] [Figure 14] Figure 14 shows the XRPD corresponding to crystal morphology E.

[0108] [Figure 15] Figure 15 shows the TGA corresponding to crystal morphology E.

[0109] [Figure 16] Figure 16 shows the DSC corresponding to crystal morphology E.

[0110] [Figure 17] Figure 17 shows the XRPD corresponding to crystal morphology F.

[0111] [Figure 18] Figure 18 shows the XRPD corresponding to the crystal morphology F'.

[0112] [Figure 19] Figure 19 shows the TGA corresponding to the crystal morphology F'.

[0113] [Figure 20] Figure 20 shows the DSC corresponding to the crystal morphology F'.

[0114] [Figure 21] Figure 21 shows the XRPD corresponding to crystal morphology G.

[0115] [Figure 22] Figure 22 shows the XRPD corresponding to crystal morphology H.

[0116] [Figure 23] Figure 23 shows the XRPD corresponding to the crystal morphology H'.

[0117] [Figure 24] Figure 24 shows the XRPD corresponding to crystal morphology J.

[0118] [Figure 25] Figure 25 shows the XRPD corresponding to crystal morphology K.

[0119] [Figure 26] Figure 26 shows the XRPD corresponding to crystal morphology L.

[0120] [Figure 27] Figure 27 shows the TGA corresponding to crystal morphology L.

[0121] [Figure 28] Figure 28 is a DSC corresponding to crystal morphology L.

[0122] [Figure 29] Figure 29 shows the XRPD corresponding to crystal morphology M.

[0123] [Figure 30] Figure 30 shows the XRPD corresponding to crystal morphology N.

[0124] [Figure 31] Figure 31 shows the XRPD corresponding to amorphous compound 1 of formula (I). [Modes for carrying out the invention]

[0125] Detailed description of the invention I. Definition To facilitate understanding of the disclosures described herein, several terms are defined below.

[0126] In general, the terminology used herein, as well as the experimental procedures in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which this disclosure belongs.

[0127] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural nouns unless the context specifically indicates otherwise. The terms “a” (or “an”), and “one or more,” and “at least one” can be used interchangeably in this specification. In certain embodiments, the terms “a” or “an” mean “single.” In other embodiments, the terms “a” or “an” include “two or more” or “plural.”

[0128] Furthermore, where used herein, “and / or” should be considered to specifically disclose each of the two specified features or components, with or without the other. Accordingly, the term “and / or” as used herein in phrases such as “A and / or B” is intended to include “A and B,” “A or B,” “A” (alone) and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B and / or C” is intended to include each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0129] The term "compound 1" refers to the single enantiomer, (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1H-imidazole-4-yl)pentanamide.

[0130] The term "subject" refers to animals, including, but not limited to, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein to refer to mammalian subjects, such as human subjects.

[0131] The terms “to treat,” “to treat,” and “treatment” are intended to include reducing or neutralizing one or more of the symptoms of a disorder, disease, or condition, or a condition associated with such a disorder, disease, or condition; or reducing or eliminating the cause of the disorder, disease, or condition itself.

[0132] The term “therapeutic dose” is intended to include the amount of a compound that, when administered, is sufficient to prevent or, to some extent, the onset of one or more symptoms of the disorder, disease, or condition being treated. The term “therapeutic dose” also refers to the amount of a compound sufficient to produce a biological or medical response in a cell, tissue, system, animal, or human, as sought by researchers, veterinarians, physicians, or clinicians.

[0133] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with other components of the pharmaceutical formulation and is suitable for use in contact with human and animal tissues or organs at a reasonable benefit / risk ratio without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications. Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; See Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0134] The terms “about” or “approximately” mean an acceptable error for a particular value as determined by those skilled in the art, which depends in part on the method by which the value was measured or determined. In certain embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0135] The terms “active ingredient” and “active substance” refer to compounds administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent or improve one or more symptoms of a condition, disorder, or disease. As used herein, “active ingredient” and “active substance” may be optically active isomers of the compounds described herein.

[0136] The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound or pharmaceutical composition administered to a subject to treat, prevent or improve one or more symptoms of a condition, disorder, or disease.

[0137] The term "solvate" refers to a compound or salt thereof provided herein, which further comprises a stoichiometric or non-stoichiometric amount of solvent bonded by non-covalent intramolecular forces. When the solvent is water, the solvate is a hydrate. When the solvent contains ethanol, the compound may be an ethanol solvate.

[0138] The term "polymorph," as used herein, refers to a crystalline form of a compound, or its salt, hydrate, or solvate, in a specific crystalline packing arrangement. All polymorphs have the same elemental composition. The term "crystallineity," as used herein, refers to a solid state form consisting of a regular arrangement of constituent units. Different crystalline forms of the same compound, or its salt, hydrate, or solvate, result from different crystalline packing arrangements of molecules in the solid state, which leads to different crystalline symmetries and / or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. For example, Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23 rd See ed., 1843–1844 (1995) (incorporated herein by reference).

[0139] Crystal morphology is most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (typically represented by peaks in 2-theta degrees) is generally considered the fingerprint region of a particular crystal morphology. The relative intensity of XRPD peaks can vary widely depending, among other things, on sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the specific instrument used. In some cases, depending on the type or setting of the instrument, new peaks may be observed or existing peaks may disappear. In some cases, any particular peak in the XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal morphology. In some cases, any particular peak in XRPD may appear symmetrically or asymmetrically, for example, with shoulders. Furthermore, instrument variability and other factors can affect the 2-theta values. Those skilled in the art, understanding these variations, can use XRPD and other known physicochemical techniques to distinguish or elucidate the definitive features or properties of particular crystal morphologies.

[0140] The term "amorphous," applied to compounds, refers to a state in which a substance lacks order over long distances at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically, such substances do not give a distinctive X-ray diffraction pattern and exhibit solid properties, while more formally being described as liquids. Upon heating, a change occurs from solid to liquid properties, which is characterized by a change in state, usually a change in a second order ("glass transition").

[0141] The term "anhydrous," when applied to compounds, refers to a solid state in which the compound does not contain structural water within its crystal lattice.

[0142] Unless the context requires interpretation of other meanings, the terms “comprise,” “comprises,” and “comprising” are used based on a fundamental and clear understanding that, unless otherwise required by context, they should be interpreted comprehensively rather than exclusively, and that each of these terms is intended to be interpreted in this way when interpreting the Patent, including the following claims. II. Solid State Form

[0143] This disclosure relates to the solid state form of the hydrobromide salt of Compound 1. As with all pharmaceutical compounds and compositions, the chemical and physical properties of the hydrobromide salt of Compound 1 are important for its commercial development. These properties include, but are not limited to, (1) packing properties such as molar volume, bulk density and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure and solubility; (3) kinetic properties such as dissolution rate and stability (including, in particular, with respect to moisture and stability under ambient conditions during storage); (4) surface properties such as surface area, wettability, interfacial tension and shape; (5) mechanical properties such as hardness, tensile strength, compressibility, handling, flowability and blendability; and (6) filtration properties. These properties may affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound.

[0144] A solid form of the hydrobromide salt of compound 1 is desirable that improves one or more of these properties compared to other solid forms of this compound. Isolating a pharmaceutically acceptable solid form of this compound that can be manufactured and formulated on a commercial scale is a challenge.

[0145] In one embodiment, this disclosure relates to formula (I) [ka] The crystalline form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, a) Crystal morphology A, characterized by an XRPD pattern with two theta peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees; b) Crystal morphology B, characterized by the XRPD pattern substantially shown in Figure 4; c) Crystal morphology D, characterized by the XRPD pattern substantially shown in Figure 11; d) Crystal morphology E, characterized by the XRPD pattern substantially shown in Figure 14; e) Crystal morphology F, characterized by the XRPD pattern substantially shown in Figure 17; f) Crystal morphology F' characterized by the XRPD pattern substantially shown in Figure 18; g) Crystal morphology G, characterized by the XRPD pattern substantially shown in Figure 21; h) Crystal morphology H characterized by the XRPD pattern substantially shown in Figure 22; i) Crystal morphology H' characterized by the XRPD pattern substantially shown in Figure 23; j) Crystal morphology J, characterized by the XRPD pattern substantially shown in Figure 24; k) Crystal morphology K, characterized by the XRPD pattern substantially shown in Figure 25; l) Crystal morphology L characterized by the XRPD pattern substantially shown in Figure 26; m) Crystal morphology M characterized by the XRPD pattern substantially shown in Figure 29; and n) Crystal morphology N characterized by the XRPD pattern substantially shown in Figure 30 This relates to crystal forms selected from the group consisting of the following.

[0146] The following sections discuss the characteristics of such solid-state forms and the solid-state forms that have been identified and selected. A. Crystal form A

[0147] In one embodiment, the present disclosure relates to a hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having formula (I). [ka] Regarding the crystal form A.

[0148] In one embodiment, crystalline form A is anhydrous.

[0149] In another embodiment, the melting point of crystalline form A is approximately 254°C.

[0150] In another embodiment, morphology A is characterized by an XRPD pattern having peaks at two thetas of 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees when measured by Cu Kα irradiation. In another embodiment, morphology A is characterized by an XRPD pattern having peaks at two thetas of 8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, and 29.3±0.2 degrees when measured by Cu Kα irradiation. In another embodiment, morphology A is characterized by an XRPD pattern having peaks at two thetas of 8.8±0.2, 9.8±0.2, 20.0±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, 29.3±0.2, and 32.5±0.2 degrees when measured by Cu Kα irradiation.

[0151] In another embodiment, form A features an XRPD pattern substantially shown in Figure 1. In another embodiment, form A features a TGA profile substantially shown in Figure 2. In another embodiment, form A features a DSC profile substantially shown in Figure 3.

[0152] In another embodiment, form A has a unit cell that is indexed as a simple monoclinic system.

[0153] In another embodiment, morphology A has a unit cell with an a value of approximately 10.035 Å, a b value of approximately 7.532 Å, and a c value of approximately 20.092 Å. In another embodiment, morphology A has a unit cell of approximately 1518.1 Å. 3 It has a unit cell having a volume of .

[0154] The unit cell parameters for morphology A are as follows: [Table 1A]

[0155] In another embodiment, form A substantially does not contain other polymorphic forms. In another embodiment, form A has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. B. Crystalline form B

[0156] In one embodiment, the present disclosure relates to a hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having formula (I). [ka] Regarding the crystal form B.

[0157] In one embodiment, form B is characterized by an XRPD pattern substantially shown in Figure 4.

[0158] In another embodiment, form B substantially contains no other polymorphic forms. In another embodiment, form B has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. C. Crystalline form C

[0159] In one embodiment, the present disclosure relates to a hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having formula (II). [ka] (In the formula, n is approximately 1 to 3.) Regarding the crystal form C.

[0160] In one embodiment, form C is a)~d): a) The XRPD pattern substantially shown in Figure 5; b) TGA profile substantially shown in Figure 6; c) DSC profile substantially shown in Figure 7; and d) TG-IR linked spectra substantially shown in a figure selected from the group consisting of Figures 8-10 One or more features are selected from the group consisting of the following.

[0161] In another embodiment, form C has a unit cell that is indexed as a simple orthorhombic system.

[0162] In another embodiment, morphology C has a unit cell with an a value of approximately 7.491 Å, a b value of approximately 10.353 Å, and a c value of approximately 48.790 Å. In yet another embodiment, morphology C has a unit cell with an a value of approximately 3783.9 Å. 3 It has a unit cell having a volume of .

[0163] The unit cell parameters for morphology C are as follows: [Table 1B]

[0164] In another embodiment, the TGA shows that form C loses at least 8% by weight between approximately 60°C and approximately 190°C. In another embodiment, form C shows a DSC thermogram with a first endothermic event at approximately 39°C and a second endothermic event at approximately 152°C.

[0165] In another embodiment, form C substantially contains no other polymorphic forms. In another embodiment, form C has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. D. Crystalline form D

[0166] In one embodiment, the present disclosure relates to a hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having formula (I). [ka] Regarding the crystal form D.

[0167] In one embodiment, form D is a)~c): a) The XRPD pattern substantially shown in Figure 11; b) TGA profiles substantially shown in Figure 12A or Figure 12B; and c) DSC profile substantially shown on line A or line B in Figure 13 One or more features are selected from the group consisting of the following.

[0168] In another embodiment, morphology D has a unit cell indexed as a simple monoclinic system. In another embodiment, morphology D has a unit cell with an a value of approximately 18.465 Å, a b value of approximately 7.441 Å, and a c value of approximately 23.885 Å. In another embodiment, morphology D has a unit cell of approximately 3250.4 Å 3 It has a unit cell having a volume of .

[0169] The unit cell parameters for morphology D are as follows: [Table 1C]

[0170] In another embodiment, TGA shows that form D undergoes a weight loss of approximately 1.2 to 2.5% by weight between approximately 24°C and approximately 109°C.

[0171] In another embodiment, form D shows a DSC thermogram with an endothermic event at approximately 65°C.

[0172] In another embodiment, form D substantially contains no other polymorphic forms. In another embodiment, form D has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. E. Crystalline form E

[0173] In one embodiment, the present disclosure relates to a hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having formula (I). [ka] Regarding the crystal form E.

[0174] In one embodiment, form E is a)~c): a) The XRPD pattern substantially shown in Figure 14; b) TGA profile substantially shown in Figure 15; and c) DSC profile substantially shown in Figure 16 One or more features are selected from the group consisting of the following.

[0175] In another embodiment, TGA shows that form E loses about 8% by weight between about 28°C and about 120°C.

[0176] In another embodiment, form E shows a DSC thermogram with an endothermic event at approximately 80°C.

[0177] In another embodiment, form E substantially does not contain other polymorphic forms. In another embodiment, form E has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. F. Crystallographic form F

[0178] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form F of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0179] In another embodiment, form F features an XRPD pattern substantially shown in Figure 17.

[0180] In another embodiment, form A substantially does not contain other polymorphic forms. In another embodiment, form A has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. G. Crystallographic form F'

[0181] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form F' of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0182] In one embodiment, form F' is a)~c): a) The XRPD pattern substantially shown in Figure 18; b) TGA profile substantially shown in Figure 19; and c) DSC profile substantially shown in Figure 20 One or more features are selected from the group consisting of the following.

[0183] In another embodiment, TGA shows that form F' loses about 12.6% by weight between about 24°C and about 90°C, and about 15.6% by weight between about 97°C and about 198°C.

[0184] In another embodiment, form A substantially contains no other polymorphic forms. In another embodiment, form A has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. H. Crystallographic form G

[0185] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form G of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0186] In one embodiment, form G is characterized by an XRPD pattern substantially shown in Figure 21.

[0187] In another embodiment, form G substantially contains no other polymorphic forms. In another embodiment, form G has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. I. Crystalline form H

[0188] In one embodiment, this disclosure relates to formula (I) [ka] Regarding crystalline form H of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentaamide.

[0189] In one embodiment, form H is characterized by an XRPD pattern substantially shown in FIG. 22.

[0190] In another embodiment, form H substantially does not contain other polymorphic forms. In another embodiment, form H has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 9%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. J. Crystalline form H'

[0191] In one aspect, the present disclosure relates to crystalline form H' of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentaamide of formula (I)

Chemical formula

[0192] In one embodiment, form H' is characterized by an XRPD pattern substantially shown in FIG. 23.

[0193] In another embodiment, form H' substantially contains no other polymorphic forms. In another embodiment, form H' has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. K. Crystal form J

[0194] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form J of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0195] In one embodiment, form J is characterized by an XRPD pattern substantially shown in Figure 24.

[0196] In another embodiment, form J substantially contains no other polymorphic forms. In another embodiment, form J has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. L. Crystalline form K

[0197] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form K of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0198] In one embodiment, form K is characterized by an XRPD pattern substantially shown in Figure 25.

[0199] In another embodiment, form K substantially contains no other polymorphic forms. In another embodiment, form K has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. M. Crystallographic form L

[0200] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the crystalline form L of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0201] In one embodiment, form L is a)~c): a) The XRPD pattern substantially shown in Figure 26; b) TGA profile substantially shown in Figure 27; and c) DSC profile substantially shown in Figure 28 One or more features are selected from the group consisting of the following.

[0202] In another embodiment, Form L exhibits an endothermic event at about 157 °C in a DSC thermogram.

[0203] In another embodiment, Form L is substantially free of other polymorphic forms. In another embodiment, Form L has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. N. Crystal Form M

[0204] In one aspect, the present disclosure relates to the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

Chemical formula

[0205] In one embodiment, Form M is characterized by an XRPD pattern substantially shown in Figure 29.

[0206] In another embodiment, Form M is substantially free of other polymorphic forms. In another embodiment, Form M has a polymorph purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%. O. Crystal Form N

[0207] <000097⑦>In one aspect, the present disclosure relates to the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

Chemical formula

[0208] In one embodiment, form N is characterized by an XRPD pattern substantially shown in Figure 30.

[0209] In another embodiment, form N substantially contains no other polymorphic forms. In another embodiment, form N has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. P. amorphous

[0210] In one embodiment, this disclosure relates to formula (I) [ka] This relates to the amorphous form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide.

[0211] In one embodiment, amorphous compound 1 of formula (I) is characterized by an XRPD pattern substantially shown in Figure 31.

[0212] In another embodiment, amorphous compound 1 of formula (I) is substantially free of polymorphic forms. In another embodiment, amorphous compound 1 of formula (I) has a polymorphic purity of at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. III. Particle Size

[0213] In another aspect, the disclosure relates to the crystalline and amorphous forms discussed above, having one or more of the following D[V,0.10] particle sizes between about 0.5 μm and about 15 μm, D[V,0.50] particle sizes between about 2 μm and about 30 μm, D[V,0.90] particle sizes between about 8 μm and about 600 μm, or D[4,3] particle sizes between about 5 μm and about 200 μm.

[0214] In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0215] In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0216] In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0217] In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 150 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 100 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 75 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 50 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[4,3] particle sizes between approximately 5 μm and approximately 25 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In another embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0218] In one embodiment, form A has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0219] In one embodiment, morphology A has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology A has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology A has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0220] In one embodiment, morphology A has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology A has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology A has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology A has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0221] In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology A has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0222] In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology A has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0223] In one embodiment, form B has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0224] In one embodiment, form B has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, form B has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, form B has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0225] In one embodiment, form B has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, form B has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, form B has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, form B has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0226] In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology B has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0227] In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology B has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0228] In one embodiment, form C has one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm.

[0229] In one embodiment, morphology C has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology C has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology C has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0230] In one embodiment, morphology C has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology C has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology C has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology C has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0231] In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology C has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0232] In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology C has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0233] In one embodiment, morphology D has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0234] In one embodiment, morphology D has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology D has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology D has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0235] In one embodiment, morphology D has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology D has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology D has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology D has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0236] In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology D has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0237] In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology D has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0238] In one embodiment, morphology E has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0239] In one embodiment, morphology E has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology E has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology E has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0240] In one embodiment, morphology E has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology E has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology E has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology E has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0241] In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology E has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0242] In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology E has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0243] In one embodiment, morphology F has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0244] In one embodiment, morphology F has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology F has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology F has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0245] In one embodiment, morphology F has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology F has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology F has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology F has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0246] In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology F has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0247] In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology F has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0248] In one embodiment, morphology F' has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0249] In one embodiment, morphology F' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology F' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology F' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0250] In one embodiment, morphology F' has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology F' has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology F' has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology F' has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0251] In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology F' has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0252] In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology F' has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0253] In one embodiment, morphology G has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0254] In one embodiment, morphology G has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology G has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology G has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0255] In one embodiment, morphology G has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology G has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology G has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology G has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0256] In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology G has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0257] In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology G has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0258] In one embodiment, morphology H has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0259] In one embodiment, morphology H has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology H has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology H has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0260] In one embodiment, morphology H has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology H has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology H has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology H has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0261] In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology H has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0262] In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology H has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0263] In one embodiment, morphology H' has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0264] In one embodiment, morphology H' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology H' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology H' has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0265] In one embodiment, morphology H' has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology H' has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology H' has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology H' has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0266] In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology H' has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0267] In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology H' has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0268] In one embodiment, morphology J has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0269] In one embodiment, morphology J has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology H has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology H has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0270] In one embodiment, morphology J has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology J has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology J has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology J has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0271] In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology J has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0272] In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology J has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0273] In one embodiment, morphology K has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0274] In one embodiment, morphology K has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology K has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology K has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0275] In one embodiment, morphology K has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology K has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology K has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology K has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0276] In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology K has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0277] In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology K has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0278] In one embodiment, morphology L has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0279] In one embodiment, morphology L has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology L has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology L has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0280] In one embodiment, morphology L has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology L has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology L has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology L has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0281] In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology L has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0282] In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology L has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0283] In one embodiment, morphology M has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0284] In one embodiment, morphology M has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology M has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology M has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0285] In one embodiment, morphology M has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology M has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology M has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology M has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0286] In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology M has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0287] In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology M has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0288] In one embodiment, morphology N has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0289] In one embodiment, morphology N has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, morphology N has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, morphology N has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0290] In one embodiment, morphology N has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, morphology N has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, morphology N has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, morphology N has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0291] In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, morphology N has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0292] In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, morphology N has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0293] In one embodiment, the amorphous morphology has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm.

[0294] In one embodiment, the amorphous form has a D[V,0.10] particle size between approximately 0.5 μm and approximately 15 μm. In one embodiment, the amorphous form has a D[V,0.10] particle size between approximately 0.5 μm and approximately 10 μm. In one embodiment, the amorphous form has a D[V,0.10] particle size between approximately 0.5 μm and approximately 5 μm.

[0295] In one embodiment, the amorphous form has a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, the amorphous form has a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, the amorphous form has a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, the amorphous form has a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0296] In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 400 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 100 μm. In one embodiment, the amorphous form has a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0297] In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 200 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 50 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 5 μm and approximately 25 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 10 μm and approximately 50 μm. In one embodiment, the amorphous form has a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0298] In one embodiment, the present disclosure relates to a composition comprising a crystalline or amorphous form of a hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having one or more of the following D[V,0.10] particle sizes: D[V,0.50] particle size: D[V,0.9

[0299] In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.10] particle size between about 0.5 μm and about 15 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.10] particle size between about 0.5 μm and about 10 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.10] particle size between about 0.5 μm and about 5 μm.

[0300] In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.50] particle size between approximately 2 μm and approximately 30 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.50] particle size between approximately 2 μm and approximately 25 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.50] particle size between approximately 2 μm and approximately 20 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.50] particle size between approximately 2 μm and approximately 15 μm.

[0301] In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between approximately 8 μm and approximately 600 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between approximately 8 μm and approximately 500 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between about 8 μm and about 400 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between approximately 8 μm and approximately 300 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between approximately 8 μm and approximately 200 μm.In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between about 8 μm and about 100 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[V,0.90] particle size between approximately 8 μm and approximately 75 μm.

[0302] In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between about 5 μm and about 200 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between approximately 5 μm and approximately 150 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between approximately 5 μm and approximately 100 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between approximately 5 μm and approximately 75 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between approximately 5 μm and approximately 50 μm.In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between about 10 μm and about 50 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between about 10 μm and about 40 μm. In one embodiment, the composition comprises a crystalline or amorphous form of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a D[4,3] particle size between approximately 10 μm and approximately 30 μm.

[0303] In one embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)pentanamide is amorphous, having one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm. In one embodiment, the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is in crystalline form and has one or more of the following D[V,0.10] particle sizes: D[V,0.50] particle size: D[V,0.90] particle size: D[V,0.90] particle size: D[V,0.90] particle size: D[V,0.3 In one embodiment, an amorphous or crystalline hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1H-imidazole-4-yl)pentanamide having one or more of the following D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm is a compound of formula (I). [ka] That is the case.

[0304] In one embodiment, (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl has one or more of the following D[V,0.10] particle sizes: between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes: between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes: between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes: between approximately 5 μm and approximately 200 μm. Hydrobromide of )amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is a compound of formula (II). [ka] That is the case.

[0305] In one embodiment, the crystal morphology is selected from the group consisting of morphology A, morphology B, morphology C, morphology D, morphology E, morphology F, morphology F', morphology G, morphology H, morphology H', morphology J, morphology K, morphology L, morphology M, and morphology N. In one embodiment, the crystal morphology is morphology A.

[0306] In some embodiments, the crystalline morphology is morphology A having one or more particle parameters selected from the group consisting of D[V,0.10], D[V,0.50], D[V,0.90], and D[4,3]. In other embodiments, the crystalline morphology is morphology A having two or more particle parameters selected from the group consisting of D[V,0.10], D[V,0.50], D[V,0.90], and D[4,3].

[0307] Each embodiment described herein can be combined with any other embodiment described herein, provided that such combination is not inconsistent with the combined embodiment.

[0308] In other embodiments, the crystalline morphology is morphology A having D[V,0.10] of approximately 0.5μm to approximately 15μm; approximately 0.5μm to approximately 10μm; approximately 0.5μm to approximately 5μm; approximately 1μm to approximately 15μm; approximately 1μm to approximately 10μm; approximately 1μm to approximately 7.5μm; approximately 1μm to approximately 5μm; approximately 2μm to approximately 10μm; approximately 2μm to approximately 7.5μm; approximately 2μm to approximately 5μm; approximately 3μm to approximately 10μm; approximately 3μm to approximately 7.5μm; or approximately 3μm to approximately 5μm. In other embodiments, the crystalline morphology is morphology A having a D[V,0.10] of less than 15 μm; less than 12.5 μm; less than 10 μm; less than 9 μm; less than 8 μm; less than 7 μm; less than 6 μm; less than 5 μm; less than 4 μm; or less than 3 μm.

[0309] In other embodiments, the crystal morphology is approximately 2 μm to 30 μm; 2 μm to 20 μm; approximately 2 μm to 15 μm; approximately 2 μm to 10 μm; approximately 5 μm to 30 μm; approximately 5 μm to 25 μm; approximately 5 μm to 20 μm; approximately 5 μm to 15 μm; approximately 5 μm to 10 μm; approximately 7.5 μm to 30 μm; approximately 7.5 μm to 25 μm; approximately 7.5 μm to 20 μm; approximately This is morphology A having D[V,0.50] in the following ranges: 7.5μm to approximately 15μm; approximately 7.5μm to approximately 10μm; approximately 10μm to approximately 30μm; approximately 10μm to approximately 25μm; approximately 10μm to approximately 20μm; approximately 10μm to approximately 15μm; approximately 12μm to approximately 15μm; approximately 15μm to approximately 30μm; approximately 15μm to approximately 25μm; approximately 15μm to approximately 20μm; and approximately 20μm to approximately 30μm. In other embodiments, the crystalline morphology is morphology A having D[V,0.50] in the following ranges: less than 30μm; less than 25μm; less than 20μm; less than 15μm; less than 12.5μm; or less than 10μm.

[0310] In other embodiments, the crystal morphology is approximately 8 μm to 600 μm; approximately 8 μm to 575 μm; approximately 8 μm to 550 μm; approximately 8 μm to 525 μm; approximately 8 μm to 500 μm; approximately 8 μm to 475 μm; approximately 8 μm to 450 μm; approximately 8 μm to 425 μm; approximately 8 μm to 400 μm; approximately 8 μm to 375 μm; approximately 8 μm to 350 μm; approximately 8 μm to 325 μm; approximately 8 μm to 300 μm; approximately 8 μm to 275 μm; approximately 8 μm to 250 μm; approximately 8 μm to 225 μm; approximately 8 μm to 200 μm; approximately 8 μm to 175 μm; approximately 8 μm to 150 μm; approximately 8 μm to Approx. 175 μm; Approx. 8 μm to approx. 150 μm; Approx. 8 μm to approx. 125 μm; Approx. 8 μm to approx. 100 μm; Approx. 8 μm to approx. 75 μm; Approx. 8 μm to approx. 50 μm; about 8 μm to about 40 μm; about 8 μm to about 30 μm; about 10 μm to about 600 μm; about 10 μm to about 575 μm; about 10 μm to about 550 μm m; about 10 μm to about 525 μm; about 10 μm to about 500 μm; about 10 μm to about 475 μm; about 10 μm to about 450 μm; about 10 μm to about 4 25μm; about 10μm to about 400μm; about 10μm to about 375μm; about 10μm to about 350μm; about 10μm to about 325μm; about 10μm ~Approx. 300μm; Approx. 10μm ~ Approx. 275μm; Approx. 10μm ~ Approx. 250μm; Approx. 10μm ~ Approx. 225μm; Approx. 10μm ~ Approx. 200μm; Approx. 1 0μm~about 175μm;about 10μm~about 150μm;about 10μm~about 125μm;about 10μm~about 100μm;about 10μm~about 75μm; Approximately 10μm to approximately 60μm; Approximately 10μm to approximately 50μm; Approximately 25μm to approximately 600μm; Approximately 25μm to approximately 575μm; Approximately 25μm to approximately 550μm ;Approx. 25μm~Approx. 525μm;Approx. 25μm~Approx. 500μm;Approx. 25μm~Approx. 475μm;Approx. 25μm~Approx. 450μm;Approx. 25μm~Approx. 42 5μm; about 25μm to about 400μm; about 25μm to about 375μm; about 25μm to about 350μm; about 25μm to about 325μm; about 25μm to about Approx. 300μm; Approx. 25μm ~ Approx. 275μm; Approx. 25μm ~ Approx. 250μm; Approx. 25μm ~ Approx. 225μm; Approx. 25μm ~ Approx. 200μm; Approx. 25 μm~about 175μm;about 25μm~about 150μm;about 25μm~about 125μm;about 25μm~about 100μm;about 25μm~about 75μm;about 25μm~about 50μm;about 40μm~about 600μm;about 40μm~about 575μm;about 40μm~about 550μm;about 40μm~about 525μm;Approximately 40μm to approximately 500μm; approximately 40μm to approximately 475μm; approximately 40μm to approximately 450μm; approximately 40μm to approximately 425μm; approximately 40μm to approximately 400μm; approximately 40μm to approximately 375μm; approximately 40μm to approximately 350μm; approximately 40μm to approximately 325μm; approximately 40μm to approximately 300μm; approximately 40μm to approximately 275μm; approx. 40μm to approx. 250μm; approx. 40μm to approx. 225μm; approx. 40μm to approx. 200μm; approx. 40μm to approx. 175μm; approx. 40μm to approx. 150μm; approx. 40μm to approx. 125μm; approx. 40μm to approx. 100μm; approx. 40μm to approx. 75μm; approx. 40μm to approx. 50μm; approx. 50μm m ~ approximately 600μm; approximately 50μm ~ approximately 575μm; approximately 50μm ~ approximately 550μm; approximately 50μm ~ approximately 525μm; approximately 50μm ~ approximately 500μm; approximately 50μm ~ approximately 475μm; approximately 50μm ~ approximately 450μm; approximately 50μm ~ approximately 425μm; approximately 50μm ~ approximately 400μm; approximately 50μm ~ approximately 375μm Approximately 50μm to 350μm; Approximately 50μm to 325μm; Approximately 50μm to 300μm; Approximately 50μm to 275μm; Approximately 50μm to 250μm; Approximately 50μm to 225μm; Approximately 50μm to 200μm; Approximately 50μm to 175μm; Approximately 50μm to 150μm; Approximately 50μm to approximately 125μm; approximately 50μm to approximately 100μm; approximately 50μm to approximately 75μm; approximately 75μm to approximately 600μm; approximately 75μm to approximately 575μm; approximately 75μm to approximately 550μm; approximately 75μm to approximately 525μm; approximately 75μm to approximately 500μm; approximately 75μm to approximately 475μm; approximately 75μm to approximately 450μm; approximately 75μm μm ~ approx. 425μm; approx. 75μm ~ approx. 400μm; approx. 75μm ~ approx. 375μm; approx. 75μm ~ approx. 350μm; approx. 75μm ~ approx. 325μm; approx. 75μm ~ approx. 300μm; approx. 75μm ~ approx. 275μm; approx. 75μm ~ approx. 250μm; approx. 75μm ~ approx. 225μm; approx. 75μm ~ approx. 200μm m; approximately 75μm to approximately 175μm; approximately 75μm to approximately 150μm; approximately 75μm to approximately 125μm; approximately 75μm to approximately 100μm; approximately 100μm to approximately 600μm; approximately 100μm to approximately 575μm; approximately 100μm to approximately 550μm; approximately 100μm to approximately 525μm; approximately 100μm to approximately 500μm; approximately 100μm ~ approx. 475μm; approx. 100μm ~ approx. 450μm; approx. 100μm ~ approx. 425μm; approx. 100μm ~ approx. 400μm; approx. 100μm ~ approx. 375μm; approx. 100μm ~ approx. 350μm; approx. 100μm ~ approx. 325μm; approx. 100μm ~ approx. 300μm; approx. 100μm ~ approx. 275μm;Approximately 100μm to approximately 250μm; approximately 100μm to approximately 225μm; approximately 100μm to approximately 200μm; approximately 100μm to approximately 175μm; approximately 100μm to approximately 150μm; approximately 100μm to approximately 125μm; approximately 125μm to approximately 600μm; approximately 125μm to approximately 575μm; approximately 125μm to approximately 550μm m; approx. 125μm to approx. 525μm; approx. 125μm to approx. 500μm; approx. 125μm to approx. 475μm; approx. 125μm to approx. 450μm; approx. 125μm to approx. 425μm; approx. 125μm to approx. 400μm; approx. 125μm to approx. 375μm; approx. 125μm to approx. 350μm; approx. 125μm to approx. 320μm 5μm; approximately 125μm to approximately 300μm; approximately 125μm to approximately 275μm; approximately 125μm to approximately 250μm; approximately 125μm to approximately 225μm; approximately 125μm to approximately 200μm; approximately 125μm to approximately 175μm; approximately 125μm to approximately 150μm; approximately 125μm to approximately 600μm; approximately 150μm to approximately 575μm; approx. 150μm to approx. 550μm; approx. 150μm to approx. 525μm; approx. 150μm to approx. 500μm; approx. 150μm to approx. 475μm; approx. 150μm to approx. 450μm; approx. 150μm to approx. 425μm; approx. 150μm to approx. 400μm; approx. 150μm to approx. 375μm; approx. 150μm~ Approximately 350 μm; approximately 150 μm to approximately 325 μm; approximately 150 μm to approximately 300 μm; approximately 150 μm to approximately 275 μm; approximately 150 μm to approximately 250 μm; approximately 150 μm to approximately 225 μm; approximately 150 μm to approximately 200 μm; approximately 150 μm to approximately 175 μm; approximately 175 μm to approximately 600 μm; approximately 175 μm m ~ approx. 575μm; approx. 175μm ~ approx. 550μm; approx. 175μm ~ approx. 525μm; approx. 175μm ~ approx. 500μm; approx. 175μm ~ approx. 475μm; approx. 175μm ~ approx. 450μm; approx. 175μm ~ approx. 425μm; approx. 175μm ~ approx. 400μm; approx. 175μm ~ approx. 375μm; approx. 17 5μm to approximately 350μm; approximately 175μm to approximately 325μm; approximately 175μm to approximately 300μm; approximately 175μm to approximately 275μm; approximately 175μm to approximately 250μm; approximately 175μm to approximately 225μm; approximately 175μm to approximately 200μm; approximately 200μm to approximately 600μm; approximately 200μm to approximately 575μm; approximately 200μm to approximately 550μm; approximately 200μm to approximately 525μm; approximately 200μm to approximately 500μm; approximately 200μm to approximately 475μm; approximately 200μm to approximately 450μm; approximately 200μm to approximately 425μm; approximately 200μm to approximately 400μm; approximately 200μm to approximately 375μm; approximately 200μm to approximately 350μm;Approximately 200μm to approximately 325μm; approximately 200μm to approximately 300μm; approximately 200μm to approximately 275μm; approximately 200μm to approximately 250μm; approximately 200μm to approximately 225μm; approximately 225μm to approximately 600μm; approximately 225μm to approximately 575μm; approximately 225μm to approximately 550μm; approximately 225μm to approximately 525μm m; approx. 225μm ~ approx. 500μm; approx. 225μm ~ approx. 475μm; approx. 225μm ~ approx. 450μm; approx. 225μm ~ approx. 425μm; approx. 225μm ~ approx. 400μm; approx. 225μm ~ approx. 375μm; approx. 225μm ~ approx. 350μm; approx. 225μm ~ approx. 325μm; approx. 225μm ~ approx. 30 0μm; approx. 225μm to approx. 275μm; approx. 225μm to approx. 250μm; approx. 250μm to approx. 600μm; approx. 250μm to approx. 575μm; approx. 250μm to approx. 550μm; approx. 250μm to approx. 525μm; approx. 250μm to approx. 500μm; approx. 250μm to approx. 475μm; approx. 250μm to approx. 450μm; approx. 250μm to approx. 425μm; approx. 250μm to approx. 400μm; approx. 250μm to approx. 375μm; approx. 250μm to approx. 350μm; approx. 250μm to approx. 325μm; approx. 250μm to approx. 300μm; approx. 250μm to approx. 275μm; approx. 275μm to approx. 600μm; approx. 275μm~ Approximately 575 μm; approximately 275 μm to approximately 550 μm; approximately 275 μm to approximately 525 μm; approximately 275 μm to approximately 500 μm; approximately 275 μm to approximately 475 μm; approximately 275 μm to approximately 450 μm; approximately 275 μm to approximately 425 μm; approximately 275 μm to approximately 400 μm; approximately 275 μm to approximately 375 μm; approximately 275 μm m ~ approx. 350μm; approx. 275μm ~ approx. 325μm; approx. 275μm ~ approx. 300μm; approx. 300μm ~ approx. 600μm; approx. 300μm ~ approx. 575μm; approx. 300μm ~ approx. 550μm; approx. 300μm ~ approx. 525μm; approx. 300μm ~ approx. 500μm; approx. 300μm ~ approx. 475μm; approx. 30 0μm ~ approximately 450μm; approximately 300μm ~ approximately 425μm; approximately 300μm ~ approximately 400μm; approximately 300μm ~ approximately 375μm; approximately 300μm ~ approximately 350μm; approximately 300μm ~ approximately 325μm; approximately 325μm ~ approximately 600μm; approximately 325μm ~ approximately 575μm; approximately 325μm ~ approximately 550μm; approximately 325μm to approximately 525μm; approximately 325μm to approximately 500μm; approximately 325μm to approximately 475μm; approximately 325μm to approximately 450μm; approximately 325μm to approximately 425μm; approximately 325μm to approximately 400μm; approximately 325μm to approximately 375μm; approximately 325μm to approximately 350μm; approximately 350μm to approximately 600μm;Approx. 350 μm to approx. 575 μm; approx. 350 μm to approx. 550 μm; approx. 350 μm to approx. 525 μm; approx. 350 μm to approx. 500 μm; approx. 25μm; about 350μm to about 400μm; about 350μm to about 375μm; about 375μm to about 600μm; about 375μm to about 575μm; about 375μm to about 550μm; about 375μm to about 525μm; about 375μm m ~ approx. 500 μm; approx. 375 μm ~ approx. 475 μm; approx. 375 μm ~ approx. 450 μm; approx. 375 μm ~ approx. 425 μm; approx. 400μm~about 550μm;about 400μm~about 525μm;about 400μm~about 500μm;about 400μm~about 475μm;about 400μm~about 450μm;about 400μm~about 425μm;about 425μm~about 600 μm; approx. 425 μm ~ approx. 575 μm; approx. 425 μm ~ approx. 550 μm; approx. 425 μm ~ approx. 525 μm; approx. 425 μm ~ approx. 500 μm; approx. Approx. 450 μm ~ approx. 550 μm; approx. 450 μm ~ approx. 525 μm; approx. 450 μm ~ approx. 500 μm; approx. 450 μm ~ approx. 475 μm; approx. This is morphology A having D[V,0.90] of approximately 5μm to 575μm; approximately 475μm to 550μm; approximately 475μm to 525μm; approximately 450μm to 500μm; approximately 450μm to 475μm; approximately 500μm to 600μm; approximately 500μm to 575μm; approximately 500μm to 550μm; approximately 500μm to 525μm; approximately 550μm to 600μm; approximately 550μm to 575μm; or approximately 575μm to 600μm. In other embodiments, the crystalline morphology is morphology A having a D[V,0.90] of less than 600 μm, less than 575 μm, less than 550 μm, less than 525 μm, less than 500 μm, less than 475 μm, less than 450 μm, less than 425 μm, less than 400 μm, less than 375 μm, less than 350 μm, less than 325 μm, less than 300 μm, less than 275 μm, less than 250 μm, less than 225 μm, less than 200 μm, less than 175 μm; less than 150 μm; less than 125 μm; less than 100 μm; less than 75 μm; or less than 50 μm.

[0311] In other embodiments, the crystal morphology is approximately 5 μm to 200 μm; approximately 5 μm to 175 μm; approximately 5 μm to 150 μm; approximately 5 μm to 125 μm; approximately 5 μm to 100 μm; approximately 5 μm to 75 μm; approximately 5 μm to 50 μm; approximately 5 μm to 40 μm; approximately 5 μm to 25 μm; approximately 10 μm to 200 μm; approximately 10 μm to 175 μm; approximately 10 μm to 150 μm; approximately 10 μm to 125 μm; approximately 10 μm to 100 μm; approximately 10 μm to 75 μm; approximately 10 μm to 50 μm; approximately 10 μm to about 40 μm; about 10 μm to about 25 μm; about 15 μm to about 200 μm; about 15 μm to about 175 μm; about 15 μm to about 150 μm; about 15 μm to about 125 μm; about 15 μm to about 100 μm; about 15 μm to about 75 μm; about 15 μm m ~ approx. 50 μm; approx. 15 μm ~ approx. 40 μm; approx. 15 μm ~ approx. 25 μm; approx. 20 μm ~ approx. 200 μm; approx. 20 μm ~ approx. 5μm; about 20μm to about 50μm; about 25μm to about 200μm; about 25μm to about 175μm; about 25μm to about 150μm; about 25μm to about 125μm; about 25μm to about 100μm; about 25μm to about 75μm; about 25μm to about 50μm Approx. 25 μm to approx. 40 μm; Approx. 50 μm to approx. 200 μm; Approx. 50 μm to approx. 175 μm; Approx. 50 μm to approx. 150 μm; Approx. 50 μm to approx. This is morphology A having D[4,3] of approximately 5μm to 175μm; approximately 75μm to 150μm; approximately 75μm to 125μm; approximately 75μm to 100μm; approximately 100μm to 200μm; approximately 100μm to 175μm; approximately 100μm to 150μm; approximately 100μm to 125μm; approximately 125μm to 200μm; approximately 125μm to 175μm; approximately 125μm to 150μm; approximately 150μm to 200μm; approximately 150μm to 175μm; or approximately 175μm to 200μm. In other embodiments, the crystalline form is form A having D[4,3] less than 200 μm; less than 175 μm; less than 150 μm; less than 125 μm; less than 100 μm; less than 75 μm; 50 μm; less than 40 μm; less than 30 μm; or less than 25 μm.

[0312] The hydrobromide form of compound 1 can be prepared based on the synthetic scheme described in U.S. Patent No. 7,795,447, which is incorporated herein by reference in its entirety. In some embodiments, a specific crystalline or amorphous form of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having a desired particle size is the product of the synthesis. In other embodiments, (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1H-imidazole-4-yl)pentanamide, which is a specific crystalline or amorphous hydrobromide having a desired particle size, is prepared using further post-synthesis processing steps. Examples of such processing steps include, but are not limited to, recrystallization and milling, such as jet milling.

[0313] In some embodiments, particle size is determined by laser diffraction (e.g., Sympatec Helos and QicPic) at a dispersion pressure of 3.0 bar.

[0314] The particle size of crystalline materials can be evaluated using laser diffraction. Laser diffraction is accredited by standard methods and guidance bodies, including ISO and ASTM, and is widely used to determine particle size distributions. During evaluation, a sample is passed through a laser beam that produces laser light scattered within a certain range of angles. A detector positioned at a fixed angle measures the intensity of the scattered light at that location. Then, a mathematical model (Mie or Fraunhoffer theory) is applied to generate the particle size distribution.

[0315] Particle size was analyzed using laser diffraction (or small-angle light scattering) techniques by dispersing dry sample powders with compressed air. Specifically, the particle size distribution was analyzed using a Sympatec HELOS RODOS system equipped with a Vibri dry powder feeder. Powder samples were dispersed at a dispersion pressure of 0.5 bar. In some cases, an Aspiros micro-dosing device was used to disperse powder samples at a dispersion pressure of 0.2 bar. A suitable lens was selected to cover the particle size range of each sample.

[0316] In particle size determination, the median value is defined as the point at which half of the population lies above and half lies below. In relation to particle size distribution, the median is called D50. D50 is the micron size that divides the distribution into upper and lower halves above this diameter. The expression Dv50 or D[v,0.5] is sometimes used for the median in volume distributions.

[0317] A mode is a peak in the frequency distribution. For example, if particles exist as primary particles and aggregates, the particle distribution may contain more than one mode.

[0318] The interval is sometimes used as a measure of the distribution width and is defined as the ratio of (D[v,0.9]-D[v,0.1]) / D[v,0.5] or (D90-D10) / D50.

[0319] The width of the distribution can also be characterized by citing one, two, or preferably three values, typically a combination of D10, D50, and D90. D50, being the median, is defined above as the diameter, in which case half of the population lies below this value. Similarly, 90 percent of the distribution lies below D90, and 10 percent of the population lies below D10.

[0320] The term D[4,3] refers to the average volume or average mass moment. Laser diffraction results are reported on a volume basis, and the average volume can be used to define the midpoint of the distribution. The D[4,3] value is susceptible to the presence of large particles in the distribution. IV. Pharmaceutical Compositions

[0321] Forms A to N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), may be administered to a subject by oral, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and injection techniques, etc.), rectal, intranasal, topical, or transdermal (e.g., by the use of a patch). In one embodiment, crystalline form A of the compound of formula (I) may be administered to a subject by oral, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and injection techniques, etc.), rectal, intranasal, topical, or transdermal (e.g., by the use of a patch).

[0322] In one embodiment, the pharmaceutical composition comprises crystalline form A of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I). In one embodiment, the pharmaceutical composition is an oral tablet comprising one or more of forms A to N and amorphous forms of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)pentanamide of formula (I) or (II), and a pharmaceutically acceptable carrier. In one embodiment, the tablet contains about 25 mg to about 400 mg of one or more of the hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II).In one embodiment, the tablets contain hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1H-imidazole-4-yl)pentanamide in one or more forms A-N or amorphous, in doses of approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 55 mg, approximately 60 mg, approximately 65 mg, approximately 70 mg, approximately 75 mg, and approximately 8 mg. Contains 0 mg, approximately 85 mg, approximately 90 mg, approximately 95 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 115 mg, approximately 120 mg, approximately 125 mg, approximately 130 mg, approximately 135 mg, approximately 140 mg, approximately 145 mg, approximately 150 mg, approximately 155 mg, approximately 160 mg, approximately 165 mg, approximately 170 mg, approximately 175 mg, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, or approximately 400 mg. In one embodiment, the tablet contains about 50 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is one or more of forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II).In one embodiment, the tablet contains about 100 mg of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is one or more of forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II). In one embodiment, the tablet contains about 150 mg of one or more of the hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II).

[0323] With regard to oral administration, known carriers may be included in the pharmaceutical composition. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine may be used together with various disintegrants such as starch (preferably corn, potato, or tapioca starch), methylcellulose, and alginic acid, and certain silicate complexes combined with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia may be included in tablets. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid compositions may also be used as fillers in gelatin capsules. Preferred substances in this regard include lactose and high molecular weight polyethylene glycol. If an aqueous suspension and / or elixir is preferred for oral administration, the active ingredient may be combined with various sweeteners or flavorings, colorants or dyes, and, if so preferred, emulsifiers and / or suspending agents, along with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[0324] For parenteral administration, solutions containing compound 1 can be prepared in either sesame oil or peanut oil, in aqueous propylene glycol, or in sterile water or physiological saline. The aqueous solutions should, if necessary, be preferably buffered (preferably to a pH greater than 8), and the liquid diluent should first be isotonic with sufficient physiological saline or glucose. These aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intra-articular, intramuscular, and subcutaneous injection. All of these solutions can be easily prepared under sterile conditions using standard pharmaceutical techniques well known to those skilled in the art. V. Treatment Methods

[0325] Forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which are formula (I) or (II), can be used to modulate or inhibit the Notch signaling pathway in organisms including humans. Notch signaling is often enhanced in various human tumors (including, but not limited to, breast, prostate, pancreatic, and T-cell acute lymphoblastic leukemia).

[0326] Therefore, forms A to N and amorphous forms of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), can be administered to treat subjects with tumors or cancer, including but not limited to tendinoid tumors, multiple myeloma, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. In one embodiment, crystalline form A of the compound of formula (I) can be administered to treat subjects with tumors or cancer, including but not limited to tendinoid tumors, multiple myeloma, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. In one embodiment, crystalline form A and pharmaceutically acceptable carriers of the compound of formula (I) can be administered to treat subjects with tumors or cancer, including, but not limited to, tendinoid tumors, multiple myeloma, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. In one embodiment, hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), can be administered to treat tumors, including tendinoid tumors. In one embodiment, forms A to N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), can be administered to treat cancers having mutations in the Notch pathway gene.In one embodiment, forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), can be administered to treat multiple myeloma. Forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), can be administered to treat adenoid cystic carcinoma. Forms A-N and amorphous forms of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which are of formula (I) or (II), can be administered to treat T-cell acute lymphoblastic leukemia.

[0327] In one embodiment, one or more of the hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II), are administered in doses ranging from about 0.1 mg to about 1000 mg per day. In one embodiment, the subject is administered approximately 50 mg to approximately 500 mg per day of one or more of the hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II). In another embodiment, the subject is administered approximately 100 mg to approximately 400 mg per day of one or more of the hydrobromide forms A to N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II). In another embodiment, the subject is administered one or more of the hydrobromide forms A-N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) or (II) in doses of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg per day. The total daily dose may be provided as a single dose or as divided doses (i.e., one, two, three, or four doses per day). In one embodiment, the total daily dose is provided as two doses.For example, a total daily dose of 300 mg or 200 mg can be administered to a subject as two separate doses of 150 mg or 100 mg, respectively. In one embodiment, a subject may be administered three tablets twice daily containing 50 mg of one or more of the hydrobromide forms A-N and amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) or (II), or two tablets twice daily containing 50 mg of one or more of the forms A-N and amorphous compound 1 of formula (I) or (II).

[0328] In one embodiment, the disclosure relates to the use of one or more of the hydrobromide salts A-N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) or formula (II) discussed above for treating tumors or cancer. In one embodiment, the disclosure relates to the use of crystalline form A of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) for treating tumors or cancer. In one embodiment, the present disclosure relates to the pharmaceutical compositions discussed above for treating tumors or cancers. In one embodiment, the use is for treating tendinoid tumors. In one embodiment, the use is for treating cancers selected from the group consisting of multiple myeloma, cancers with mutations in the Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

[0329] In one embodiment, the present disclosure relates to one or more of the hydrobromide forms A to N or amorphous forms of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide, which is formula (I) or (II) discussed above, for use in methods of treating tumors or cancer. In one embodiment, the disclosure relates to a crystalline form A of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide of formula (I) for use in methods of treating tumors or cancer. In one embodiment, the disclosure relates to the pharmaceutical composition discussed above for use in methods of treating tumors or cancer. In one embodiment, the use is for treating tendinoid tumors. In one embodiment, the use is for treating cancers selected from the group consisting of multiple myeloma, cancers with mutations in the Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. [Examples]

[0330] A. Abbreviations and acronyms [Table 1D]

[0331] B. Experimental Method (Example 1) Approximate kinetic solubility

[0332] A weighed sample of the substance was treated with a fixed amount of the specified solvent at ambient temperature. The sample was typically subjected to sonication between additions to promote dissolution. Complete dissolution was observed by visual inspection. Solubility was calculated based on the total amount of solvent added to achieve complete dissolution, and may be greater than the reported value due to the gradual increase in solvent addition and the inherent kinetics of dissolution. If dissolution was not observed, the value was reported as "less than". If dissolution was observed at the initial addition of the solvent, the value was reported as "greater than". Table 1 shows the kinetic solubility of the hydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propane-2-yl)-1h-imidazole-4-yl)pentanamide. [Table 1-1] [Table 1-2] (Example 2) Screening of stable forms and hydrates

[0333] Method a: Grinding experiment

[0334] Samples of the hydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazole-4-yl)pentanamide were ground in a specified solvent system at ambient or set temperature. After approximately 24 hours, the solid was isolated by centrifugation using an Eppendorf centrifuge tube equipped with a 0.45 μm nylon filter. The mixture was then stirred in a fresh solvent for a total of approximately 1 week and 3 weeks, after which the solid was isolated as described above, observed under polarized light, and analyzed by XRPD.

[0335] Method b: Equilibrium solubility test

[0336] The equilibrium solubility of the isolated solid was determined by weight as follows: A fixed amount of mother liquor measured from a slurry prepared over three weeks was placed in a pre-weighed aluminum TGA pan. Subsequently, the solvent was evaporated under ambient conditions or using a vacuum. The residual solid was weighed.

[0337] Table 2 shows the screening results for stable forms and hydrates. [Table 2-1] [Table 2-2] (Example 3) Polymorphic screening

[0338] Unless otherwise specified, the hydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazole-4-yl)pentanamide was used as the starting material. The substances produced in this study were selected for the experiments.

[0339] The starting materials were subjected to crystallization techniques, which are summarized below. The solids were typically isolated by suction filtration, observed under polarized light, and analyzed by XRPD.

[0340] Method a: Grinding experiment:

[0341] The solid was combined with a small amount of solvent and transferred to an agate milling container. Agate balls were added, and the container was attached to a Lechner mill. The sample was milled at 30 Hz for one 20-minute cycle, or by refilling, and this cycle was repeated for another 20 minutes.

[0342] Method b: Slurry experiment

[0343] The solid was suspended in the specified solvent. The suspension was then stirred at ambient temperature or the set temperature. After a given time, the solid was isolated.

[0344] Method c: Solvent / antisolvent precipitation

[0345] Solutions of the starting materials were prepared at ambient temperature or high temperature and filtered using a 0.2 μm nylon filter. These were then mixed with a suitable antisolvent at high temperature. If no solid was observed, the sample was cooled to ambient temperature or below, or another crystallization technique was applied.

[0346] Method d: Grinding and precipitation

[0347] A solution of the starting material was prepared at high temperature in the specified solvent, filtered at warm temperature through a 0.2 μm nylon filter, and placed in a suitable antisolvent that had been pre-cooled on a dry ice / acetone bath or a water / ice bath. If solids precipitated, they were immediately isolated by suction filtration while still cold. If the solution remained clear, the sample was either maintained below ambient temperature or further crystallization techniques were applied.

[0348] Method e: Cooling experiment

[0349] Using a heating hot plate, the starting material solution was prepared at high temperature in the specified solvent. These solutions were typically filtered at warm temperature through a 0.2 μm nylon filter and placed in a warm receiving vial. This vial was either rapidly transferred to a sub-ambient temperature bath (usually dry ice / acetone) for impact cooling (CC), removed from a warm location for rapid cooling (FC), or the heating power was turned off to allow for slow cooling (SC). If solids precipitated, these solids were isolated by cooling and filtration using suction. If the solution remained clear, the sample was either maintained below ambient temperature or subjected to further crystallization techniques.

[0350] Method f: Solvent evaporation experiment

[0351] The starting material solution was partially evaporated at ambient temperature or high temperature, or evaporated to dryness, either from an open vial for rapid solvent evaporation (FE) or from a vial covered with pinhole aluminum foil for slow solvent evaporation (SE). Prior to solvent evaporation, the solution was filtered at ambient temperature or high temperature using a 0.2 μm nylon filter.

[0352] Method g: Liquid-gas diffusion experiment

[0353] A solution of the starting material was prepared at ambient temperature, filtered through a 0.2 μm nylon filter, and placed in a receiving vial. Next, the open vial was placed in a secondary container with a suitable antisolvent. The container was sealed and allowed to stand under ambient conditions.

[0354] Method h: Steam stress experiment

[0355] The starting material solid was transferred to a vial, and this vial was placed unsealed in a secondary container with a suitable antisolvent. The secondary container was sealed and allowed to stand under ambient or near-ambient conditions.

[0356] Method i: Low relative humidity stress experiment

[0357] The starting material solid was transferred to a vial, and this vial was placed in an RH jar containing P2O5 without a lid. It was then maintained at ambient temperature for a specified period.

[0358] Method j: Drying experiment

[0359] The starting material solid was dried for a specified period at ambient temperature, or under reduced pressure at a set temperature.

[0360] Table 3 summarizes the polymorphic screening results for the hydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazole-4-yl)pentanamide. [Table 3-1] [Table 3-2]

[0361] Table 4 summarizes the polymorph screening results for the hydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazole-4-yl)pentanamide, starting from X-ray amorphous material. [Table 4] (Example 4) Preparation of X-ray amorphous materials

[0362] A solution of the starting materials was prepared at ambient temperature in dioxane / water (50 / 50), filtered, and placed in a round-bottom flask. This flask was immersed in a dry ice / acetone bath to freeze the solution. Once frozen, the flask was placed in a freeze-drying oven at approximately -50°C for two days. (Example 5) Preparation of selected substances

[0363] Table 5 summarizes the preparation conditions for the selected substances. [Table 5-1] [Table 5-2]

[0364] Table 6 summarizes the drying conditions for the selected substances. [Table 6] (Example 6) Interconversion experiment

[0365] The starting materials, except for form A, were dried in a vacuum oven at 45°C for approximately one day. A saturated solution of form A was prepared in the specified solvent system, and seed crystals of the dried material and seed crystals of form A were added. The samples were stirred in a sealed vial at ambient temperature for approximately one week.

[0366] Table 7 summarizes the results of the interconversion experiments. [Table 7] (Example 7) Single crystal growth experiment

[0367] The following crystallization techniques were used to process samples of morphology A. In attempts to induce crystallization, seed crystals of morphology A were added to selected experiments.

[0368] Method a: Solvent evaporation / volume reduction experiment

[0369] The starting material solution was partially evaporated at ambient temperature or high temperature, or evaporated to dryness, either from an open vial for rapid solvent evaporation (FE) or from a loosely sealed vial or a vial covered with pinhole aluminum foil for slow solvent evaporation (SE). Prior to solvent evaporation, the solution was filtered at ambient temperature or high temperature using a 0.2 μm nylon filter.

[0370] Method b: Liquid-gas and liquid-liquid diffusion experiments

[0371] The starting material solution was prepared in the specified solvent at ambient temperature and filtered, typically using a 0.2 μm nylon filter. For liquid-gas diffusion (LVD), the vial containing the filtered solution was placed in a secondary container with a suitable anti-solvent and allowed to stand at or below ambient temperature. For liquid-liquid diffusion (LLD), the test material solution was carefully brought into contact with the specified solvent and allowed to stand at or below ambient temperature.

[0372] Method c: Cooling experiment

[0373] A solution of the starting material was prepared at a high temperature using a heating hot plate. Next, this solution was filtered while still warm using a 0.2 μm nylon filter and allowed to cool slowly to the set temperature (SC) by leaving it on the heat source. After the specified period, the solution was further cooled to below ambient temperature.

[0374] Table 8 summarizes the single crystal growth results for morphology A. [Table 8] (Example 8) X-ray powder diffraction (XRPD)

[0375] Method A: Transparency geometry

[0376] XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer, employing an incident beam of Cu irradiation generated using an Optix long fine focus source. An elliptical tilting multilayer mirror was used to pass the Cu Kα X-rays through the specimen and focus them on the detector surface. Prior to analysis, silicon specimens (NIST SRM 640d or 640e) were analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. The specimen was sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using beam stopping, a short antiscatter extension, and an antiscatter knife edge. Solar slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning positional high-sensitivity detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b.

[0377] Method b. Reflection geometry

[0378] XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer, employing an incident beam of Cu Kα irradiation generated using a long fine-focus source and a nickel filter. The diffractometer was constructed using symmetric Bragg-Brentano geometry. Prior to analysis, silicon specimens (NIST SRM 640d or 640e) were analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. The specimens were prepared as thin circular layers centered on the silicon zero-background substrate surface. A scattering prevention slit (SS) was used to minimize background generated by air. Solar slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning positional high-sensitivity detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b. (Example 9) Thermogravimetric analysis (TGA)

[0379] TGA analysis was performed using a TA Instruments 2050 or Discovery thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel®. Each sample was placed in an aluminum or platinum pan and inserted into the TG furnace. The furnace was heated under nitrogen purge. The method code on the thermogram is an abbreviation of the start and end temperatures, as well as the heating rate. For example, 25-350-10 means "from 25°C to 350°C at 10°C / min". (Example 10) Differential Scanning Calorimetry (DSC)

[0380] DSC was performed using a TA Instruments Q2000 differential scanning calorimetry instrument. Temperature calibration was performed using NIST-traceable indium metal. The sample was placed in an aluminum DSC pan (T0C), covered with a lid, and its weight was accurately recorded. The weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. The method code on the thermogram is an abbreviation of the start and end temperatures, as well as the heating rate. For example, -30-250-10 means "from -30°C to 250°C at 10°C / min". (Example 11) Thermogravimetric-infrared spectroscopy (TG-IR)

[0381] Thermogravimetric infrared (TG-IR) analysis was performed on a TA Instruments model 2050 thermogravimetric (TG) analyzer interfaced to a Magna-IR 560 (registered trademark) Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid / far IR source, a potassium bromide (KBr) beam splitter, and a mercury cadmium telluride (MCT-A) detector. Verification of the FT-IR wavelengths was performed using polystyrene, and the TG calibration standards were nickel and Alumel (trademark). Samples were placed in platinum sample pans, and these pans were inserted into the TG furnace. The TG instrument was started first, and then immediately, the FT-IR instrument was started. The TG instrument was operated under a helium flow of 90 cc / min and 10 cc / min for purge and balance, respectively. The furnace was heated under helium to a final temperature of 250 °C at a rate of 20 °C / min. IR spectra were collected approximately every 32 seconds for approximately 13 minutes. The IR spectra each represent 16 simultaneous scans collected at a spectral resolution of 4 cm -1 of the spectrum. Volatiles were identified by searching a high-resolution Nicolet vapor phase spectral library. A search from this library is considered non-cGMP. (Example 12) Polarizing optical microscopy (PLM)

[0382] Optical microscopy was performed using a Leica DM LP microscope equipped with a SPOT Insight (trademark) color digital camera. Typically, each sample was placed on a slide glass, a cover glass was placed over the sample, and 1 drop of mineral oil was added to and covered the sample by a capillary. Each sample was observed using a 0.8 - 10.0x objective lens equipped with a crossed polarizer and a first-order red compensator plate. (Example 14) Calculation method (indexing)

[0383] The successful indexing of the XRPD pattern indicates that the sample consists primarily of a single-crystal phase. The agreement between the acceptable peak positions and the observed peaks indicates a consistent unit cell determination. Indexing was performed using X'Pert High Score Plus 2.2a(2.2.1) and TRIADS®. No attempts were made to confirm the provisional indexing solution within the scope of this work. The present invention provides, for example, the following items: (Item 1) a) Crystal morphology A, characterized by an XRPD pattern with two theta peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees; b) Crystal morphology B, characterized by the XRPD pattern substantially shown in Figure 4; c) Crystal morphology D, characterized by the XRPD pattern substantially shown in Figure 11; d) Crystal morphology E, characterized by the XRPD pattern substantially shown in Figure 14; e) Crystal morphology F, characterized by the XRPD pattern substantially shown in Figure 17; f) Crystal morphology F' characterized by the XRPD pattern substantially shown in Figure 18; g) Crystal morphology G, characterized by the XRPD pattern substantially shown in Figure 21; h) Crystal morphology H characterized by the XRPD pattern substantially shown in Figure 22; i) Crystal morphology H' characterized by the XRPD pattern substantially shown in Figure 23; j) Crystal morphology J, characterized by the XRPD pattern substantially shown in Figure 24; k) Crystal morphology K, characterized by the XRPD pattern substantially shown in Figure 25; l) Crystal morphology L characterized by the XRPD pattern substantially shown in Figure 26; m) Crystal morphology M characterized by the XRPD pattern substantially shown in Figure 29; and n) Crystal morphology N characterized by the XRPD pattern substantially shown in Figure 30 Selected from the group consisting of equation (I) [ka] The crystalline form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 2) The crystal morphology described in item 1, wherein the crystal morphology is morphology A, characterized by an XRPD pattern having peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees in a two-theta configuration. (Item 3) The crystal form described in item 2, wherein the crystal form A is anhydrous. (Item 4) The crystal form described in item 2 or 3, wherein the melting point of crystal form A is approximately 254°C. (Item 5) A crystal morphology described in any one of items 2 to 4, characterized in that morphology A has an XRPD pattern with peaks at 2 theta degrees of 8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, and 29.3±0.2 degrees. (Item 6) A crystal morphology as described in any one of items 2 to 5, characterized in that morphology A has an XRPD pattern with peaks at 2 theta degrees of 8.8±0.2, 9.8±0.2, 20.0±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, 29.3±0.2 and 32.5±0.2 degrees. (Item 7) Morphology A is a crystalline morphology described in any one of items 2 to 6, characterized by the XRPD pattern substantially shown in Figure 1. (Item 8) Morphology A is a crystalline morphology described in any one of items 2 to 7, characterized by a TGA profile substantially shown in Figure 2. (Item 9) Morphology A is a crystalline morphology described in any one of items 2 to 8, characterized by the DSC profile substantially shown in Figure 3. (Item 10) A crystal morphology described in any one of items 2 to 9, wherein morphology A has a unit cell that is indexed as a simple monoclinic system. (Item 11) Morphology A is a crystal morphology described in any one of items 2 to 10, having a unit cell with an a value of approximately 10.035 Å, a b value of approximately 7.532 Å, and a c value of approximately 20.092 Å. (Item 12) Morphology A is approximately 1518.1 Å. 3 A crystalline form according to any one of items 2 to 11, having a unit cell having a volume of . (Item 13) The crystalline form A described above is one of the items 2 to 12, wherein the crystalline form A substantially does not include other polymorphic forms. (Item 14) The crystalline form A described above has a polymorphic purity of at least 90% according to any one of items 2 to 12. (Item 15) The crystalline form A described above has a polymorphic purity of at least 99% according to any one of items 2 to 12. (Item 16) The crystalline morphology described in any one of items 2 to 15, wherein morphology A has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 17) The crystal morphology described in item 1, wherein the crystal morphology is crystal morphology B characterized by the XRPD pattern substantially shown in Figure 4. (Item 18) The crystalline form described in item 17, wherein form B substantially does not include other polymorphic forms. (Item 19) The crystalline form according to item 17, wherein form B has a polymorphic purity of at least 90%. (Item 20) The crystalline form according to item 17, wherein form B has a polymorphic purity of at least 99%. (Item 21) The crystalline morphology described in any one of items 7 to 20, wherein morphology B has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 22) The crystal morphology described in item 1, wherein the crystal morphology is crystal morphology D characterized by the XRPD pattern substantially shown in Figure 11. (Item 23) Form D is, a)~b): a) TGA profile substantially shown in Figure 12A or Figure 12B; and b) DSC profile substantially shown on line A or line B in Figure 13 Characterized by one or more of the following: The crystalline form described in item 22. (Item 24) The crystal morphology described in item 22 or 23, wherein morphology D has a unit cell that is indexed as a simple monoclinic system. (Item 25) Morphology D is a crystal morphology described in any one of items 22 to 24, having a unit cell with an a value of approximately 18.465 Å, a b value of approximately 7.441 Å, and a c value of approximately 23.885 Å. (Item 26) Morphology D is approximately 3250.4 Å. 3 A crystalline form according to any one of items 22 to 25, having a unit cell having a volume of . (Item 27) The crystalline morphology described in any one of items 22 to 26, wherein the TGA indicates that morphology D undergoes a weight reduction of approximately 1.2 to approximately 2.5% by weight between approximately 24°C and approximately 109°C. (Item 28) Morphology D is a crystal morphology described in any one of items 22 to 27, which shows a DSC thermogram exhibiting an endothermic event at approximately 65°C. (Item 29) The crystalline form described in any one of items 22 to 28, wherein form D substantially does not include other polymorphic forms. (Item 30) The crystalline form D described above is the form according to any one of items 22 to 28, wherein the form D has a polymorphic purity of at least 90%. (Item 31) The crystalline form D described above is the one described in any one of items 22 to 28, wherein the crystalline form D has a polymorphic purity of at least 99%. (Item 32) The crystalline morphology described in any one of items 22 to 31, wherein morphology D has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm. (Item 33) The crystal morphology described in item 1, wherein the crystal morphology is morphology E characterized by the XRPD pattern substantially shown in Figure 14. (Item 34) Form E is, a)~b): a) TGA profile substantially shown in Figure 15; and b) DSC profile substantially shown in Figure 16 Characterized by one or more of the following: The crystalline form described in item 33. (Item 35) The crystalline morphology described in item 33 or 34, wherein the TGA indicates that morphology E undergoes a weight loss of approximately 8% by weight between approximately 28°C and approximately 120°C. (Item 36) Morphology E is a crystal morphology described in any one of items 33 to 35, which exhibits an endothermic DSC thermogram at approximately 80°C. (Item 37) The crystalline form described in any one of items 33 to 36, wherein form E substantially does not include other polymorphic forms. (Item 38) The crystalline form E described above has a polymorphic purity of at least 90% according to any one of items 33 to 36. (Item 39) The crystalline form E described above has a polymorphic purity of at least 99% according to any one of items 33 to 36. (Item 40) The crystalline morphology described in any one of items 33 to 39, wherein morphology E has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 41) The crystal morphology described in item 1, wherein the crystal morphology is morphology F characterized by the XRPD pattern substantially shown in Figure 17. (Item 42) The crystalline form described in item 41, wherein form F substantially does not include other polymorphic forms. (Item 43) The crystalline form according to item 41, wherein form F has a polymorphic purity of at least 90%. (Item 44) The crystalline form according to item 41, wherein the form F has a polymorphic purity of at least 99%. (Item 45) The crystalline morphology described in any one of items 41 to 44, wherein morphology F has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 46) The crystal morphology described in item 1, wherein the crystal morphology is morphology F' characterized by the XRPD pattern substantially shown in Figure 18. (Item 47) Form F' is, a)~b): a) TGA substantially shown in Figure 19; and b) DSC substantially shown in Figure 20 Characterized by one or more of the following: The crystalline form described in item 46. (Item 48) The crystalline morphology described in item 46 or 47, wherein the TGA indicates that morphology F' undergoes a weight loss of approximately 12.6% by weight between approximately 24°C and approximately 90°C, and a weight loss of approximately 15.6% by weight between approximately 97°C and approximately 198°C. (Item 49) The crystalline form described in any one of items 46 to 48, wherein the form F' substantially does not include other polymorphic forms. (Item 50) The crystalline form according to any one of items 46 to 49, wherein the form F' has a polymorphic purity of at least 90%. (Item 51) The crystalline form according to any one of items 46 to 49, wherein the form F' has a polymorphic purity of at least 99%. (Item 52) The crystalline morphology described in any one of items 46 to 51, wherein the morphology F' has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 53) The crystal morphology described in item 1, wherein the crystal morphology is morphology G characterized by the XRPD pattern substantially shown in Figure 21. (Item 54) The crystalline form described in item 53, wherein form G substantially does not include other polymorphic forms. (Item 55) The crystalline form according to item 53, wherein form G has a polymorphic purity of at least 90%. (Item 56) The crystalline form according to item 53, wherein form G has a polymorphic purity of at least 99%. (Item 57) The crystalline morphology described in any one of items 53 to 56, wherein morphology G has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 58) The crystal morphology described in item 1, wherein the crystal morphology is morphology H characterized by the XRPD pattern substantially shown in Figure 22. (Item 59) The crystalline form described in item 58, wherein form H substantially does not include other polymorphic forms. (Item 60) The crystalline form according to item 58, wherein the form H has a polymorphic purity of at least 90%. (Item 61) The crystalline form according to item 58, wherein the form H has a polymorphic purity of at least 99%. (Item 62) The crystalline morphology described in any one of items 58 to 61, wherein the morphology H has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 63) The crystal morphology described in item 1, wherein the crystal morphology is morphology H' characterized by the XRPD pattern substantially shown in Figure 23. (Item 64) The crystalline form described in item 63, wherein the form H' substantially does not include other polymorphic forms. (Item 65) The crystalline form described in item 63, wherein the form H' has a polymorphic purity of at least 90%. (Item 66) The crystalline form described in item 63, wherein the form H' has a polymorphic purity of at least 99%. (Item 67) The crystalline morphology described in any one of items 63 to 66, wherein the morphology H' has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 68) The crystal morphology described in item 1, wherein the crystal morphology is morphology J characterized by the XRPD pattern substantially shown in Figure 24. (Item 69) The crystalline form described in item 68, wherein form J substantially does not include other polymorphic forms. (Item 70) The crystalline form described in item 68, wherein form J has a polymorphic purity of at least 90%. (Item 71) The crystalline form described in item 68, wherein form J has a polymorphic purity of at least 99%. (Item 72) The crystalline morphology described in any one of items 68 to 71, wherein morphology J has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 73) The crystal morphology described in item 1, wherein the crystal morphology is morphology K characterized by the XRPD pattern substantially shown in Figure 25. (Item 74) The crystalline form described in item 73, wherein form K substantially does not include other polymorphic forms. (Item 75) The crystalline form described in item 73, wherein form K has a polymorphic purity of at least 90%. (Item 76) The crystalline form according to item 73, wherein the form K has a polymorphic purity of at least 99%. (Item 77) The crystalline morphology described in any one of items 73 to 76, wherein the morphology K has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 78) The crystal morphology described in item 1, wherein the crystal morphology is morphology L characterized by the XRPD pattern substantially shown in Figure 26. (Item 79) Form L is, a)~b): a) TGA profile substantially shown in Figure 27; and b) DSC profile substantially shown in Figure 28 Characterized by one or more of the following: The crystalline form described in item 78. (Item 80) The crystalline morphology described in item 78 or 79, wherein morphology L exhibits a DSC thermogram with an endothermic event at approximately 157°C. (Item 81) The crystalline form L described above is the form described in any one of items 78 to 80, wherein the form L substantially does not include other polymorphic forms. (Item 82) The crystalline form L described above has a polymorphic purity of at least 90% according to any one of items 78 to 80. (Item 83) The crystalline form L described above has a polymorphic purity of at least 99% according to any one of items 78 to 80. (Item 84) The crystalline morphology described in any one of items 78 to 83, wherein the morphology L has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 85) The crystal morphology described in item 1, wherein the crystal morphology is morphology M characterized by the XRPD pattern substantially shown in Figure 29. (Item 86) The crystalline form described in item 85, wherein the form M substantially does not include other polymorphic forms. (Item 87) The crystalline form according to item 85, wherein the form M has a polymorphic purity of at least 90%. (Item 88) The crystalline form according to item 85, wherein the form M has a polymorphic purity of at least 99%. (Item 89) The crystalline morphology described in any one of items 85 to 88, wherein the morphology M has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 90) The crystal morphology described in item 1, wherein the crystal morphology is morphology N characterized by the XRPD pattern substantially shown in Figure 30. (Item 91) The crystalline form described in item 90, wherein form N substantially does not include other polymorphic forms. (Item 92) The crystalline form according to item 90, wherein the form N has a polymorphic purity of at least 90%. (Item 93) The crystalline form according to item 90, wherein the form N has a polymorphic purity of at least 99%. (Item 94) The crystalline morphology described in any one of items 90 to 93, wherein the morphology N has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 95) Formula (II) [ka] (In the formula, n is approximately 1 to 3, and morphology C is characterized by the XRPD pattern substantially shown in Figure 5.) Crystalline form C of hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 96) Form C is, a)~c): a) TGA profile substantially shown in Figure 6; b) DSC profile substantially shown in Figure 7; and c) TG-IR linked spectra substantially shown in the figure selected from the group consisting of Figures 8-10 A crystal form described in item 95, having one or more features, selected from the group consisting of the following. (Item 97) The crystal morphology described in item 95 or 96, wherein morphology C has a unit cell that is indexed as a simple orthorhombic system. (Item 98) The crystal morphology described in any one of items 95 to 97, wherein morphology C has a unit cell with an a value of approximately 7.491 Å, a b value of approximately 10.353 Å, and a c value of approximately 48.790 Å. (Item 99) Morphology C is approximately 3783.9 Å. 3 A crystalline form according to any one of items 95 to 98, having a unit cell having a volume of . (Item 100) The crystalline morphology according to any one of items 95 to 99, wherein the TGA shows that morphology C undergoes a weight loss of at least 8% by weight between approximately 60°C and approximately 190°C. (Item 101) The crystal morphology described in any one of items 95 to 100, wherein morphology C shows a DSC thermogram having a first endothermic event at approximately 39°C and a second endothermic event at approximately 152°C. (Item 102) The crystalline form described in any one of items 95 to 101, wherein form C substantially does not include other polymorphic forms. (Item 103) The crystalline form according to any one of items 95 to 101, wherein the form C has a polymorphic purity of at least 90%. (Item 104) The crystalline form described in any one of items 95 to 101, wherein the form C has a polymorphic purity of at least 99%. (Item 105) The crystalline morphology described in any one of items 95 to 104, wherein morphology C has one or more of the following: D[V,0.10] particle sizes between approximately 0.5 μm and approximately 15 μm, D[V,0.50] particle sizes between approximately 2 μm and approximately 30 μm, D[V,0.90] particle sizes between approximately 8 μm and approximately 600 μm, or D[4,3] particle sizes between approximately 5 μm and approximately 200 μm. (Item 106) Equation (I) [ka] The amorphous form of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 107) The amorphous form described in item 106, wherein the crystalline form is characterized by the XRPD pattern substantially shown in Figure 31. (Item 108) The amorphous form described in item 106 or 107, wherein the amorphous form substantially does not include other polymorphic forms. (Item 109) The amorphous form according to item 106 or 107, wherein the amorphous form has a polymorphic purity of at least 90%. (Item 110) The amorphous form according to item 106 or 107, wherein the amorphous form has a polymorphic purity of at least 99%. (Item 111) The crystalline morphology according to either item 106 or 107, wherein the amorphous morphology has one or more of the following particle sizes: D[V,0.10] between approximately 0.5 μm and approximately 15 μm, D[V,0.50] between approximately 2 μm and approximately 30 μm, D[V,0.90] between approximately 8 μm and approximately 600 μm, or D[4,3] between approximately 5 μm and approximately 200 μm. (Item 112) A composition comprising a hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide having one or more of the following D[V,0.10] particle sizes: approximately 0.5 μm to approximately 15 μm, D[V,0.50] particle sizes: approximately 2 μm to approximately 30 μm, D[V,0.90] particle sizes: approximately 8 μm to approximately 600 μm, or D[4,3] particle sizes: approximately 5 μm to approximately 200 μm, in crystalline or amorphous form. (Item 113) The composition according to item 112, wherein the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is in amorphous form. (Item 114) The composition according to item 112, wherein the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is in crystalline form. (Item 115) The hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is a compound of formula (I). [ka] The composition described in item 114. (Item 116) The hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide is a compound of formula (II). [ka] The composition described in item 114. (Item 117) The composition according to item 115 or 116, wherein the crystalline form is selected from the group consisting of form A, form B, form C, form D, form E, form F, form F', form G, form H, form H', form J, form K, form L, form M, and form N. (Item 118) The composition according to item 117, wherein the crystalline form is form A. (Item 119) A pharmaceutical composition comprising any form or composition described in any one of items 1 to 116, and a pharmaceutically acceptable carrier. (Item 120) The pharmaceutical composition according to item 119, wherein the pharmaceutical composition is a tablet. (Item 121) The pharmaceutical composition according to item 119, wherein the pharmaceutical composition contains about 25 mg to about 400 mg of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 122) The pharmaceutical composition according to item 119, wherein the pharmaceutical composition comprises about 50 mg of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 123) The pharmaceutical composition according to item 119, wherein the pharmaceutical composition comprises about 100 mg of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 124) The pharmaceutical composition according to item 119, wherein the pharmaceutical composition comprises about 150 mg of the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide. (Item 125) A method for treating a tumor or cancer, comprising the step of administering a pharmaceutical composition described in any one of items 119 to 124 to a subject requiring such treatment. (Item 126) The method according to item 125, wherein the tumor is a tendinoid tumor. (Item 127) The method according to item 125, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with mutations in the Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. (Item 128) The method according to item 127, wherein the cancer is multiple myeloma. (Item 129) The method according to item 127, wherein the cancer is a cancer having a mutation in the Notch pathway gene. (Item 130) The method according to item 127, wherein the cancer is adenoid cystic carcinoma. (Item 131) The method according to item 127, wherein the cancer is T-cell acute lymphoblastic leukemia. (Item 132) The method according to any one of items 125 to 131, wherein the subject is administered approximately 50 mg to approximately 500 mg of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. (Item 133) The method according to any one of items 125 to 131, wherein the subject is administered approximately 100 mg to approximately 400 mg of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. (Item 134) The method according to any one of items 125 to 131, wherein the subject is administered approximately 300 mg of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. (Item 135) The method according to any one of items 123 to 131, wherein the subject is administered approximately 200 mg of the hydrobromide of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazole-4-yl)pentanamide daily. (Item 136) The method according to any one of items 125 to 135, wherein the total daily dose is supplied as two separate doses. (Item 137) The method according to item 136, wherein the total daily dose is supplied as two separate 150 mg doses. (Item 138) The method according to item 136, wherein the total daily dose is supplied as two separate 100 mg doses. (Item 139) Use of any one of the pharmaceutical compositions described in items 119 to 124 for the manufacture of a pharmaceutical for treating a tumor or cancer. (Item 140) The use described in item 139, where the tumor is a tendinoid tumor. (Item 141) The use described in item 139, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with mutations in the Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. (Item 142) A pharmaceutical composition according to any one of items 119 to 124, for use in a method of treating a tumor or cancer. (Item 143) The use described in item 142, where the tumor is a tendinoid tumor. (Item 144) The use described in item 142, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with mutations in the Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia.

Claims

[Claim 1] The invention as shown in the drawings.

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