Solid state forms 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 and uses thereof

Abstract

The present disclosure relates to a) a solid-state form of the hydrobromide salt of Compound 1; b) a pharmaceutical composition comprising one or more solid-state forms of the hydrobromide salt of Compound 1 and, optionally, a pharmaceutically acceptable carrier; c) a method of treating tumors or cancer by administering to a subject in need thereof one or more solid-state forms of the hydrobromide salt of Compound 1; and d) a method of preparing the solid-state forms of Compound 1. In one aspect, the disclosure relates to crystalline Form A 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 formula (I).

Description

[Technical field]

[0001] Technical Field The present disclosure relates to a) a solid state form 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 ("Compound 1"); b) a pharmaceutical composition comprising one or more solid state forms of the hydrobromide salt of Compound 1, and optionally a pharma- ceutically acceptable carrier; c) a method of treating a tumor or cancer by administering one or more solid state forms of the hydrobromide salt of Compound 1 to a subject in need thereof; and d) a method of preparing the solid state form of the hydrobromide salt of Compound 1. [Background technology]

[0002] background (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 ("Compound 1") is a gamma-secretase inhibitor capable of inhibiting Aβ-peptide production.

[0003] Not all compounds that are gamma-secretase inhibitors necessarily have the characteristics that make them the best possible therapeutic agents.Some of these characteristics include high affinity for gamma-secretase, the period during which gamma-secretase is inactivated, oral bioavailability, tissue distribution and stability (e.g., the ability to be formulated or crystallized, shelf life).Advantageous characteristics can bring about improvements in safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, ease of manufacture, etc.

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

[0005] Thus, there is currently a need for one or more solid state forms of the hydrobromide salt of Compound 1 that have an acceptable balance of these properties and that can be used to prepare pharma- ceutically acceptable solid dosage forms. Summary of the Invention [Means for solving the problem]

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

[0007] In one aspect, the present disclosure provides a compound of formula (I): [ka] 1. A crystalline form 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, comprising: a) Crystalline form A, characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees 2-theta; b) Crystalline form B, characterized by an XRPD pattern substantially as shown in FIG. 4; c) Crystalline form D, characterized by an XRPD pattern substantially as shown in FIG. 11; d) Crystalline form E, characterized by an XRPD pattern substantially as shown in FIG. 14; e) Crystalline form F, characterized by an XRPD pattern substantially as shown in FIG. 17; f) Crystalline form F', characterized by an XRPD pattern substantially as shown in FIG. 18; g) Crystalline form G, characterized by an XRPD pattern substantially as shown in FIG. 21; h) Crystalline form H, characterized by an XRPD pattern substantially as shown in FIG. 22; i) crystalline form H', characterized by an XRPD pattern substantially as shown in Figure 23; j) Crystalline form J, characterized by an XRPD pattern substantially as shown in FIG. 24; k) Crystalline form K, characterized by an XRPD pattern substantially as shown in FIG. 25; l) Crystalline form L, characterized by an XRPD pattern substantially as shown in FIG. 26; m) crystalline form M, characterized by an XRPD pattern substantially as shown in FIG. 29; and n) Crystalline form N, characterized by an XRPD pattern substantially as shown in FIG. The present invention relates to a crystalline form selected from the group consisting of:

[0008] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form A 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:

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

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

[0011] In another embodiment, Form A is characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees two-theta. In another embodiment, Form A is characterized by an XRPD pattern with peaks at 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 two-theta. In another embodiment, Form A is characterized by an XRPD pattern with peaks at 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 two-theta.

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

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

[0014] In another embodiment, Form A has a unit cell with an a value of about 10.035 Å, a b value of about 7.532 Å, and a c value of about 20.092 Å. In another embodiment, Form A has a unit cell with an a value of about 1518.1 Å 3 has a unit cell with a volume of

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

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

[0017] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a 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:

[0018] In one embodiment, Form B is characterized by an XRPD pattern substantially as shown in FIG.

[0019] In another embodiment, Form B is substantially free of other polymorphic forms. In another embodiment, Form B has a polymorphic purity of at least 90%. In another embodiment, Form B has a polymorphic purity of at least 99%.

[0020] In another embodiment, Form B has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0021] In one aspect, the present disclosure provides a compound of formula (II): [ka] (wherein n is about 1 to 3). The present invention relates to crystalline form C 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:

[0022] In one embodiment, Form C comprises: a) XRPD pattern substantially as shown in FIG. 5; b) TGA profile substantially as shown in Figure 6; c) a DSC profile substantially as shown in FIG. 7; and d) A TG-IR coordinated spectrum substantially as shown in a figure selected from the group consisting of Figures 8 to 10. The compound has one or more characteristics selected from the group consisting of:

[0023] In another embodiment, Form C has a unit cell indexed as simple orthorhombic.

[0024] In another embodiment, Form C has a unit cell with an a value of about 7.491 Å, a b value of about 10.353 Å, and a c value of about 48.790 Å. In another embodiment, Form C has a unit cell with an a value of about 3783.9 Å 3 has a unit cell with a volume of

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

[0026] In another embodiment, Form C is substantially free of 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 a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0028] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form D 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:

[0029] In one embodiment, Form D comprises: a) XRPD pattern substantially as shown in FIG. 11; b) a TGA profile substantially as shown in FIG. 12A or FIG. 12B; and c) A DSC profile substantially as shown in line A or line B of FIG. The compound has one or more characteristics selected from the group consisting of:

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

[0031] In another embodiment, TGA shows that Form D loses weight of about 1.2 to about 2.5% by weight between about 24°C and about 109°C.

[0032] In another embodiment, Form D exhibits a DSC thermogram with an endothermic event at about 65°C.

[0033] In another embodiment, Form D is substantially free of 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, Form D has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0035] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form E 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:

[0036] In one embodiment, Form E comprises: a) XRPD pattern substantially as shown in FIG. 14; b) a TGA profile substantially as shown in FIG. 15; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

[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 exhibits a DSC thermogram with an endothermic event at about 80°C.

[0039] In another embodiment, Form E is substantially free of 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 a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0041] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form F 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:

[0042] In another embodiment, Form F is characterized by an XRPD pattern substantially as shown in FIG.

[0043] In another embodiment, Form F is substantially free of 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, Form F has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0045] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form F' 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:

[0046] In one embodiment, Form F' comprises: a) an XRPD pattern substantially as shown in FIG. 18; and b) a TGA profile substantially as shown in FIG. 19; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

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

[0048] In another embodiment, Form F' is substantially free of 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 a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0050] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form G 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:

[0051] In one embodiment, Form G is characterized by an XRPD pattern substantially as shown in FIG.

[0052] In another embodiment, Form G is substantially free of 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, Form G has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0054] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention 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)pentanamide having the formula:

[0055] In one embodiment, Form H is characterized by an XRPD pattern substantially as shown in FIG.

[0056] In another embodiment, Form H is substantially free of 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, Form H has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0058] In one aspect, the present disclosure provides a compound of 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-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.

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

[0060] In another embodiment, Form H' is substantially free of 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, Form H' has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0062] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form J 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:

[0063] In one embodiment, Form J is characterized by an XRPD pattern substantially as shown in FIG.

[0064] In another embodiment, Form J is substantially free of 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, Form J has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0066] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form K 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:

[0067] In one embodiment, Form K is characterized by an XRPD pattern substantially as shown in FIG.

[0068] In another embodiment, Form K is substantially free of 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, Form K has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0070] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form L 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:

[0071] In one embodiment, Form L comprises: a) XRPD pattern substantially as shown in Figure 26; b) a TGA profile substantially as shown in FIG. 27; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

[0072] In another embodiment, Form L exhibits a DSC thermogram with an endothermic event at about 157°C.

[0073] In another embodiment, Form L is substantially free of 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, Form L has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0075] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form M 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.

[0076] In one embodiment, Form M is characterized by an XRPD pattern substantially as shown in FIG.

[0077] In another embodiment, Form M is substantially free of 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, Form M has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0079] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form N 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:

[0080] In one embodiment, Form N is characterized by an XRPD pattern substantially as shown in FIG.

[0081] In another embodiment, Form N is substantially free of 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, Form N has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0083] In one aspect, the present disclosure provides a compound of formula (I): [ka] This relates to an amorphous form 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.

[0084] In one embodiment, the amorphous form 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 of formula (I) is characterized by an XRPD pattern substantially as shown in FIG. 31.

[0085] In another embodiment, the amorphous form 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 of formula (I) is substantially free of polymorphic forms. In one embodiment, the amorphous form 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 of formula (I) has a polymorphic purity of at least 90%. In one embodiment, the amorphous form 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 of formula (I) has a polymorphic purity of at least 99%.

[0086] In another embodiment, the amorphous form has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0087] In one aspect, the disclosure relates to a composition comprising a crystalline or amorphous form 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 one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. In one embodiment, 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 is in amorphous form. In one embodiment, 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 is in crystalline form.

[0088] In one embodiment, 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 is represented by the formula (I): [ka] It is a compound of the formula:

[0089] In another embodiment, 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 is a compound of formula (II) [ka] It is.

[0090] In another embodiment, 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. In another embodiment, the crystalline form is Form A.

[0091] In one aspect, the disclosure relates to a pharmaceutical composition comprising one or more of the forms or compositions discussed above and a pharma- ceutically 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 (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 hydrobromide salt. In one embodiment, the pharmaceutical composition comprises about 50 mg 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. In one embodiment, the pharmaceutical composition comprises about 100 mg 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. In one embodiment, the pharmaceutical composition comprises about 150 mg 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.

[0092] In one aspect, the disclosure relates to a method of treating a tumor or cancer comprising administering to a subject in need of such treatment one or more of Forms A-N or an amorphous form 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 discussed above. In one embodiment, a method of treating a tumor or cancer comprises administering to a subject in need of such treatment crystalline Form A 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. In one aspect, the disclosure relates to a method of treating a tumor or cancer comprising administering to a subject in need of such treatment a pharmaceutical composition comprising one or more of Forms A-N or an amorphous form 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 discussed above and a pharma- ceutically acceptable carrier. In one embodiment, a method of treating a tumor or cancer comprises administering to a subject in need of such treatment a pharmaceutical composition comprising crystalline Form A 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 and a pharma- ceutically acceptable carrier. In one embodiment of this method, the tumor is a dendroid tumor. In one embodiment of this method, the cancer is selected from the group consisting of multiple myeloma, cancer with a mutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. In another embodiment of this method, the cancer is multiple myeloma.In another embodiment, the cancer is a cancer with a mutation in a 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 about 50 mg to about 500 mg 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 hydrobromide salt daily. In another embodiment, the subject is administered about 100 mg to about 400 mg 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 daily. In another embodiment, the subject is administered about 300 mg 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 daily. In another embodiment, the subject is administered about 200 mg 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 hydrobromide salt daily. In another embodiment, the total daily dose is provided as two separate doses. In another embodiment, the total daily dose is provided as two separate doses of 150 mg. In another embodiment, the total daily dose is provided as two separate doses of 100 mg.

[0093] In one aspect, the present disclosure relates to the use of one or more of Forms A-N or amorphous forms 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 discussed above for the manufacture of a medicament for treating a tumor or cancer. In one embodiment, the present disclosure relates to the use of crystalline Form A 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 for the manufacture of a medicament for treating a tumor or cancer. In one embodiment, the present disclosure relates to the pharmaceutical composition discussed above for treating tumor or cancer.In one embodiment, the use is for treating dendroid tumor.In one embodiment, the use is for treating cancer selected from the group consisting of multiple myeloma, cancer with mutation in Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

[0094] In one aspect, the disclosure relates to one or more of Forms A-N or amorphous forms 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 discussed above for use in a method of treating a tumor or cancer. In one embodiment, the disclosure relates to a pharmaceutical composition discussed above for use in a method of treating a tumor or cancer. In one embodiment, the use is for treating dendroid tumors. In one embodiment, the use is for treating a cancer selected from the group consisting of multiple myeloma, cancer with a mutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. [Brief description of the drawings]

[0095] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern (“XRPD”) corresponding to crystalline form A.

[0096] [Diagram 2] FIG. 2 is a thermogravimetric analysis thermogram (“TGA”) corresponding to crystalline form A.

[0097] [Diagram 3] FIG. 3 is a differential scanning calorimetry thermogram (“DSC”) corresponding to crystalline form A.

[0098] [Figure 4] FIG. 4 is an XRPD corresponding to crystalline form B.

[0099] [Diagram 5] FIG. 5 is an XRPD corresponding to crystalline form C.

[0100] [Figure 6] FIG. 6 is a TGA corresponding to crystalline form C.

[0101] [Figure 7] FIG. 7 is a DSC corresponding to crystalline form C.

[0102] [Figure 8] 8-10 are thermogravimetric infrared analyses ("TG-IR") corresponding to crystalline form C. [Figure 9] 8-10 are thermogravimetric infrared analyses ("TG-IR") corresponding to crystalline form C. [Figure 10] 8-10 are thermogravimetric infrared analyses ("TG-IR") corresponding to crystalline form C.

[0103] [Figure 11] FIG. 11 is an XRPD corresponding to crystalline form D.

[0104] [Figure 12A]FIG. 12A is a TGA corresponding to as-prepared crystalline form D.

[0105] [Figure 12B] FIG. 12B is a TGA corresponding to crystalline form D when dried under vacuum at 75° C.

[0106] [Figure 13] Figure 13 is a DSC corresponding to crystalline form D. Line A is the DSC of as-prepared form D. Line B is the DSC of form D when dried under vacuum at 75°C.

[0107] [Figure 14] FIG. 14 is an XRPD corresponding to crystalline form E.

[0108] [Figure 15] FIG. 15 is a TGA corresponding to crystalline form E.

[0109] [Figure 16] FIG. 16 is a DSC corresponding to crystalline form E.

[0110] [Figure 17] FIG. 17 is an XRPD corresponding to crystalline form F.

[0111] [Figure 18] FIG. 18 is an XRPD corresponding to crystalline form F'.

[0112] [Figure 19] FIG. 19 is a TGA corresponding to crystalline form F'.

[0113] [Figure 20] FIG. 20 is the DSC corresponding to crystalline form F'.

[0114] [Figure 21] FIG. 21 is an XRPD corresponding to crystalline form G.

[0115] [Figure 22] FIG. 22 is an XRPD corresponding to crystalline form H.

[0116] [Figure 23] FIG. 23 is an XRPD corresponding to crystalline form H′.

[0117] [Figure 24] FIG. 24 is an XRPD corresponding to crystalline form J.

[0118] [Diagram 25] FIG. 25 is an XRPD corresponding to crystalline form K.

[0119] [Figure 26] FIG. 26 is an XRPD corresponding to crystalline form L.

[0120] [Figure 27] FIG. 27 is a TGA corresponding to crystalline form L.

[0121] [Figure 28] FIG. 28 is a DSC corresponding to crystalline form L.

[0122] [Figure 29] FIG. 29 is an XRPD corresponding to crystalline form M.

[0123] [Diagram 30] FIG. 30 is an XRPD corresponding to crystalline form N.

[0124] [Diagram 31] FIG. 31 is an XRPD corresponding to amorphous compound 1 of formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0125] Detailed Description of the Invention I. Definition To facilitate understanding of the disclosure described herein, several terms are defined below.

[0126] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry and pharmacology described herein are those well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill 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 referents unless the context clearly dictates otherwise. The term "a" (or "an") and the terms "one or more than one," and "at least one" can be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single." In other embodiments, the term "a" or "an" includes "two or more than two" or "multiple."

[0128] Furthermore, "and / or", when used herein, should be considered as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B", "A or B", "A" (single) and "B" (single). Similarly, the term "and / or" used in phrases such as "A, B and / or C" is intended to encompass 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 (single); B (single); and C (single).

[0129] The term "Compound 1" refers to the single enantiomer (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.

[0130] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject.

[0131] The terms "treat," "treating," and "treatment" are intended to include alleviating or reversing a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0132] The term "therapeutically effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent or alleviate to some extent one or more of the symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to produce the biological or medical response in a cell, tissue, system, animal or human that is desired by a researcher, veterinarian, physician or clinician.

[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 of being compatible with the other ingredients of the pharmaceutical formulation, and suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. See 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; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0134] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on the manner in which the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to 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 a compound administered to a subject, either alone or in combination with one or more pharma- ceutically acceptable excipients, to treat, prevent or ameliorate one or more symptoms of a condition, disorder or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer of the compounds described herein.

[0136] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0137] The term "solvate" refers to the compounds provided herein or their salts, which further comprise a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intramolecular forces.When the solvent is water, the solvate is a hydrate.When the solvent comprises ethanol, the compound can be an ethanol solvate.

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

[0139] Crystal forms are most commonly characterized by X-ray powder diffraction (XRPD). The XRPD pattern of reflections (peaks usually expressed in degrees 2-theta) is generally considered the fingerprint region of a particular crystal form. The relative intensities of XRPD peaks can vary widely depending on, among other things, the sample preparation technique, crystal size distribution, filters, sample mounting procedures, and the particular instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument. 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 settings of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystal form. In some cases, any particular peak in the XRPD pattern may appear symmetrically or asymmetrically, e.g., with a shoulder. Additionally, instrumental variability and other factors may affect the 2-theta values. One of ordinary skill in the art who understands these variations can use XRPD, and other known physicochemical techniques, to distinguish or elucidate the defining characteristics or properties of a particular crystalline form.

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

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

[0142] Unless the context requires otherwise, the terms "comprise," "comprises," and "comprising" are used with the underlying and clear understanding that they are to be interpreted inclusively rather than exclusively, and that Applicant intends that each of those terms be so interpreted in interpreting this patent, including the claims which follow. II. Solid State Forms

[0143] The present disclosure relates to a 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 to 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 stability against moisture and at ambient conditions under storage conditions, among others); (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 can affect, for example, the processing and storage of the compound and pharmaceutical compositions containing the compound.

[0144] A solid state form of the hydrobromide salt of Compound 1 that improves one or more of these properties relative to other solid state forms of the compound is desirable. Isolation of a pharma- ceutically acceptable solid state form of the compound that can be manufactured and formulated on a commercial scale is a challenge.

[0145] In one aspect, the present disclosure provides a compound of formula (I): [ka] A crystalline form 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, a) Crystalline form A, characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees 2-theta; b) Crystalline form B, characterized by an XRPD pattern substantially as shown in FIG. 4; c) Crystalline form D, characterized by an XRPD pattern substantially as shown in FIG. 11; d) Crystalline form E, characterized by an XRPD pattern substantially as shown in FIG. 14; e) Crystalline form F, characterized by an XRPD pattern substantially as shown in FIG. 17; f) Crystalline form F', characterized by an XRPD pattern substantially as shown in FIG. 18; g) Crystalline form G, characterized by an XRPD pattern substantially as shown in FIG. 21; h) Crystalline form H, characterized by an XRPD pattern substantially as shown in FIG. 22; i) crystalline form H', characterized by an XRPD pattern substantially as shown in Figure 23; j) Crystalline form J, characterized by an XRPD pattern substantially as shown in FIG. 24; k) Crystalline form K, characterized by an XRPD pattern substantially as shown in FIG. 25; l) Crystalline form L, characterized by an XRPD pattern substantially as shown in FIG. 26; m) crystalline form M, characterized by an XRPD pattern substantially as shown in FIG. 29; and n) Crystalline form N, characterized by an XRPD pattern substantially as shown in FIG. The present invention relates to a crystalline form selected from the group consisting of:

[0146] The following sections discuss solid state forms in which the properties of such solid state forms have been identified and selected. A. Crystal form A

[0147] In one aspect, the present disclosure provides a compound comprising 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 formula (I): [ka] This relates to crystalline form A of the compound.

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

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

[0150] In another embodiment, Form A is characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees 2-theta as measured by Cu Kα radiation. In another embodiment, Form A is characterized by an XRPD pattern with peaks at 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 2-theta as measured by Cu Kα radiation. In another embodiment, Form A is characterized by an XRPD pattern with peaks at 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 2-theta as measured by Cu Kα radiation.

[0151] In another embodiment, Form A is characterized by an XRPD pattern substantially as shown in Figure 1. In another embodiment, Form A is characterized by a TGA profile substantially as shown in Figure 2. In another embodiment, Form A is characterized by a DSC profile substantially as shown in Figure 3.

[0152] In another embodiment, Form A has a unit cell indexed as simple monoclinic.

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

[0154] The unit cell parameters of Form A are as follows: [Table 1A]

[0155] In another embodiment, Form A is substantially free of 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. Crystal form B

[0156] In one aspect, the present disclosure provides a compound comprising 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 formula (I): [ka] This relates to crystalline form B of the compound.

[0157] In one embodiment, Form B is characterized by an XRPD pattern substantially as shown in FIG.

[0158] In another embodiment, Form B is substantially free of 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. Crystal form C

[0159] In one aspect, the present disclosure provides a compound comprising 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 formula (II): [ka] (wherein n is about 1 to 3). This relates to crystalline form C of

[0160] In one embodiment, Form C comprises: a) XRPD pattern substantially as shown in FIG. 5; b) TGA profile substantially as shown in Figure 6; c) a DSC profile substantially as shown in FIG. 7; and d) A TG-IR coordinated spectrum substantially as shown in a figure selected from the group consisting of Figures 8 to 10. The compound has one or more characteristics selected from the group consisting of:

[0161] In another embodiment, Form C has a unit cell indexed as simple orthorhombic.

[0162] In another embodiment, Form C has a unit cell with an a value of about 7.491 Å, a b value of about 10.353 Å, and a c value of about 48.790 Å. In another embodiment, Form C has a unit cell with an a value of about 3783.9 Å 3 has a unit cell with a volume of

[0163] The unit cell parameters of Form C are as follows: [Table 1B]

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

[0165] In another embodiment, Form C is substantially free of 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. Crystal form D

[0166] In one aspect, the present disclosure provides a compound comprising 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 formula (I): [ka] This relates to crystalline form D of

[0167] In one embodiment, Form D comprises: a) XRPD pattern substantially as shown in FIG. 11; b) a TGA profile substantially as shown in FIG. 12A or FIG. 12B; and c) A DSC profile substantially as shown in line A or line B of FIG. The compound has one or more characteristics selected from the group consisting of:

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

[0169] The unit cell parameters of Form D are as follows: [Table 1C]

[0170] In another embodiment, TGA shows that Form D loses weight of about 1.2 to about 2.5% by weight between about 24°C and about 109°C.

[0171] In another embodiment, Form D exhibits a DSC thermogram with an endothermic event at about 65°C.

[0172] In another embodiment, Form D is substantially free of 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. Crystal form E

[0173] In one aspect, the present disclosure provides a compound comprising 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 formula (I): [ka] This relates to crystalline form E of the compound.

[0174] In one embodiment, Form E comprises: a) XRPD pattern substantially as shown in FIG. 14; b) a TGA profile substantially as shown in FIG. 15; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

[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 exhibits a DSC thermogram with an endothermic event at about 80°C.

[0177] In another embodiment, Form E is substantially free of 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. Crystal form F

[0178] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form F 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:

[0179] In another embodiment, Form F is characterized by an XRPD pattern substantially as shown in FIG.

[0180] In another embodiment, Form A is substantially free of 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. Crystal form F'

[0181] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form F' 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:

[0182] In one embodiment, Form F' has a structure comprising: a) XRPD pattern substantially as shown in FIG. 18; b) a TGA profile substantially as shown in FIG. 19; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

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

[0184] In another embodiment, Form A is substantially free of 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. Crystal form G

[0185] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form G 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:

[0186] In one embodiment, Form G is characterized by an XRPD pattern substantially as shown in FIG.

[0187] In another embodiment, Form G is substantially free of 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. Crystal form H

[0188] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention 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)pentanamide having the formula:

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

[0190] In another embodiment, Form H is substantially free of 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%. J. Crystal form H'

[0191] In one aspect, the present disclosure provides a compound of 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-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide.

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

[0193] In another embodiment, Form H' is substantially free of 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 aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form J 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:

[0195] In one embodiment, Form J is characterized by an XRPD pattern substantially as shown in FIG.

[0196] In another embodiment, Form J is substantially free of 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. Crystal form K

[0197] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to a crystalline form K 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:

[0198] In one embodiment, Form K is characterized by an XRPD pattern substantially as shown in FIG.

[0199] In another embodiment, Form K is substantially free of 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. Crystal form L

[0200] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form L 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:

[0201] In one embodiment, Form L comprises: a) XRPD pattern substantially as shown in Figure 26; b) a TGA profile substantially as shown in FIG. 27; and c) A DSC profile substantially as shown in FIG. The compound has one or more characteristics selected from the group consisting of:

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

[0203] In another embodiment, Form L is substantially free of other polymorphic forms. In another embodiment, Form L 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%. N. Crystal form M

[0204] In one aspect, the present disclosure provides a compound of formula (I): [ka] This relates to crystalline form M 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.

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

[0206] In another embodiment, Form M is substantially free of other polymorphic forms. In another embodiment, Form M 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%. O. Crystal form N

[0207] In one aspect, the present disclosure provides a compound of formula (I): [ka] The present invention relates to crystalline form N 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:

[0208] In one embodiment, Form N is characterized by an XRPD pattern substantially as shown in FIG.

[0209] In another embodiment, Form N is substantially free of 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 aspect, the present disclosure provides a compound of formula (I): [ka] This relates to an amorphous form 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.

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

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

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

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

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

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

[0218] In one embodiment, Form A has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0223] In one embodiment, Form B has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0228] In one embodiment, Form C has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0233] In one embodiment, Form D has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0238] In one embodiment, Form E has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0243] In one embodiment, Form F has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0248] In one embodiment, Form F' has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0253] In one embodiment, Form G has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0258] In one embodiment, Form H has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0263] In one embodiment, Form H' has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0268] In one embodiment, Form J has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0273] In one embodiment, Form K has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0278] In one embodiment, Form L has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0283] In one embodiment, Form M has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0288] In one embodiment, Form N has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

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

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

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

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

[0293] In one embodiment, the amorphous form 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 of about 5 μm to about 200 μm.

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

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

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

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

[0298] In one aspect, the disclosure relates to a composition comprising a crystalline or amorphous form 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 one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm.

[0299] In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.10] particle size of between about 0.5 μm and about 15 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.10] particle size of between about 0.5 μm and about 10 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.10] particle size of between about 0.5 μm and about 5 μm.

[0300] In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.50] particle size of between about 2 μm and about 30 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.50] particle size of between about 2 μm and about 25 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.50] particle size of between about 2 μm and about 20 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.50] particle size of between about 2 μm and about 15 μm.

[0301] In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 600 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 500 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 400 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 300 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 200 μm.In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 100 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[V,0.90] particle size of between about 8 μm and about 75 μm.

[0302] In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 5 μm and about 200 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 5 μm and about 150 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 5 μm and about 100 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 5 μm and about 75 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 5 μm and about 50 μm.In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 10 μm and about 50 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 10 μm and about 40 μm. In one embodiment, the composition comprises a crystalline or amorphous form 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 a D[4,3] particle size of between about 10 μm and about 30 μm.

[0303] In one embodiment, 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 is in amorphous form having one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. In one embodiment, 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 is in a crystalline form having one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. In one embodiment, the amorphous or crystalline 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 one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm, is [ka] It is.

[0304] In one embodiment, the hydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydroaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide having one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm, is a compound of formula (II) [ka] It is.

[0305] In one embodiment, 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. In one embodiment, the crystalline form is Form A.

[0306] In some embodiments, the crystalline form is Form A with 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 form is Form A with 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 may be combined with any other embodiment described herein that is not inconsistent with the combined embodiment.

[0308] In other embodiments, the crystalline form is Form A having a D[V,0.10] of about 0.5 μm to about 15 μm; about 0.5 μm to about 10 μm; about 0.5 μm to about 5 μm; about 1 μm to about 15 μm; about 1 μm to about 10 μm; about 1 μm to about 7.5 μm; about 1 μm to about 5 μm; about 2 μm to about 10 μm; about 2 μm to about 7.5 μm; about 2 μm to about 5 μm; about 3 μm to about 10 μm; about 3 μm to about 7.5 μm; or about 3 μm to about 5 μm. In other embodiments, the crystalline form is Form A with 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 crystalline form is from about 2 μm to about 30 μm; 2 μm to about 20 μm; from about 2 μm to about 15 μm; from about 2 μm to about 10 μm; from about 5 μm to about 30 μm; from about 5 μm to about 25 μm; from about 5 μm to about 20 μm; from about 5 μm to about 15 μm; from about 5 μm to about 10 μm; from about 7.5 μm to about 30 μm; from about 7.5 μm to about 25 μm; from about 7.5 μm to about 20 μm; Form A has a D[V,0.50] of 7.5 μm to about 15 μm; about 7.5 μm to about 10 μm; about 10 μm to about 30 μm; about 10 μm to about 25 μm; about 10 μm to about 20 μm; about 10 μm to about 15 μm; about 12 μm to about 15 μm; about 15 μm to about 30 μm; about 15 μm to about 25 μm; about 15 μm to about 20 μm; about 20 μm to about 30 μm. In other embodiments, the crystalline form is Form A with a D[V,0.50] of less than 30 μm; less than 25 μm; less than 20 μm; less than 15 μm; less than 12.5 μm; or less than 10 μm.

[0310] In other embodiments, the crystalline form is from about 8 μm to about 600 μm; from about 8 μm to about 575 μm; from about 8 μm to about 550 μm; from about 8 μm to about 525 μm; from about 8 μm to about 500 μm; from about 8 μm to about 475 μm; from about 8 μm to about 450 μm; from about 8 μm to about 425 μm; from about 8 μm to about 400 μm; from about 8 μm to about 375 μm; from about 8 μm to about 350 μm; from about 8 μm to about 325 μm; from about 8 μm to about 300 μm; from about 8 μm to about 275 μm; from about 8 μm to about 250 μm; from about 8 μm to about 225 μm; from about 8 μm to about 200 μm; from about 8 μm to about 175 μm; from about 8 μm to about 150 μm; from about 8 μm to about 2 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 about 25μm~about 525μm;about 25μm~about 500μm;about 25μm~about 475μm;about 25μm~about 450μm;about 25μm~about 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;From about 40 μm to about 500 μm; from about 40 μm to about 475 μm; from about 40 μm to about 450 μm; from about 40 μm to about 425 μm; from about 40 μm to about 400 μm; from about 40 μm to about 375 μm; from about 40 μm to about 350 μm; from about 40 μm to about 325 μm; from about 40 μm to about 300 μm; from about 40 μm to about 275 μm; from about 40 μm to about 250 μm; from about 40 μm to about 225 μm; from about 40 μm to about 200 μm; from about 40 μm to about 175 μm; from about 40 μm to about 150 μm; from about 40 μm to about 125 μm; from about 40 μm to about 100 μm; from about 40 μm to about 75 μm; from about 40 μm to about 50 μm; from about 50 μm to about 600 μm; from about 50 μm to about 575 μm; from about 50 μm to about 550 μm; from about 50 μm to about 525 μm; from about 50 μm to about 500 μm; from about 50 μm to about 475 μm; from about 50 μm to about 450 μm; from about 50 μm to about 425 μm; from about 50 μm to about 400 μm; from about 50 μm to about 375 μm; from about 50 μm to about 350 μm; from about 50 μm to about 325 μm; from about 50 μm to about 300 μm; from about 50 μm to about 275 μm; from about 50 μm to about 250 μm; from about 50 μm to about 225 μm; from about 50 μm to about 200 μm; from about 50 μm to about 175 μm; from about 50 μm to about 150 μm; from about 50 μm to about 125 μm; from about 50 μm to about 100 μm; from about 75 μm to about 600 μm; from about 75 μm to about 575 μm; from about 75 μm to about 550 μm; from about 75 μm to about 525 μm; from about 75 μm to about 500 μm; from about 75 μm to about 475 μm; from about 75 μm to about 450 μm; from about 75 μm to about 425 μm; from about 75 μm to about 400 μm; from about 75 μm to about 375 μm; from about 75 μm to about 350 μm; from about 75 μm to about 325 μm; from about 75 μm to about 300 μm; from about 75 μm to about 275 μm; from about 75 μm to about 250 μm; from about 75 μm to about 225 μm; from about 75 μm to about 200 μm; from about 75 μm to about 175 μm; from about 75 μm to about 150 μm; from about 75 μm to about 125 μm; from about 75 μm to about 100 μm; from about 100 μm to about 600 μm; from about 100 μm to about 575 μm; from about 100 μm to about 550 μm; from about 100 μm to about 525 μm; from about 100 μm to about 500 μm; from about 100 μm to about 475 μm; from about 100 μm to about 450 μm; from about 100 μm to about 425 μm; from about 100 μm to about 400 μm; from about 100 μm to about 375 μm; from about 100 μm to about 350 μm; from about 100 μm to about 325 μm; from about 100 μm to about 300 μm; from about 100 μm to about 275 μm;from about 100 μm to about 250 μm; from about 100 μm to about 225 μm; from about 100 μm to about 200 μm; from about 100 μm to about 175 μm; from about 100 μm to about 150 μm; from about 100 μm to about 125 μm; from about 125 μm to about 600 μm; from about 125 μm to about 575 μm; from about 125 μm to about 550 μm; from about 125 μm to about 525 μm; from about 125 μm to about 500 μm; from about 125 μm to about 475 μm; from about 125 μm to about 450 μm; from about 125 μm to about 425 μm; from about 125 μm to about 400 μm; from about 125 μm to about 375 μm; from about 125 μm to about 350 μm; from about 125 μm to about 325 μm; from about 125 μm to about 300 μm; from about 125 μm to about 275 μm; from about 125 μm to about 250 μm; from about 125 μm to about 225 μm; from about 125 μm to about 200 μm; from about 125 μm to about 175 μm; from about 125 μm to about 150 μm; from about 125 μm to about 600 μm; from about 150 μm to about 575 μm; from about 150 μm to about 550 μm; from about 150 μm to about 525 μm; from about 150 μm to about 500 μm; from about 150 μm to about 475 μm; from about 150 μm to about 450 μm; from about 150 μm to about 425 μm; from about 150 μm to about 400 μm; from about 150 μm to about 375 μm; from about 150 μm to about 350 μm; from about 150 μm to about 325 μm; from about 150 μm to about 300 μm; from about 150 μm to about 275 μm; from about 150 μm to about 250 μm; from about 150 μm to about 225 μm; from about 150 μm to about 200 μm; from about 175 μm to about 600 μm; from about 175 μm to about 575 μm; from about 175 μm to about 550 μm; from about 175 μm to about 525 μm; from about 175 μm to about 500 μm; from about 175 μm to about 475 μm; from about 175 μm to about 450 μm; from about 175 μm to about 425 μm; from about 175 μm to about 400 μm; from about 175 μm to about 375 μm; from about 175 μm to about 350 μm; from about 175 μm to about 325 μm; from about 175 μm to about 300 μm; from about 175 μm to about 275 μm; from about 175 μm to about 250 μm; from about 175 μm to about 225 μm; from about 175 μm to about 200 μm; from about 200 μm to about 600 μm; from about 200 μm to about 575 μm; from about 200 μm to about 550 μm; from about 200 μm to about 525 μm; from about 200 μm to about 500 μm; from about 200 μm to about 475 μm; from about 200 μm to about 450 μm; from about 200 μm to about 425 μm; from about 200 μm to about 400 μm; from about 200 μm to about 375 μm; from about 200 μm to about 350 μm;From about 200 μm to about 325 μm; from about 200 μm to about 300 μm; from about 200 μm to about 275 μm; from about 200 μm to about 250 μm; from about 200 μm to about 225 μm; from about 225 μm to about 600 μm; from about 225 μm to about 575 μm; from about 225 μm to about 550 μm; from about 225 μm to about 525 μm; from about 225 μm to about 500 μm; from about 225 μm to about 475 μm; from about 225 μm to about 450 μm; from about 225 μm to about 425 μm; from about 225 μm to about 400 μm; from about 225 μm to about 375 μm; from about 225 μm to about 350 μm; from about 225 μm to about 325 μm; from about 225 μm to about 300 μm; from about 225 μm to about 275 μm; from about 225 μm to about 250 μm; from about 250 μm to about 600 μm; from about 250 μm to about 575 μm; from about 250 μm to about 550 μm; from about 250 μm to about 525 μm; from about 250 μm to about 500 μm; from about 250 μm to about 475 μm; from about 250 μm to about 450 μm; from about 250 μm to about 425 μm; from about 250 μm to about 400 μm; from about 250 μm to about 375 μm; from about 250 μm to about 350 μm; from about 250 μm to about 325 μm; from about 250 μm to about 300 μm; from about 250 μm to about 275 μm; from about 275 μm to about 600 μm; from about 275 μm to about 575 μm; from about 275 μm to about 550 μm; from about 275 μm to about 525 μm; from about 275 μm to about 500 μm; from about 275 μm to about 475 μm; from about 275 μm to about 450 μm; from about 275 μm to about 425 μm; from about 275 μm to about 400 μm; from about 275 μm to about 375 μm; from about 275 μm to about 350 μm; from about 275 μm to about 325 μm; from about 275 μm to about 300 μm; from about 300 μm to about 600 μm; from about 300 μm to about 575 μm; from about 300 μm to about 550 μm; from about 300 μm to about 525 μm; from about 300 μm to about 500 μm; from about 300 μm to about 475 μm; from about 300 μm to about 450 μm; from about 300 μm to about 425 μm; from about 300 μm to about 400 μm; from about 300 μm to about 375 μm; from about 300 μm to about 350 μm; from about 300 μm to about 325 μm; from about 325 μm to about 600 μm; from about 325 μm to about 575 μm; from about 325 μm to about 550 μm; from about 325 μm to about 525 μm; from about 325 μm to about 500 μm; from about 325 μm to about 475 μm; from about 325 μm to about 450 μm; from about 325 μm to about 425 μm; from about 325 μm to about 400 μm; from about 325 μm to about 375 μm; from about 325 μm to about 350 μm; from about 350 μm to about 600 μm;Approx. 350 μm ~ approx. 575 μm; approx. 350 μm ~ approx. 550 μm; approx. 350 μm ~ approx. 525 μm; approx. 350 μm ~ 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 425μm~about 575μm;about 425μm~about 550μm;about 425μm~about 500μm;about 425μm~about 475μm;about 425μm~about 450μm;about 450μm~ Approx. 600 μm; Approx. 450 μm ~ approx. 575 μm; Approx. 450 μm ~ approx. 550 μm; Approx. 450 μm ~ approx. 525 μm; Approx. or form A having a D[V,0.90] of 5 μm to about 575 μm; about 475 μm to about 550 μm; about 475 μm to about 525 μm; about 450 μm to about 500 μm; about 450 μm to about 475 μm; about 500 μm to about 600 μm; about 500 μm to about 575 μm; about 500 μm to about 550 μm; about 500 μm to about 525 μm; about 550 μm to about 600 μm; about 550 μm to about 575 μm; or about 575 μm to about 600 μm. In other embodiments, the crystalline form is Form A with 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 crystalline form has a diameter of about 5 μm to about 200 μm; about 5 μm to about 175 μm; about 5 μm to about 150 μm; about 5 μm to about 125 μm; about 5 μm to about 100 μm; about 5 μm to about 75 μm; about 5 μm to about 50 μm; about 5 μm to about 40 μm; about 5 μm to about 25 μm; about 10 μm to about 200 μm; about 10 μm to about 175 μm; about 10 μm to about 150 μm; about 10 μm to about 125 μm; about 10 μm to about 100 μm; about 10 μm to about 75 μm; about 10 μm to about 50 μm; about 10μm to about 40μm; about 10μm to about 25μm; about 15μm to about 200μm; about 15μm to about 175μm; about 15μm to about 150μm; about 15μm to about 125μm; about 15μm to about 100μm; about 15μm to about 75μm; about 15μm 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. 175 μm; approx. 5 μm; about 20 μm to about 50 μm; about 25 μm to about 200 μm; about 25 μm to about 175 μm; about 25 μm to about 150 μm; about 25 μm to about 125 μm; about 25 μm to about 100 μm; about 25 μm to about 75 μm; ;Approx. 25μm~Approx. 40μm;Approx. 50μm~Approx. 200μm;Approx. 50μm~Approx. 175μm;Approx. 50μm~Approx. 150μm;Approx. Form A having a D[4,3] of 5 μm to about 175 μm; about 75 μm to about 150 μm; about 75 μm to about 125 μm; about 75 μm to about 100 μm; about 100 μm to about 200 μm; about 100 μm to about 175 μm; about 100 μm to about 150 μm; about 100 μm to about 125 μm; about 125 μm to about 200 μm; about 125 μm to about 175 μm; about 125 μm to about 150 μm; about 150 μm to about 200 μm; about 150 μm to about 175 μm; or about 175 μm to about 200 μm. In other embodiments, the crystalline form is form A with a D[4,3] of 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 salt form of compound 1 can be prepared based on the synthesis scheme described in U.S. Patent No. 7,795,447, the entirety of which is incorporated herein by reference. In some embodiments, a particular crystalline or amorphous form 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 a desired particle size is the product of the synthesis. In other embodiments, the (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 resulting in a specific crystalline or amorphous hydrobromide salt having a desired particle size is prepared using additional post-synthetic 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 (eg, Sympatec Helos and QicPic) at a dispersion pressure of 3.0 bar.

[0314] The particle size of crystalline materials can be assessed using laser diffraction. Laser diffraction is recognized by standards and guidance bodies, including ISO and ASTM, and is widely used to determine particle size distributions. In performing the assessment, the sample is passed through a laser beam which causes the laser light to be scattered at a range of angles. A detector placed at a fixed angle measures the intensity of the light scattered at that position. A mathematical model (Mie or Fraunhoffer theory) is then applied to generate a particle size distribution.

[0315] Particle size was analyzed using laser diffraction (or small angle light scattering) technique by dispersing the dry sample powder with compressed air. Specifically, 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 microdosing device was used to disperse the powder samples at a dispersion pressure of 0.2 bar. Suitable lenses were selected to cover the particle size range of each sample.

[0316] In particle size determination, the median value is defined as the value above which half of the population lies and below which half lies. In terms of particle size distributions, the median is called the D50. D50 is the size in microns that divides the distribution in half above and below this diameter. The expressions Dv50 or D[v,0.5] are sometimes used for the median of a volume distribution.

[0317] A mode is a peak in a 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 (D[v,0.9]-D[v,0.1]) / D[v,0.5] or (D90-D10) / D50.

[0319] The distribution width can also be characterized by reciting some combination of one, two or preferably three values, usually D10, D50 and D90. The median, D50, is defined above as the diameter below which half of the population lies. 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 mean volume, or mean mass moment. Laser diffraction results are reported on a volumetric basis, and the mean volume can be used to define the midpoint of the distribution. D[4,3] values ​​are sensitive to the presence of large particles in the distribution. IV. Pharmaceutical Compositions

[0321] Forms A-N and the amorphous form 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 of formula (I) or (II) may be administered to a subject by oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, intranasal, topical or transdermal (e.g., by use of a patch) routes. In one embodiment, crystalline Form A of the compound of formula (I) may be administered to a subject by oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, intranasal, topical or transdermal (e.g., by use of a patch) routes.

[0322] In one embodiment, the pharmaceutical composition comprises crystalline Form A 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 of formula (I). In one embodiment, the pharmaceutical composition is an oral tablet comprising one or more of Forms A-N and an amorphous form 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 of formula (I) or (II), and a pharma- ceutically acceptable carrier. In one embodiment, the tablet contains from about 25 mg to about 400 mg of one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II).In one embodiment, the tablet contains about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 8 ...9 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 8 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 8 mg, about 29 mg, about 30 mg, about 35 mg, about 40 mg, 0 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 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. In one embodiment, the tablet contains about 50 mg 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, which is one or more of Forms A-N and an amorphous form 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 of formula (I) or (II).In one embodiment, the tablet contains about 100 mg 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, which is one or more of Forms A-N and an amorphous form 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 of formula (I) or (II). In one embodiment, the tablet contains about 150 mg of one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II).

[0323] For oral administration, known carriers can be included in the pharmaceutical composition.For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used with various disintegrating agents such as starch (preferably corn, potato or tapioca starch), methylcellulose, alginic acid, and certain silicate complexes can be included in tablets together with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes.Similar types of solid compositions can also be used as fillers in gelatin capsules.Preferred materials in this regard include lactose or milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof, as well as various sweetening or flavoring agents, coloring substances or dyes, and, if so desired, emulsifying and / or suspending agents.

[0324] For parenteral administration, solutions containing Compound 1 can be prepared in either sesame or peanut oil, aqueous propylene glycol, or in sterile water or saline. Aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary, and the liquid diluent is first rendered isotonic with sufficient saline or glucose. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions is easily carried out under sterile conditions by standard pharmaceutical techniques well known to those skilled in the art. V. Treatment Method

[0325] Forms A-N and the amorphous form 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 of formula (I) or (II) can be used to modulate or inhibit the Notch signaling pathway in organisms, including humans. Notch signaling is frequently elevated in a variety of human tumors, including but not limited to breast, prostate, pancreatic and T-cell acute lymphoblastic leukemia.

[0326] Thus, Forms A-N and the amorphous form 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 of formula (I) or (II) can be administered to treat a subject having a tumor or cancer, including, but not limited to, dendroid tumor, 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 a subject having a tumor or cancer, including, but not limited to, dendroid tumor, multiple myeloma, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. In one embodiment, crystalline Form A of the compound of formula (I) and a pharma- ceutically acceptable carrier can be administered to treat a subject having a tumor or cancer, including, but not limited to, dendroid tumors, multiple myeloma, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. In one embodiment, Forms A-N and amorphous forms 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 of formula (I) or (II) can be administered to treat tumors, including dendroid tumors. In one embodiment, Forms A-N and the amorphous form 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 of formula (I) or (II) can be administered to treat cancers having mutations in Notch pathway genes.In one embodiment, Forms A-N and amorphous forms 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 of formula (I) or (II) can be administered to treat multiple myeloma. Forms A-N and amorphous forms 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 of formula (I) or (II) can be administered to treat adenoid cystic carcinoma. Forms A-N and the amorphous form 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 of formula (I) or (II) can be administered to treat T-cell acute lymphoblastic leukemia.

[0327] In one embodiment, one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II) is administered in a dosage range of from about 0.1 mg to about 1000 mg per day. In one embodiment, a subject is administered about 50 mg to about 500 mg per day of one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II). In another embodiment, a subject is administered about 100 mg to about 400 mg per day of one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II). In another embodiment, a subject is administered 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 of one or more of Forms A-N and the amorphous form 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 of Formula (I) or (II). The total daily dose can be provided as a single dose or as divided doses (i.e., 1, 2, 3 or 4 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 can be administered three tablets twice daily containing 50 mg of one or more of Forms A-N and amorphous forms 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 of formula (I) or (II), or a daily dose of 200 mg can be administered twice daily as two tablets containing 50 mg of one or more of Forms A-N and amorphous compound 1 of formula (I) or (II).

[0328] In one aspect, the present disclosure relates to the use of one or more of Forms A-N or amorphous forms 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 of formula (I) or formula (II) discussed above to treat tumors or cancer. In one embodiment, the present disclosure relates to the use of crystalline Form A 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 of formula (I) to treat tumors or cancer. In one embodiment, the present disclosure relates to the pharmaceutical composition discussed above for treating tumor or cancer.In one embodiment, the use is for treating dendroid tumor.In one embodiment, the use is for treating cancer selected from the group consisting of multiple myeloma, cancer with mutation in Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

[0329] In one aspect, the disclosure relates to one or more of Forms A-N or amorphous forms 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 of formula (I) or (II) discussed above for use in a method of treating a tumor or cancer. In one embodiment, the disclosure relates to crystalline form A 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 of formula (I) for use in a method of treating a tumor or cancer. In one embodiment, the disclosure relates to the pharmaceutical composition discussed above for use in a method of treating a tumor or cancer. In one embodiment, the use is for treating dendroid tumors. In one embodiment, the use is for treating a cancer selected from the group consisting of multiple myeloma, cancer with a mutation in a 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] Weighed samples of material were treated with aliquots of the specified solvent at ambient temperature. Samples were typically sonicated between additions to aid in 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 incremental solvent addition and inherent kinetics of dissolution. If no dissolution was observed, the value is reported as "less than". If dissolution was observed upon the first addition of solvent, the value is reported as "greater than". Table 1 shows the kinetic solubility of the dihydrobromide 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. [Table 1-1] [Table 1-2] Example 2 Screening for stable forms and hydrates

[0333] Method A: Crushing experiments

[0334] A sample of the dihydrobromide 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 was ground in the specified solvent system at ambient or set temperature. After approximately 24 hours, the solid was isolated by centrifugation using an Eppendorf centrifuge equipped with a 0.45 μm nylon filter. Stirring was then continued in fresh solvent for a total of approximately one and three weeks, after which the solid was isolated as above, viewed under polarized light, and analyzed by XRPD.

[0335] Method B: Equilibrium solubility test

[0336] The equilibrium solubility of the isolated solids was determined gravimetrically as follows: A measured aliquot of the mother liquor from the 3 week slurry was placed into a pre-weighed aluminum TGA pan. The solvent was then evaporated under ambient conditions or using vacuum. The remaining solids were weighed.

[0337] Table 2 shows the results of the stable form and hydrate screening. [Table 2-1] [Table 2-2] Example 3 Polymorphism Screening

[0338] Unless otherwise stated, (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 dihydrobromide salt was used as the starting material. The material produced in this study was utilized in selected experiments.

[0339] Starting materials were subjected to crystallization techniques which are summarized below: Solids were typically isolated by suction filtration, viewed under polarized light, and analyzed by XRPD.

[0340] Method A: Grinding Experiments:

[0341] The solids were combined with a small amount of solvent and transferred to an agate mill grinding vessel. Agate balls were added and the vessel was attached to a Retsch mill. Samples were typically milled at 30 Hz for either one cycle of 20 minutes or refilling, and the cycle was repeated for an additional 20 minutes.

[0342] Method B: Slurry experiments

[0343] The solids were suspended in the specified solvent. The suspension was then stirred at ambient or set temperature. The solids were isolated after a given amount of time.

[0344] Method c: Solvent / anti-solvent precipitation

[0345] Solutions of the starting materials were prepared at ambient or elevated temperature and filtered using a 0.2 μm nylon filter. They were then mixed with an appropriate anti-solvent at elevated temperature. If no solids were observed, the samples were either cooled to ambient or below ambient temperature or other crystallization techniques were applied.

[0346] Method D: Grinding and Sedimentation

[0347] Solutions of starting materials were prepared at elevated temperatures in the specified solvents and filtered hot through 0.2 μm nylon filters into the appropriate anti-solvent pre-cooled over a dry ice / acetone or 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 kept below ambient temperature or further crystallization techniques were applied.

[0348] Method e: Cooling experiment

[0349] Solutions of starting materials were prepared at elevated temperatures in the specified solvents using a heating hot plate. These solutions were typically filtered hot through a 0.2 μm nylon filter into a warm receiving vial. The vial was either quickly transferred to a subambient bath (typically dry ice / acetone) for impingement cooling (CC), removed from the warm for rapid cooling (FC), or the heating was turned off to allow slow cooling (SC). If solids precipitated, they were cooled and isolated by suction filtration. If the solution remained clear, the sample was either kept at subambient temperature or further crystallization techniques were applied.

[0350] Method F: Solvent evaporation experiments

[0351] Solutions of starting materials were either partially evaporated or evaporated to dryness at ambient or elevated temperatures from open vials for rapid solvent evaporation (FE) or from aluminum foil-covered vials with pinholes for slow solvent evaporation (SE). Prior to solvent evaporation, solutions were filtered at ambient or elevated temperatures using a 0.2 μm nylon filter.

[0352] Method g: Liquid-gas diffusion experiments

[0353] A solution of the starting material was prepared at ambient temperature and filtered through a 0.2 μm nylon filter into a receiving vial. The open vial was then placed into a secondary container with an appropriate anti-solvent. The container was sealed and allowed to stand at ambient conditions.

[0354] Method H: Steam stress experiments

[0355] The starting solids were transferred to a vial and the vial was placed uncapped in a secondary container with an appropriate anti-solvent The secondary container was sealed and allowed to stand at ambient or sub-ambient conditions.

[0356] Method I: Low relative humidity stress experiments

[0357] The starting solid was transferred to a vial and the vial was placed, uncapped, into a RH jar containing P2O5, which was maintained at ambient temperature for the specified period of time.

[0358] Method J: Drying experiment

[0359] The starting solids were dried at ambient temperature or under vacuum at set temperatures for the specified time periods.

[0360] Table 3 summarizes the polymorph screening results for the dihydrobromide 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. [Table 3-1] [Table 3-2]

[0361] Table 4 summarizes the polymorph screening results of the dihydrobromide 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, starting from X-ray amorphous material. [Table 4] Example 4 Preparation of X-ray amorphous materials

[0362] A solution of the starting material was prepared in dioxane / water (50 / 50) at ambient temperature and filtered into a round bottom flask. The flask was immersed in a dry ice / acetone bath to freeze the solution. Once frozen, the flask was placed in a freeze dryer at approximately -50°C for 2 days. Example 5 Preparation of selected substances

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

[0364] Table 6 summarizes the drying conditions for selected materials. [Table 6] Example 6 Mutual conversion experiment

[0365] The starting materials were dried in a vacuum oven at 45° C. for approximately 1 day, except for Form A. A saturated solution of Form A in the specified solvent system was prepared and seeded with crystals of the dried material and Form A. The samples were stirred in sealed vials at ambient temperature for approximately 1 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 Form A. In an attempt to induce crystallization, seed crystals of Form A were added to selected experiments.

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

[0369] Solutions of starting materials were either partially evaporated or evaporated to dryness at ambient or elevated temperatures from open vials for fast solvent evaporation (FE) or from loosely capped or pinhole aluminum foil covered vials for slow solvent evaporation (SE). Prior to solvent evaporation, solutions were filtered at ambient or elevated temperatures using a 0.2 μm nylon filter.

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

[0371] A solution of the starting material was prepared in the specified solvent at ambient temperature and typically filtered using a 0.2 μm nylon filter. For liquid-vapor diffusion (LVD), a vial containing the filtered solution was placed in a secondary container with an appropriate anti-solvent and allowed to sit at ambient or sub-ambient temperature. For liquid-liquid diffusion (LLD), a solution of the test material was carefully contacted with the specified solvent and allowed to sit at ambient or sub-ambient temperature.

[0372] Method C: Cooling Experiments

[0373] Solutions of the starting materials were prepared at elevated temperatures using a heating hot plate. The solutions were then filtered hot using a 0.2 μm nylon filter and left on the heat source to slowly cool to a set temperature (SC). After a designated period of time, the solutions were further cooled to below ambient temperature.

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

[0375] Method A: Transparent geometry

[0376] XRPD patterns were collected using a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation 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 onto the detector surface. Prior to analysis, silicon specimens (NIST SRM 640d or 640e) were analyzed to ensure that the observed position of the Si 111 peak was consistent with the certified position by NIST. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, short antiscatter extension, and antiscatter knife edge were used to minimize background caused by air. Soller slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position sensitive 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 using an incident beam of Cu Kα radiation generated using a long fine focus source and a nickel filter. The diffractometer was configured using a 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 was consistent with the certified position by NIST. Sample specimens were prepared as thin circular layers centered on the silicon zero background substrate surface. Anti-scatter slits (SS) were used to minimize background caused by air. Soller slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b. 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 a nitrogen purge. The method code on the thermogram is an abbreviation for the start and end temperatures, and the heating rate. For example, 25-350-10 means "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 Calorimeter. Temperature calibration was performed using NIST traceable indium metal. Samples were placed in aluminum DSC pans (T0C), covered with lids, and their weights were accurately recorded. A pre-weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. The method codes on the thermograms are abbreviations for the start and end temperatures, and the heating rate. For example, -30-250-10 means "-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 Thermogravimetric (TG) analyzer model 2050 interfaced to a Magna-IR 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid / far IR source, potassium bromide (KBr) beam splitter and mercury cadmium telluride (MCT-A) detector. FT-IR wavelength verification was performed using polystyrene, and TG calibration standards were nickel and Alumel™. Samples were placed in platinum sample pans, which were inserted into the TG furnace. The TG instrument was started first, followed immediately by the FT-IR instrument. The TG instrument was operated under helium flows of 90 cc / min and 10 cc / min for purging and balancing, respectively. The furnace was heated under helium at a rate of 20° C. / min to a final temperature of 250° C. IR spectra were collected approximately every 32 seconds for approximately 13 minutes. Each IR spectrum was collected at 4 cm -1 The data represent 16 simultaneous scans collected at a spectral resolution of 100 kHz. Volatiles were identified by searching the high resolution Nicolet vapor phase spectral library. Searches from this library are considered to be non-cGMP. Example 12 Polarized Optical Microscopy (PLM)

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

[0383] Successful indexing of the XRPD pattern indicates that the sample consists primarily of a single crystalline phase. Agreement between accepted peak positions and 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 molecular packing attempts were made to confirm the tentative indexing solution within the scope of this work. The present invention provides, for example, the following items. (Item 1) a) Crystalline form A, characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees 2-theta; b) Crystalline form B, characterized by an XRPD pattern substantially as shown in FIG. 4; c) Crystalline form D, characterized by an XRPD pattern substantially as shown in FIG. 11; d) Crystalline form E, characterized by an XRPD pattern substantially as shown in FIG. 14; e) Crystalline form F, characterized by an XRPD pattern substantially as shown in FIG. 17; f) Crystalline form F', characterized by an XRPD pattern substantially as shown in FIG. 18; g) Crystalline form G, characterized by an XRPD pattern substantially as shown in FIG. 21; h) Crystalline form H, characterized by an XRPD pattern substantially as shown in FIG. 22; i) crystalline form H', characterized by an XRPD pattern substantially as shown in Figure 23; j) Crystalline form J, characterized by an XRPD pattern substantially as shown in FIG. 24; k) Crystalline form K, characterized by an XRPD pattern substantially as shown in FIG. 25; l) Crystalline form L, characterized by an XRPD pattern substantially as shown in FIG. 26; m) crystalline form M, characterized by an XRPD pattern substantially as shown in FIG. 29; and n) Crystalline form N, characterized by an XRPD pattern substantially as shown in FIG. Formula (I) [ka] A crystalline form 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. (Item 2) 2. The crystalline form of claim 1, wherein the crystalline form is Form A characterized by an XRPD pattern with peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees 2-theta. (Item 3) 3. The crystalline form according to item 2, wherein said crystalline form A is anhydrous. (Item 4) 4. The crystalline form according to item 2 or 3, wherein the melting point of crystalline form A is about 254° C. (Item 5) 5. The crystalline form of any one of items 2 to 4, wherein Form A is characterized by an XRPD pattern having peaks at 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 two-theta. (Item 6) 6. The crystalline form of any one of items 2 to 5, wherein Form A is characterized by an XRPD pattern with peaks at 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 two-theta. (Item 7) 7. The crystalline form according to any one of items 2 to 6, wherein Form A is characterized by an XRPD pattern substantially as shown in FIG. (Item 8) 8. The crystalline form according to any one of items 2 to 7, wherein form A is characterized by a TGA profile substantially as shown in FIG. (Item 9) 9. The crystalline form according to any one of items 2 to 8, wherein form A is characterized by a DSC profile substantially as shown in FIG. (Item 10) 10. The crystalline form of any one of items 2 to 9, wherein Form A has a unit cell indexed as simple monoclinic. (Item 11) 11. The crystalline form of any one of items 2 to 10, wherein form A has a unit cell with an a value of about 10.035 Å, a b value of about 7.532 Å, and a c value of about 20.092 Å. (Item 12) Form A is approximately 1518.1 Å 3 12. The crystalline form according to any one of items 2 to 11, having a unit cell having a volume of (Item 13) 13. The crystalline form according to any one of items 2 to 12, wherein said Form A is substantially free of other polymorphic forms. (Item 14) 13. The crystalline form according to any one of items 2 to 12, wherein said Form A has a polymorphic purity of at least 90%. (Item 15) 13. The crystalline form according to any one of items 2 to 12, wherein said Form A has a polymorphic purity of at least 99%. (Item 16) 16. The crystalline form of any one of items 2 to 15, wherein the Form A has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 17) Item 1. The crystalline form according to item 1, wherein the crystalline form is crystalline form B characterized by an XRPD pattern substantially as shown in FIG. (Item 18) 18. The crystalline form according to item 17, wherein said Form B is substantially free of other polymorphic forms. (Item 19) 18. The crystalline form according to item 17, wherein said Form B has a polymorphic purity of at least 90%. (Item 20) 18. The crystalline form according to item 17, wherein said form B has a polymorphic purity of at least 99%. (Item 21) 21. The crystalline form of any one of items 7 to 20, wherein the form B has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 22) Item 1. The crystalline form according to item 1, wherein the crystalline form is crystalline form D characterized by an XRPD pattern substantially as shown in FIG. (Item 23) Form D is a)~b): a) a TGA profile substantially as shown in FIG. 12A or FIG. 12B; and b) A DSC profile substantially as shown in line A or line B of FIG. 23. The crystalline form according to claim 22, characterized by one or more of: (Item 24) 24. The crystalline form according to item 22 or 23, wherein form D has a unit cell indexed as simple monoclinic. (Item 25) 25. The crystalline form of any one of items 22 to 24, wherein form D has a unit cell with an a value of about 18.465 Å, a b value of about 7.441 Å, and a c value of about 23.885 Å. (Item 26) Form D is approximately 3250.4 Å 3 26. The crystalline form according to any one of items 22 to 25, having a unit cell having a volume of (Item 27) 27. The crystalline form according to any one of items 22 to 26, wherein the TGA shows that form D loses about 1.2 to about 2.5 wt.% weight between about 24° C. and about 109° C. (Item 28) 28. The crystalline form according to any one of items 22 to 27, wherein form D exhibits a DSC thermogram with an endothermic event at about 65°C. (Item 29) 29. The crystalline form according to any one of items 22 to 28, wherein said Form D is substantially free of other polymorphic forms. (Item 30) 29. The crystalline form according to any one of items 22 to 28, wherein said Form D has a polymorphic purity of at least 90%. (Item 31) 29. The crystalline form according to any one of items 22 to 28, wherein said Form D has a polymorphic purity of at least 99%. (Item 32) 32. The crystalline form of any one of items 22-31, wherein the form D has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 33) Item 1. The crystalline form according to item 1, wherein the crystalline form is Form E, characterized by an XRPD pattern substantially as shown in FIG. (Item 34) Form E is a)~b): a) a TGA profile substantially as shown in FIG. 15; and b) A DSC profile substantially as shown in FIG. 34. The crystalline form according to claim 33, characterized by one or more of: (Item 35) 35. The crystalline form according to item 33 or 34, wherein the TGA shows that form E loses about 8% by weight between about 28° C. and about 120° C. (Item 36) 36. The crystalline form according to any one of items 33 to 35, wherein form E exhibits a DSC thermogram having an endothermic event at about 80°C. (Item 37) 37. The crystalline form according to any one of items 33 to 36, wherein said Form E is substantially free of other polymorphic forms. (Item 38) 37. The crystalline form according to any one of items 33 to 36, wherein said Form E has a polymorphic purity of at least 90%. (Item 39) 37. The crystalline form according to any one of items 33 to 36, wherein said Form E has a polymorphic purity of at least 99%. (Item 40) 40. The crystalline form of any one of items 33-39, wherein the Form E has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 41) Item 1. The crystalline form according to item 1, wherein the crystalline form is Form F, characterized by an XRPD pattern substantially as shown in FIG. (Item 42) 42. The crystalline form according to item 41, wherein said Form F is substantially free of other polymorphic forms. (Item 43) 42. The crystalline form according to item 41, wherein said form F has a polymorphic purity of at least 90%. (Item 44) 42. The crystalline form according to item 41, wherein said form F has a polymorphic purity of at least 99%. (Item 45) 45. The crystalline form of any one of items 41 to 44, wherein form F has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 46) Item 1. The crystalline form according to item 1, wherein the crystalline form is Form F' characterized by an XRPD pattern substantially as shown in FIG. (Item 47) The form F' is a)~b): a) TGA substantially as shown in FIG. 19; and b) DSC substantially as shown in FIG. 47. The crystalline form according to claim 46, characterized by one or more of: (Item 48) Item 48. The crystalline form of item 46 or 47, wherein the TGA shows that form F' loses about 12.6 wt.% weight between about 24° C. and about 90° C., and loses about 15.6 wt.% weight between about 97° C. and about 198° C. (Item 49) 49. The crystalline form according to any one of items 46 to 48, wherein said Form F' is substantially free of other polymorphic forms. (Item 50) 50. The crystalline form according to any one of items 46 to 49, wherein said form F' has a polymorphic purity of at least 90%. (Item 51) 50. The crystalline form according to any one of items 46 to 49, wherein said form F' has a polymorphic purity of at least 99%. (Item 52) 52. The crystalline form of any one of items 46-51, wherein form F' has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 53) 21. The crystalline form according to claim 1, wherein the crystalline form is Form G, characterized by an XRPD pattern substantially as shown in FIG. (Item 54) 54. The crystalline form according to item 53, wherein said Form G is substantially free of other polymorphic forms. (Item 55) 54. The crystalline form according to item 53, wherein said Form G has a polymorphic purity of at least 90%. (Item 56) 54. The crystalline form according to item 53, wherein said Form G has a polymorphic purity of at least 99%. (Item 57) 57. The crystalline form of any one of items 53-56, wherein the form G has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 58) 22. The crystalline form according to claim 1, wherein the crystalline form is form H, characterized by an XRPD pattern substantially as shown in FIG. (Item 59) 59. The crystalline form according to item 58, wherein said Form H is substantially free of other polymorphic forms. (Item 60) 59. The crystalline form according to item 58, wherein said Form H has a polymorphic purity of at least 90%. (Item 61) 59. The crystalline form according to item 58, wherein said Form H has a polymorphic purity of at least 99%. (Item 62) 62. The crystalline form of any one of items 58-61, wherein the form H has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 63) 23. The crystalline form according to claim 1, wherein the crystalline form is form H', characterized by an XRPD pattern substantially as shown in FIG. (Item 64) 64. The crystalline form according to item 63, wherein said Form H' is substantially free of other polymorphic forms. (Item 65) 64. The crystalline form according to item 63, wherein said form H' has a polymorphic purity of at least 90%. (Item 66) 64. The crystalline form according to item 63, wherein said form H' has a polymorphic purity of at least 99%. (Item 67) 67. The crystalline form of any one of items 63-66, wherein form H' has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 68) 23. The crystalline form according to claim 1, wherein the crystalline form is Form J, characterized by an XRPD pattern substantially as shown in FIG. (Item 69) 69. The crystalline form according to item 68, wherein said Form J is substantially free of other polymorphic forms. (Item 70) 70. The crystalline form of item 68, wherein said Form J has a polymorphic purity of at least 90%. (Item 71) 70. The crystalline form according to item 68, wherein said Form J has a polymorphic purity of at least 99%. (Item 72) 72. The crystalline form of any one of items 68-71, wherein the Form J has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 73) 25. The crystalline form according to claim 1, wherein the crystalline form is form K, characterized by an XRPD pattern substantially as shown in FIG. (Item 74) 74. The crystalline form according to item 73, wherein said Form K is substantially free of other polymorphic forms. (Item 75) 74. The crystalline form according to item 73, wherein said form K has a polymorphic purity of at least 90%. (Item 76) 74. The crystalline form according to item 73, wherein said form K has a polymorphic purity of at least 99%. (Item 77) 77. The crystalline form of any one of items 73-76, wherein the form K has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 78) 26. The crystalline form according to claim 1, wherein the crystalline form is form L, characterized by an XRPD pattern substantially as shown in FIG. (Item 79) Form L is a) ~ b): a) a TGA profile substantially as shown in FIG. 27; and b) A DSC profile substantially as shown in FIG. 79. The crystalline form according to claim 78, characterized by one or more of: (Item 80) 80. The crystalline form according to item 78 or 79, wherein form L exhibits a DSC thermogram with an endothermic event at about 157°C. (Item 81) 81. The crystalline form according to any one of items 78 to 80, wherein said form L is substantially free of other polymorphic forms. (Item 82) 81. The crystalline form according to any one of items 78 to 80, wherein said form L has a polymorphic purity of at least 90%. (Item 83) 81. The crystalline form according to any one of items 78 to 80, wherein said form L has a polymorphic purity of at least 99%. (Item 84) 84. The crystalline form of any one of items 78-83, wherein the form L has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 85) 29. The crystalline form according to claim 1, wherein the crystalline form is Form M, characterized by an XRPD pattern substantially as shown in FIG. (Item 86) 86. The crystalline form according to item 85, wherein said Form M is substantially free of other polymorphic forms. (Item 87) 86. The crystalline form according to item 85, wherein said Form M has a polymorphic purity of at least 90%. (Item 88) 86. The crystalline form according to item 85, wherein said Form M has a polymorphic purity of at least 99%. (Item 89) 89. The crystalline form of any one of items 85-88, wherein the Form M has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 90) Item 3. The crystalline form according to item 1, wherein the crystalline form is Form N, characterized by an XRPD pattern substantially as shown in FIG. (Item 91) 91. The crystalline form according to item 90, wherein said Form N is substantially free of other polymorphic forms. (Item 92) 91. The crystalline form according to item 90, wherein said Form N has a polymorphic purity of at least 90%. (Item 93) 91. The crystalline form according to item 90, wherein said Form N has a polymorphic purity of at least 99%. (Item 94) 94. The crystalline form of any one of items 90 to 93, wherein Form N has one or more of a D[V,0.10] particle size of between about 0.5 μm and about 15 μm, a D[V,0.50] particle size of between about 2 μm and about 30 μm, a D[V,0.90] particle size of between about 8 μm and about 600 μm, or a D[4,3] particle size of about 5 μm to about 200 μm. (Item 95) Formula (II)

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Claims

1. Formula (I) 【Chemical 39】 1. A crystalline form 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, wherein the crystalline form is Form A characterized by an XRPD pattern having peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2 degrees two-theta.

2. The crystal of claim 1 , wherein said Form A is anhydrous.

3. The crystal according to claim 1 or 2, wherein the melting point of form A is 254°C.

4. 4. The crystalline form of any one of claims 1 to 3, wherein Form A is characterized by an XRPD pattern having peaks at 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 two-theta.

5. 5. The crystalline form of any one of claims 1 to 4, wherein Form A is characterized by an XRPD pattern having peaks at 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 two-theta.

6. Form A is shown in FIG. 【Chemistry 39A】 The crystal according to any one of claims 1 to 5, having an XRPD pattern as shown in:

7. Form A is shown in FIG. 【Chemistry 39B】 The crystal according to any one of claims 1 to 6, which has a TGA profile as shown in:

8. Form A is shown in FIG. 【Chemistry 39C】 The crystal according to any one of claims 1 to 7, which has a DSC profile as shown in:

9. 9. The crystal of any one of claims 1 to 8, wherein Form A has a unit cell indexed as simple monoclinic.

10. 10. The crystal of any one of claims 1 to 9, wherein Form A has a unit cell with an a value of 10.035 Å, a b value of 7.532 Å, and a c value of 20.092 Å.

11. Form A is 1518.1 Å ３ The crystal according to any one of claims 1 to 10, having a unit cell having a volume of

12. The crystalline form of any one of claims 1 to 11, wherein said Form A is substantially free of other polymorphic forms.

13. The crystalline form of any one of claims 1 to 11, wherein said Form A has a polymorphic purity of at least 90%.

14. The crystalline form of any one of claims 1 to 11, wherein said Form A has a polymorphic purity of at least 99%.

15. 15. The crystal of any one of claims 1 to 14, wherein the Form A has one or more of a D[V,0.10] particle size between 0.5 μm and 15 μm, a D[V,0.50] particle size between 2 μm and 30 μm, a D[V,0.90] particle size between 8 μm and 600 μm, or a D[4,3] particle size of 5 μm to 200 μm.

16. 16. A composition comprising the crystal of any one of claims 1 to 15 having one or more of a D[V,0.10] particle size between 0.5 μm and 15 μm, a D[V,0.50] particle size between 2 μm and 30 μm, a D[V,0.90] particle size between 8 μm and 600 μm, or a D[4,3] particle size of 5 μm to 200 μm.

17. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 15 and a pharma- ceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is a tablet.

19. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises 25 mg to 400 mg 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.

20. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises 50 mg 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.

21. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises 100 mg 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.

22. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises 150 mg 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.

23. The pharmaceutical composition according to any one of claims 17 to 22, for treating a tumor or cancer in a subject.

24. The pharmaceutical composition of claim 23, wherein the tumor is a desmoid tumor.

25. 24. The pharmaceutical composition of claim 23, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with a mutation in a Notch pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia.

26. 26. The pharmaceutical composition of claim 25, wherein the cancer is multiple myeloma.

27. The pharmaceutical composition of claim 25, wherein the cancer is a cancer having a mutation in a Notch pathway gene.

28. The pharmaceutical composition of claim 25, wherein the cancer is adenoid cystic carcinoma.

29. 26. The pharmaceutical composition of claim 25, wherein the cancer is T-cell acute lymphoblastic leukemia.

30. 30. The pharmaceutical composition of any one of claims 23 to 29, wherein the subject is administered 50 mg to 500 mg 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 daily.

31. 30. The pharmaceutical composition of any one of claims 23 to 29, wherein the subject is administered 100 mg to 400 mg 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 daily.

32. 30. The pharmaceutical composition of any one of claims 23 to 29, wherein the subject is administered 300 mg 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 daily.

33. 30. The pharmaceutical composition of any one of claims 23 to 29, wherein the subject is administered 200 mg 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 daily.

34. A pharmaceutical composition according to any one of claims 23 to 33, wherein the total daily dose is supplied as two separate doses.

35. 35. The pharmaceutical composition of claim 34, wherein the total daily dose is supplied as two separate 150 mg doses.

36. 35. The pharmaceutical composition of claim 34, wherein the total daily dose is supplied as two separate 100 mg doses.

37. Use of a pharmaceutical composition according to any one of claims 17 to 22 for the manufacture of a medicament for treating a tumor or cancer.

38. 38. The use according to claim 37, wherein the tumor is a desmoid tumor.

39. 38. The use of claim 37, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with a mutation in a Notch pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

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