EA046472B1 - SOLID-STATE FORMS (S)-2-(((S)-6,8-DIFLUORO-1,2,3,4-TETRAHYDRONAPHTHALENE-2-YL)AMINO)-N-(1-(2-METHYL-1-( NEOPENTYLAMINO)PROPAN-2-YL)-1H-IMIDAZOL-4-YL)PENTANAMIDE AND THEIR APPLICATIONS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to: a) solid-state forms of hydrobromide salts of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1-(neopentylamino)propan-2-yl)-Shimidazol-4-yl)pentanamide (compound 1); b) pharmaceutical compositions containing one or more solid-state forms of hydrobromide salts of compound 1 and, optionally, a pharmaceutically acceptable carrier; c) methods of treating tumors or oncological diseases by administering one or more solid-state forms of hydrobromide salts of Compound 1 to a subject in need thereof; and d) methods for preparing solid-state forms of hydrobromide salts of compound 1.

State of the art

^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-H-(1-(2-methyl-1(neopentylamino)propan-2 -yl)-N-imidazol-4-yl)pentanamide (compound 1) is a gamma secretase inhibitor that can inhibit the production of Ae peptides.

Not all gamma secretase inhibitor compounds have the characteristics that provide the best potential to become useful therapeutic agents. Some of these characteristics include high affinity for gamma secretase, duration of gamma secretase inactivation, oral bioavailability, tissue distribution, stability (eg, processability, crystallization ability, shelf life). Favorable characteristics can provide improved safety, tolerability, efficacy, therapeutic index, better patient compliance with the treatment regimen, greater cost-effectiveness and better manufacturability, etc.

In addition, the isolation and production on an industrial scale of solid-state forms of hydrobromide salts of compound 1, as well as corresponding pharmaceutical preparations, having acceptable properties in the solid state (including chemical resistance, thermal stability, solubility, hygroscopicity and/or particle size), which are technologically advanced from the point of view of in terms of production feasibility (including high product yield, absence of contaminants during crystallization, filtration properties, desiccant capacity and grindability) and ability to be processed for the production of drugs (including resistance to high pressure or compression forces during tabletting), involves a number of problems.

Accordingly, there is currently a need for one or more solid-state forms of hydrobromide salts of Compound 1 that have an acceptable balance of these properties and can be used in the preparation of pharmaceutically acceptable solid dosage forms.

Brief description of the invention

In one aspect, the present invention provides a solid form of the hydrobromide salt of Compound 1. In yet another embodiment, the solid form is a crystalline form of the hydrobromide salt of Compound 1. In yet another embodiment, the solid form is a crystalline form of the dihydrobromide salt of Compound 1. In another embodiment the solid form is the amorphous form of the dihydrobromide salt of compound 1.

In one aspect, the present invention relates to a crystalline form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-( 2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

selected from the group consisting of:

a) crystalline form A, wherein form A is characterized by a powder x-ray diffraction pattern (XRD) containing peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2° two theta;

b) crystalline form B, wherein form B is characterized by the PDH essentially represented in FIG. 4;

c) crystalline form D, wherein form D is characterized by the PDH essentially represented in FIG. eleven;

d) crystalline form E, wherein form E is characterized by the PDH essentially represented in FIG. 14;

e) crystalline form F, wherein form F is characterized by the PDH essentially represented in FIG. 17;

f) crystalline form F', wherein form F' is characterized by the PDH essentially represented in FIG. 18;

- 1 046472

g) crystalline form G, wherein form G is characterized by the PDH essentially represented in FIG. 21;

h) crystalline form H, wherein form H is characterized by the PDH essentially represented in FIG. 22;

i) crystalline form H', wherein form H' is characterized by the PDH essentially represented in FIG. 23;

j) crystalline form J, wherein form J is characterized by the PDH essentially represented in FIG. 24;

k) crystalline form K, wherein form K is characterized by the PDH essentially represented in FIG. 25;

l) crystalline form L, wherein form L is characterized by the PDH essentially represented in FIG. 26;

m) crystalline form M, wherein form M is characterized by the PDH essentially represented in FIG. 29; And

n) crystalline form N, wherein form N is characterized by the PDH essentially represented in FIG. thirty.

In one aspect, the present invention relates to crystalline Form A of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-M-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, crystalline Form A is anhydrous.

In another embodiment, the melting point of crystalline Form A is about 254°C.

In another embodiment, Form A is characterized by a PDH containing peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2° two theta. In another embodiment, Form A is characterized by a PDH containing 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° two theta. In another embodiment, Form A is characterized by a PDH containing 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° two theta.

In another embodiment, Form A is characterized by a PDH essentially as shown in FIG. 1.

In another embodiment, Form A is characterized by a thermogravimetric analysis (TGA) profile substantially as shown in FIG. 2. In another embodiment, Form A is characterized by a differential scanning calorimetry (DSC) profile substantially as shown in FIG. 3.

In another embodiment, the unit cell of shape A is indexed as primitive monoclinic.

In another embodiment, the Form A unit cell has the following parameters: an a value of about 10.035 A, a b value of about 7.532 A, and a c value of about 20.092 A. In another embodiment, the volume of the Form A unit cell is about 1518.1 A ³ .

In another embodiment, Form A is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form A is at least 90%. In one embodiment, the polymorphic purity of Form A is at least 99%.

In another embodiment, Form A is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form B of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-M-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

- 2 046472

In one embodiment, Form B is characterized by a PDH essentially as shown in FIG. 4.

In another embodiment, Form B is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form B is at least 90%. In another embodiment, the polymorphic purity of Form B is at least 99%.

In another embodiment, Form B is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form C of the hydrobromide salt of (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl -1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (II) where n is about 1-3.

In one embodiment, Form C has one or more characteristics selected from the group of characteristics of items a)-d):

a) PRDG, essentially presented in Fig. 5;

b) TGA profile essentially as shown in FIG. 6;

c) DSC profile essentially shown in FIG. 7; And

d) TGA profile coupled to infrared spectrum (TG-IR) substantially represented in a figure selected from the group of FIGS. from 8 to 10.

In another embodiment, the unit cell of shape C is indexed as a primitive rhombic.

In another embodiment, a Form C unit cell has the following parameters: an a value of about 7.491 A, a b value of about 10.353 A, and a c value of about 48.790 A. In another embodiment, the volume of a Form C unit cell is about 3783.9 A ³ .

In another embodiment, TGA shows that Form C loses at least 8 wt.% in the temperature range from about 60°C to about 190°C. In another embodiment, the DSC thermogram of Form C shows a first endothermic event at approximately 39°C and a second endothermic event at approximately 152°C.

In another embodiment, Form C is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form C is at least 90%. In one embodiment, the polymorphic purity of Form C is at least 99%.

In another embodiment, Form C is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form D of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form D has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG, essentially presented in Fig. eleven;

b) TGA profile essentially as shown in FIG. 12A or FIG. 12B; And

c) DSC profile essentially represented by line A or line B in FIG. 13.

In another embodiment, the unit cell of shape D is indexed as primitive monoclinic.

In another embodiment, the unit cell of shape D is characterized by the following parameters:

- 3,046,472 dimensions: a value is about 18.465 A, b value is about 7.441 A, and c value is about 23.885 A. In another embodiment, the unit cell volume of Form D is about 3250.4 A ³ .

In another embodiment, the TGA thermogram shows that Form D loses from about 1.2 to about 2.5 wt.% in the temperature range from about 24°C to about 109°C.

In another embodiment, the DSC thermogram of Form D shows an endothermic event at approximately 65°C.

In another embodiment, Form D is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form D is at least 90%. In one embodiment, the polymorphic purity of Form D is at least 99%.

In another embodiment, Form D is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline Form E hydrobromide salt (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl -1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form E has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG, essentially presented in Fig. 14;

b) TGA profile essentially as shown in FIG. 15; And

c) DSC profile essentially shown in FIG. 16.

In another embodiment, the TGA thermogram shows that Form E loses about 8 wt.% in the temperature range from about 28°C to about 120°C.

In another embodiment, the DSC thermogram of Form E shows an endothermic event at approximately 80°C.

In another embodiment, Form E is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form E is at least 90%. In one embodiment, the polymorphic purity of Form E is at least 99%.

In another embodiment, Form E is characterized by one or more of the following particle size indices: D[V,0.10] in the range of about 0.5 microns to about 15 microns, D[V,0.50] in the range of about 2 microns to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form F of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

In another embodiment, Form F is characterized by a PDH essentially as shown in FIG. 17.

In another embodiment, Form F is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of Form F is at least 90%.

In one embodiment, the polymorphic purity of Form F is at least 99%.

In another embodiment, Form F is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form F' of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1- 4 046472 (neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form F' has one or more characteristics selected from the group consisting of items a)-b):

a) PRDG essentially shown in FIG. 18;

b) TGA profile essentially as shown in FIG. 19; And

c) DSC profile essentially shown in FIG. 20.

In another embodiment, TGA shows that Form F' loses about 12.6 wt.% in the temperature range from about 24°C to about 90°C and loses about 15.6 wt.% in the temperature range from about 97°C to approximately 198°C.

In another embodiment, Form F' is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of form F' is at least 90%. In one embodiment, the polymorphic purity of form F' is at least 99%.

In another embodiment, Form F' is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form G of hydrobromide salt (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl -1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form G is characterized by a PDG substantially represented in FIG. 21.

In another embodiment, Form G is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of Form G is at least 90%. In one embodiment, the polymorphic purity of Form G is at least 99%.

In another embodiment, Form G is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to the crystalline form H of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form H is characterized by PDH, essentially as shown in FIG. 22.

In another embodiment, Form H is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of Form H is at least 90%.

In one embodiment, the polymorphic purity of Form H is at least 99%.

In another embodiment, Form H is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to example

- 5 046472 but 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention provides a crystalline form of H' hydrobromide salt of H)-2-((H)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the H' form is characterized by a PDH, essentially represented in FIG. 23.

In another embodiment, Form H' is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of form H' is at least 90%.

In one embodiment, the polymorphic purity of form H' is at least 99%.

In another embodiment, Form H' is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline form J of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form J is characterized by a PDH essentially as shown in FIG. 24.

In another embodiment, Form J is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form J is at least 90%. In one embodiment, the polymorphic purity of Form J is at least 99%.

In another embodiment, Form J is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to crystalline Form K hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form K is characterized by a PDH essentially as shown in FIG. 25.

In another embodiment, Form K is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form K is at least 90%. In one embodiment, the polymorphic purity of Form K is at least 99%.

In another embodiment, Form K is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 μm , D[V,0.90] in the range from about 8 μm to about 600 μm or D[4,3] in the range from about 5 μm to about 200 μm.

In one aspect, the present invention relates to crystalline form L of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1- 6 046472 (neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the L shape has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG essentially shown in FIG. 26;

b) TGA profile essentially as shown in FIG. 27; And

c) DSC profile essentially shown in FIG. 28.

In another embodiment, the DSC thermogram of Form L shows an endothermic event at approximately 157°C.

In another embodiment, Form L is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of Form L is at least 90%.

In one embodiment, the polymorphic purity of Form L is at least 99%.

In another embodiment, Form L is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 μm, D[V,0.90] in the range from about 8 μm to about 600 μm, or D[4,3] in the range from about 5 μm to about 200 μm.

In one aspect, the present invention relates to crystalline form M of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form M is characterized by a PDG substantially represented in FIG. 29.

In another embodiment, Form M is substantially free from other polymorphic forms.

In one embodiment, the polymorphic purity of Form M is at least 90%.

In one embodiment, the polymorphic purity of Form M is at least 99%.

In another embodiment, Form M is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to a crystalline form of N hydrobromide salt of N)-2-((N)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form N is characterized by a PDH essentially as shown in FIG. thirty.

In another embodiment, Form N is substantially free from other polymorphic forms. In one embodiment, the polymorphic purity of Form N is at least 90%. In one embodiment, the polymorphic purity of Form N is at least 99%.

In another embodiment, Form N is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to example

- 7 046472 but 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to an amorphous form of (S)-2(((b)-6,8-di(|)tor-1,2,3,4-tetrahydrone(|)talin-2-yl) hydrobromide salt amino)-H-(1-(2-methyl-1-(neopentylamino)propan-2yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide formula! (I) is characterized by the PDH essentially represented in FIG. 31.

In another embodiment, the amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide of formula (I) is free from polymorphic forms. In one embodiment, the polymorphic purity of the amorphous form of the hydrobromide salt is ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl -1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide of formula (I) is at least 90%. In one embodiment, the polymorphic purity of the amorphous form of the hydrobromide salt is ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl The -1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide of formula (I) is at least 99%.

In another embodiment, the amorphous form is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one aspect, the present invention relates to a composition comprising a crystalline or amorphous form of the hydrobromide salt (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2yl)amino)-N-( 1 -(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, which is characterized by one or more of the following particle size parameters: D[V,0.10] in the range of about 0.5 μm to about 15 µm, D[V,0.50] in the range from about 2 µm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to approximately 200 µm. In one embodiment, the hydrobromide salt form of (S)-2-(((S)-6,8difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl- 1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide is amorphous. In one embodiment, the hydrobromide salt form of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl- 1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide is crystalline.

In one embodiment, the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1 -( neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide is a compound of formula (I)

In another embodiment, the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1 -( neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide is a compound with the formula! (II)

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.

In one aspect, the present invention relates to a pharmaceutical composition comprising

- 8 046472 one or more of the forms or compositions discussed above, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition includes crystalline Form A of a compound of formula (I). In one embodiment, the pharmaceutical composition is a tablet. In one embodiment, the pharmaceutical composition includes from about 25 mg to about 400 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N- (1-(2-methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide. In one embodiment, the pharmaceutical composition includes about 50 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1- (2-methyl1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide. In one embodiment, the pharmaceutical composition includes about 100 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide. In one embodiment, the pharmaceutical composition includes about 150 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1- (2methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide.

In one aspect, the present invention relates to a method of treating tumors or cancer, comprising administering to a subject in need of such treatment one or more forms A-N or an amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1, 2,3,4-tetragcdronaphthalen-2-yl)amino)N(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, which are discussed above. In one embodiment, a method of treating tumors or cancer comprises administering to a subject in need of such treatment crystalline Form A hydrobromide salt of (S)-2-(((S)-6,8difluoro-1,2,3,4-tetragzdronaphthalene-2 -yl)amino)-H-( 1 -(2-methyl-1-(neopentylamino)propan-2-yl)-Shimidazol-4-yl)pentanamide. In one aspect, the present invention relates to a method of treating tumors or cancer, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising one or more forms A-N or an amorphous form of the hydrobromide salt (b)-2-(((b)-6.8- difluoro-1.2.3.4-tetrahydronaphthalen-2-yl)amino)-H-(1-(2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide, which are discussed above, and a pharmaceutically acceptable carrier. In one embodiment, a method of treating tumors or cancer comprises administering to a subject in need of such treatment a pharmaceutical composition comprising crystalline Form A hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene -2-yl)amino)-N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide and a pharmaceutically acceptable carrier. In one embodiment of the methods, the tumors are desmoid tumors. In one embodiment of the methods, the cancer is selected from the group consisting of multiple myeloma, cancer with a mutation in the Notch signaling pathway gene, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia. In another embodiment of the methods, the cancer is multiple myeloma. In another embodiment, the cancer is a cancer with a mutation in the Notch signaling pathway gene. In another embodiment, the cancer is an adenoid cystic carcinoma. In another embodiment, the cancer is T-cell acute lymphoblastic leukemia. In another embodiment, the subject is administered daily from about 50 mg to about 500 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H- (1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide. In another embodiment, the subject is administered daily from about 100 mg to about 400 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetragcdronaphthalene-2-yl)amino)No. (1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In another embodiment, the subject is administered daily approximately 300 mg of (S)-2-(((S)-6,8difluoro-1,2,3,4-tetragcdronaphthalene-2-yl)amino)-H-( 1 - (2-methyl-1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide. In another embodiment, the subject is administered approximately 200 mg of κ)-2-((Δ)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-) hydrobromide salt daily to the subject. (2methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. In another embodiment, the total daily dose is provided in two separate doses. In another embodiment, the total daily dose is provided in two separate 150 mg doses. In another embodiment, the total daily dose is provided in two separate 100 mg doses.

In one aspect, the present invention relates to the use of one or more of the forms A-N or amorphous forms of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2yl)amino)- N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, which are discussed above, in the production of a drug for the treatment of tumors or cancer. In one embodiment, the present invention relates to the use of crystalline form A of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-( 1-(2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide in the production of a drug for the treatment of tumors or cancer. In one embodiment, the present invention relates to a pharmaceutical composition discussed above for the treatment of tumors or cancer. In one embodiment, the use is for the treatment of desmoid tumors. In one embodiment, the use is the treatment of a cancer selected from the group consisting of multiple

- 9 046472 natural myeloma, cancer with a mutation in the Notch signaling pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia.

In one aspect, the present invention relates to one or more of the A-N forms or amorphous forms of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino) -N(1-(2-methyl-1-(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide, as discussed above, for use in a method of treating tumors or cancer. In one embodiment, the present invention relates to a pharmaceutical composition, as discussed above, for use in a method of treating tumors or cancer. In one embodiment, the use is for the treatment of desmoid tumors. In one embodiment, the use is for the treatment of a cancer selected from the group consisting of multiple myeloma, Notch signaling pathway mutated cancer, adenoid cystic carcinoma, and T-cell acute lymphoblastic leukemia.

Brief description of the figures

Fig. 1 is a powder X-ray diffraction (XRD) pattern corresponding to crystal form A.

Fig. 2 is a thermogravimetric analysis (TGA) thermogram corresponding to crystal form A.

Fig. 3 is a differential scanning calorimetry (DSC) thermogram corresponding to crystal form A.

Fig. 4 is the PRDH corresponding to crystal form B.

Fig. 5 is a PRDH corresponding to crystal form C.

Fig. 6 is a TGA thermogram corresponding to crystal form C.

Fig. 7 is a DSC thermogram corresponding to crystal form C.

In fig. 8-10 show the results of thermogravimetric infrared analysis (TG-IR) analysis corresponding to the crystalline form of C.

Fig. 11 is a PRDH corresponding to crystal form D.

Fig. 12A is a TGA thermogram corresponding to the resulting crystal form D.

Fig. 12B is a TGA thermogram corresponding to crystalline form D after vacuum drying at 75°C.

Fig. 13 is a DSC thermogram corresponding to crystalline Form D. Line A is a DSC thermogram of the resulting Form D. Line B is a DSC thermogram of Form D after vacuum drying at 75°C.

Fig. 14 is a PRDH corresponding to crystal form E.

Fig. 15 is a TGA thermogram corresponding to crystalline form E.

Fig. 16 is a DSC thermogram corresponding to crystalline form E.

Fig. 17 is a PRDH corresponding to crystal form F.

Fig. 18 is a PDH corresponding to crystal form F'.

Fig. 19 is a TGA thermogram corresponding to crystal form F'.

Fig. 20 is a DSC thermogram corresponding to crystal form F'.

Fig. 21 is a PRDH corresponding to crystal form G.

Fig. 22 is a PRDH corresponding to the crystalline form of H.

Fig. 23 is a PRDH corresponding to the crystalline form of H'.

Fig. 24 is a PRDH corresponding to crystal form J.

Fig. 25 is the PRDH corresponding to crystal form K.

Fig. 26 is a PRDH corresponding to crystal form L.

Fig. 27 is a TGA thermogram corresponding to crystal form L.

Fig. 28 is a DSC thermogram corresponding to crystal form L.

Fig. 29 is a PRDH corresponding to the crystalline form of M.

Fig. 30 is the PRDH corresponding to the N crystalline form.

Fig. 31 is a PRDH corresponding to amorphous compound 1 of formula (I).

Detailed Description of the Invention

I. Definitions.

To facilitate understanding of the invention described herein, a number of terms are defined below.

In general, the nomenclature used herein and the laboratory techniques described herein related to the fields of organic chemistry, medicinal chemistry, and pharmacology are well known and conventionally used in the art. Unless otherwise defined, all technical and scientific terms used in the description generally have the meanings known to those skilled in the art to which the present invention relates.

In the present specification and the accompanying claims, the singular forms a, an and the also include references to the plural unless the context clearly dictates

- 10 046472 other. Terms with the article a (or an), as well as terms indicating one or more and at least one, may be used interchangeably herein. In certain aspects, a term with the article a or an means singular. In other aspects, a term with the article a or an means two or more or more.

Additionally, where the compound conjunction and/or is used, it should be understood to refer to each of the two specified distinguishing features or components, with or without the other. Thus, the conjunction and/or used in a phrase such as A and/or B is herein intended to include the variants A and B, A or B, A (alone) and B (alone). Likewise, the conjunction and/or used in a phrase such as A, B and/or C is intended to cover each of the following: 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 (separately); B (separately); and C (separately).

The term compound 1 refers to the individual enantiomer - ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide.

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

The terms treat, treating and treatment mean the relief or elimination of a disorder, disease or condition or one or more symptoms associated with the disorder, disease or condition; alleviation or elimination of the cause(s) of the disorder, disease, or condition itself.

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

The terms pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, physiologically acceptable carrier or physiologically acceptable excipient refer to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid excipient, diluent, excipient, solvent or encapsulating material. In one embodiment, each component is pharmaceutically acceptable, that is, compatible with the other ingredients of the pharmaceutical composition and suitable for use in contact with tissue or organ of humans and animals without undue toxicity, irritation, allergic reaction, immunogenicity or other problems or complications, in a reasonable ratio benefit/risk. 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 (which are incorporated herein by reference).

The terms approximately or approximate mean the permissible error for a particular quantity, which is determined by one skilled in the art and depends to some extent on how the specified quantity is measured or determined. In certain embodiments, the term about or about means a value within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term about or approximately means a deviation from a specified value or range of values by 50, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.05 % of its value or range of values.

The terms active ingredient and active substance refer to a compound that is administered alone or in combination with one or more pharmaceutically acceptable excipients to a subject for the treatment, prevention, or amelioration of one or more symptoms of a condition, disorder, or disease. The active ingredient and active substance, when specified herein, may be an optically active isomer of the compound described herein.

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

The term solvate refers to a compound or salt thereof as provided herein that is bound by non-covalent intermolecular forces to a stoichiometric or non-stoichiometric amount of solvent. When the solvent is water, the solvate is

- 11 046472 hydrate. If the solvent includes ethanol, the compound may be an ethanol solvate.

The term polymorph, as used herein, refers to the crystalline form of a compound or a salt, hydrate or solvate thereof in a particular crystal package. All polymorphs have the same elemental composition. The term crystalline as used herein refers to a solid-state form that consists of an ordered arrangement of structural units. Different crystalline forms of the same compound or its salt, hydrate or solvate result from different molecular packings in the solid state, resulting in different crystal symmetries and/or different unit cell parameters. Different crystalline forms typically differ in X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. See, for example, Remington's Pharmaceutical Sciences, ^18th ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23 ^rd ed., 1843-1844 (1995) (which are incorporated herein by reference).

Crystalline forms are most often characterized by X-ray powder diffraction (XRPD). A powder X-ray diffraction pattern (XRD) of reflections (peaks usually expressed in °2-theta) is generally considered to be a fingerprint of a specific crystalline form. The relative intensities of the peaks in the XRDG can vary significantly depending, in particular, on the method of sample preparation, crystal size distribution, filters, method of sample placement, and the specific apparatus used. In some cases, new peaks may be observed or existing peaks may disappear depending on the instrument type or settings. In some cases, any given peak in a PDT may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the instrument type or settings, instrument sensitivity, measurement conditions, and/or crystalline form purity. In some cases, any given peak on the PDRG may have a symmetrical shape or an asymmetrical shape, such as a shoulder. In addition, instrument vibration and other factors may affect 2-theta angle values. One skilled in the art with an understanding of these differences can distinguish or determine the essential features or characteristics of a particular crystalline form using PDR and other known physicochemical techniques.

The term amorphous, when referring to a compound, means a state in which the material lacks long-range order at the molecular level and said material can exhibit, depending on temperature, the physical properties of a solid or liquid. Typically such materials do not produce distinctive X-ray diffraction patterns and, although exhibiting solid-state properties, are more formally described as liquids. When they are heated, a change in properties occurs from the properties of a solid to the properties of a liquid, which is characterized by a change in state, usually of the second order (glass transition).

The term anhydrous, when referring to a compound, means a solid state in which the compound does not contain structural water within the crystal lattice.

Unless the context otherwise requires, the terms include, includes and including are used on the basis and with the express understanding that they are to be construed as inclusive and not exclusive, and that it is the intention of the applicant that each of these words be so interpreted in construing this patent, including the following claims.

II. Solid (solid-state) forms.

The present invention relates to solid (solid state) forms 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 of great importance in the commercial development of new products. 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 point, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability under environmental conditions, especially to moisture, and stability under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and surface shape, (5) mechanical properties such as hardness , tensile or tear strength, compressibility, ease of handling, flowability and mixability; and (6) filtration properties. These properties may affect, for example, the processing and storage of the compound and pharmaceutical compositions comprising the compound.

What is needed are solid-state forms of the hydrobromide salt of Compound 1 with improved one or more of these properties compared to the properties of other solid forms of the compound. Isolation of pharmaceutically acceptable solid-state forms of a compound that can be produced on an industrial scale and based on the motors can be used to produce drugs on an industrial scale is a difficult task.

In one aspect, the present invention relates to a crystalline form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-( 2-methyl-1- 12 046472 (neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

selected from the group consisting of:

a) crystalline form A, where form A is characterized by a PRDH containing peaks at 8.8±0.2, 9.8±0.2 and 23.3±0.2° two theta;

b) crystalline Form B, wherein Form B is characterized by the PDH essentially represented in FIG. 4;

c) crystalline form D, wherein form D is characterized by the PDH essentially represented in FIG. eleven;

d) crystalline form E, wherein form E is characterized by the PDH essentially represented in FIG. 14;

e) crystalline form F, wherein form F is characterized by the PDH essentially represented in FIG. 17;

f) crystalline form F', wherein form F' is characterized by the PDH essentially represented in FIG. 18;

g) crystalline form G, wherein form G is characterized by the PDH essentially represented in FIG. 21;

h) crystalline form H, wherein form H is characterized by the PDH essentially represented in FIG. 22;

i) crystalline form H', wherein form H' is characterized by the PDH essentially represented in FIG. 23;

j) crystalline form J, wherein form J is characterized by the PDH essentially represented in FIG. 24;

k) crystalline form K, wherein form K is characterized by the PDH essentially represented in FIG. 25;

l) crystalline form L, wherein form L is characterized by the PDH essentially represented in FIG. 26;

m) crystalline form M, wherein form M is characterized by the PDH essentially represented in FIG. 29; And

n) crystalline form N, wherein form N is characterized by the PDH essentially represented in FIG. thirty.

The sections below discuss the solid (solid) forms that have been identified and selected properties of these solid (solid) forms.

A. Crystal form A.

In one aspect, the present invention relates to crystalline Form A of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, crystalline Form A is anhydrous.

In another embodiment, the melting point of crystalline Form A is about 254°C.

In another embodiment, Form A is characterized by a PDT containing peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2° two theta, which is obtained using a Cu Ka radiation source. In another embodiment, Form A is characterized by a PDH containing 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° two theta, which is obtained using a Cu Ka radiation source. In another embodiment, Form A is characterized by a PDH containing 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° two theta, which was obtained using a Cu Ka radiation source.

In another embodiment, Form A is characterized by a PDH essentially as shown in FIG. 1. In another embodiment, Form A is characterized by a TGA profile, essentially pre

- 13 046472 placed in Fig. 2. In another embodiment, Shape A is characterized by a DSC profile substantially as shown in FIG. 3.

In another embodiment, the unit cell of form A is indexed as primitive monoclinic.

In another embodiment, the Form A unit cell has the following parameters: an a value of about 10.035 A, a b value of about 7.532 A, and a c value of about 20.092 A. In another embodiment, the volume of the Form A unit cell is about 1518.1 A ³ .

Parameters of the unit cell of form A.

Bravais crystal grid Primitive monoclinic a [A] 10.035 b[A] 7,532 s [A] 20,092 a[deg] 90 β [deg] 91.39 γ[deg] 90 Volume [A/cell] 1518.1 Chiral content? Chiral Extinction simpol R 1 21 1 Space group(s) P21(4)

In another embodiment, Form A is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form A is 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 according at least 99%.

B. Crystal form B.

In one aspect, the present invention relates to crystalline Form B hydrobromide salt of (D)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1 -(2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form B is characterized by a PDH essentially as shown in FIG. 4.

In another embodiment, Form B is substantially free from other polymorphic forms.

In another embodiment, the polymorphic purity of Form B is at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90% , at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

C. Crystalline form C.

In one aspect, the present invention relates to crystalline form C of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-X-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of formula (II)

where n is approximately 1-3.

- 14 046472

In one embodiment, Form C has one or more characteristics selected from the group consisting of items a)-d):

a) PRDG essentially shown in FIG. 5;

b) TGA profile essentially as shown in FIG. 6;

c) DSC profile essentially shown in FIG. 7; And

d) Thermogravimetric profile associated with the IR spectrum, substantially represented in a figure selected from the group consisting of FIGS. from 8 to 10.

In another embodiment, the unit cell of shape C is indexed as a primitive rhombic.

In another embodiment, the Form C unit cell has the following characteristics: a value is about 7.491 A, b value is about 10.353 A, and c value is about 48.790 A. In another embodiment, the volume of the Form C unit cell is about 3783.9 A ³ .

Unit cell parameters of form C.

Bravais crystal grid Primitive rhombic a [A] 7,491 b[A] 10,353 s [A] 48,790 a [deg] 90 β [deg] 90 γ[deg] 90 Volume [AUcell] 3783.9 Chiral content? Chiral Sympol touch P2i 2 _l 2i Space group(s) R212D (19)

In another embodiment, TGA shows that Form C loses at least 8 wt.% in the temperature range from about 60°C to about 190°C.

In another embodiment, the DSC thermogram of Form C shows a first endothermic event at approximately 39°C and a second endothermic event at approximately 152°C.

In another embodiment, Form C is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form C is 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 according at least 99%.

D. Crystal form D.

In one aspect, the present invention provides crystalline Form D of (^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-X-(1) hydrobromide salt -(2-methyl-1 (neopentylamino)propan-2-yl)-1 H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form D has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG essentially shown in FIG. eleven;

b) TGA profile essentially as shown in FIG. 12A or FIG. 12B; And

c) DSC profile essentially represented by line A or line B in FIG. 13.

In another embodiment, the unit cell of shape D is indexed as primitive monoclinic. In another embodiment, a unit cell of the form

B is characterized by the following parameters: a value is approximately 18.465 A, b value is approximately 7.441 A, and c value is approximately 23.885 A.

In another embodiment, the unit cell volume of Form D is approximately 3250.4 A ³ .

- 15 046472

Parameters of the unit cell of form D.

Bravais crystal grid Primitive monoclinic a [A] 18,465 b [A] 7,441 s [A] 23,885 a [deg] 90 β [deg] 97.95 γ [deg] 90 Volume [A’/cell] 3250.4 Chiral content? Chiral Extinction simpol R 1 21 1 Space group(s) P21 (4)

In another embodiment, TGA shows that Form D loses from about 1.2 to about 2.5 wt.% in the temperature range from about 24°C to about 109°C.

In another embodiment, the DSC thermogram of Form D shows an endothermic event at approximately 65°C.

In another embodiment, Form D is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form D is 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 according at least 99%.

E. Crystalline form E.

In one aspect, the present invention relates to crystalline form E of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-X-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1 H-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form E has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG essentially shown in FIG. 14;

b) TGA profile essentially as shown in FIG. 15; And

c) DSC profile essentially shown in FIG. 16.

In another embodiment, TGA shows that Form E loses from about 8 wt.% in the temperature range from about 28°C to about 120°C.

In another embodiment, the DSC thermogram of Form E shows an endothermic event at approximately 80°C.

In another embodiment, Form E is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form E is 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 according at least 99%.

F. Crystal form F.

In one aspect, the present invention relates to crystalline form F of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-X-(1- (2-methyl-1(neopentylamino)propan-2-yl)-1 H-imidazol-4-yl)pentanamide of formula (I)

- 16 046472

In another embodiment, Form F is characterized by a PDH essentially as shown in FIG. 17.

In another embodiment, Form F is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form F is 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 according at least 99%.

G. Crystal form F'.

In one aspect, the present invention relates to crystalline form F' of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the shape F' has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG essentially shown in FIG. 18;

b) TGA profile essentially as shown in FIG. 19; And

c) DSC profile essentially shown in FIG. 20.

In another embodiment, TGA shows that Form F' loses about 12.6 wt.% in the temperature range from about 24°C to about 90°C and loses about 15.6 wt.% in the temperature range from about 97°C to approximately 198°C.

In another embodiment, Form F' is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form F' is 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.

In one aspect, the present invention relates to crystalline form G of hydrobromide salt (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl -1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form G is characterized by a PDG substantially represented in FIG. 21.

In another embodiment, Form G is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form G is 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 according at least 99%.

I. Crystal form of H.

In one aspect, the present invention relates to the crystalline form H of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form H is characterized by a PDH essentially represented by

- 17 046472 fig. 22.

In another embodiment, Form H is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form H is 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 according at least 99%.

J. Crystal form H'.

In one aspect, the present invention provides a crystalline form of H' hydrobromide salt of H)-2-((H)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the H' form is characterized by a PDH, essentially represented in FIG. 23.

In another embodiment, Form H' is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form H' is 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.

In one aspect, the present invention relates to crystalline form J of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form J is characterized by a PDH essentially as illustrated in FIG. 24.

In another embodiment, Form J is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form J is 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 according at least 99%.

L. Crystal form K.

In one aspect, the present invention relates to crystalline Form K hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form K is characterized by a PDH essentially as shown in FIG. 25.

In another embodiment, Form K is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form K is 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%,

- 18 046472 at least 98% or at least 99%.

M. Crystal form L.

In one aspect, the present invention relates to crystalline form L of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the L shape has one or more characteristics selected from the group of characteristics of items a)-c):

a) PRDG essentially shown in FIG. 26;

b) TGA profile essentially as shown in FIG. 27; And

c) DSC profile essentially shown in FIG. 28.

In another embodiment, the Form L DSC thermogram shows an endothermic event at approximately 157°C.

In another embodiment, Form L is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form L is 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 according at least 99%.

N. Crystalline form of M.

In one aspect, the present invention relates to crystalline form M of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form M is characterized by a PDG substantially represented in FIG. 29.

In another embodiment, Form M is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form M is 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 according at least 99%.

O. Crystalline form N.

In one aspect, the present invention relates to a crystalline form of N hydrobromide salt of N)-2-((N)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, Form N is characterized by a PDH essentially as shown in FIG. thirty.

In another embodiment, Form N is substantially free from other polymorphic forms. In another embodiment, the polymorphic purity of Form N is 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 according at least 99%.

- 19 046472

P. Amorphous form.

In one aspect, the present invention provides an amorphous form of (S)-2((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-( 2-methyl-1-(neopentylamino)propan-2yl)-III-imidazol-4-yl)pentanamide of formula (I)

In one embodiment, the amorphous compound of formula 1! (I) is characterized by the PDH essentially represented in FIG. 31.

In another embodiment, amorphous compound 1 of formula (I) is substantially free of polymorphic forms. In another embodiment, the polymorphic purity of amorphous compound 1 of formula (I) is 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 at least 98% or at least 99%.

III. Particle size.

In another aspect, the present invention provides crystalline and aformal forms as discussed above, characterized by one or more of the following particle size indices: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50 ] in the range from about 2 μm to about 30 μm, D[V,0.90] in the range from about 8 μm to about 600 μm, or D[4,3] in the range from about 5 μm to about 200 μm.

In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent value D[V,0.10] ranging from about 0.5 μm to about 15 μm. In one embodiment, for the crystalline and amorphous forms discussed above, D[V,0.10] is in the range from about 0.5 μm to about 10 μm. In one embodiment, the crystalline and amorphous forms discussed above have D[V,0.10] in the range of about 0.5 μm to about 5 μm.

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

In one embodiment, the crystalline and amorphous forms discussed above have a particle size index value D[V,0.90] ranging from about 8 μm to about 600 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent value D[V,0.90] ranging from about 8 μm to about 500 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent value D[V,0.90] ranging from about 8 μm to about 400 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent value D[V,0.90] ranging from about 8 μm to about 300 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size index value D[V,0.90] ranging from about 8 μm to about 200 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent value D[V,0.90] ranging from about 8 μm to about 100 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size index value D[V,0.90] ranging from about 8 μm to about 75 μm.

In one embodiment, the crystalline and amorphous forms discussed above have a particle size exponent D[4,3] value ranging from about 5 μm to about 200 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 5 μm to about 150 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 5 μm to about 100 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 5 μm to about 75 μm. In one embodiment, the crystalline and amorphous forms discussed above have a particle size index value of

- 20 046472

D[4,3] is in the range from about 5 μm to about 50 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 5 μm to about 25 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 10 μm to about 50 μm. In one embodiment, the crystalline and amorphous forms discussed above have a D[4,3] particle size index value ranging from about 10 μm to about 30 μm.

In one embodiment, Form A is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form A ranges from about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form A is in the range from about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form A is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form A is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form A ranges from about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form A is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form A is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form A ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form A ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form A ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form A ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form A ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form A is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form A ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form A ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form A ranges from about 10 μm to about 30 μm.

In one embodiment, Form B is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form B is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form B is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form B is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form B is in the range of about 2 μm to about 30 μm. In one embodiment, the [V,0.50] value of Form B is in the range of about 2 μm to about 25 μm. In one embodiment, the [V,0.50] value of Form B is in the range of about 2 μm to about 20 μm. In one embodiment, the [V,0.50] value of Form B is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form B ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form B ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form B is in the range of about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form B ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form B ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form B ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form B is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form B is in the range of about 5

- 21 046472 µm to approximately 200 µm. In one embodiment, the D[4,3] value of Form B ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form B ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form B ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of the shape is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form B ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form B ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form B is in the range of about 10 μm to about 30 μm.

In one embodiment, Form C is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range of about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form C is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form C is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form C is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form C is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form C is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form C is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form C is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form C ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form C is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form C ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form C ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form C ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form C ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form C is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form C ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form C ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form C is in the range of about 10 μm to about 30 μm.

In one embodiment, Form D is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form D ranges from about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form D is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form D is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form D is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form D is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form D is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form D is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form D ranges from about 8 μm to about 100 μm. In one embodiment, the value

- 22 046472

The D[V,0.90] of Form D ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form D ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form D ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form D ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form D ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form D is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form D ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form D ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form D is in the range of about 10 μm to about 30 μm.

In one embodiment, Form E is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form E is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form E is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form E is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form E is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form E is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form E is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form E is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form E ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form E ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form E ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form E ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form E ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form E is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form E ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form E ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form E ranges from about 10 μm to about 30 μm.

In one embodiment, Form F is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form F is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form F is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form F is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form F is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form F ranges from about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form F is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form F is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form F is in the range of about

- 23 046472 µm to approximately 200 µm. In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form F ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form F ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form F ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form F ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form F ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form F is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form F ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form F ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form F ranges from about 10 μm to about 30 μm.

In one embodiment, Form F' is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form F' is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form F' is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form F' is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form F' is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form F' is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form F' is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form F' is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form F' is in the range from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range of about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range of about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form F' is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form F' is in the range of about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form F' is in the range from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form F' is in the range of about 10 μm to about 30 μm.

In one embodiment, Form G is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form G is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form G is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form G is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form G is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form G is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form G is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form G is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 400 μm. In one version

- 24 046472 implementation value D[V,0.90] of form G is in the range from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form G ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form G ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form G ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form G ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form G ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form G is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form G ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form G ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form G is in the range of about 10 μm to about 30 μm.

In one embodiment, Form H is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form H is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form H is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form H is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form H is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form H ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 500 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 400 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 200 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.50] value of Form H is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form H ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form H ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form H ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form H is in the range of about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form H is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form H is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form H is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form H is in the range of about 10 μm to about 30 μm.

In one embodiment, Form H' is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm, or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of form H' is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of the H' form is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of form H' is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of form H' is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of form H' is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of form H' is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of form H' is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of the H' form ranges from about 8 μm to about 600 μm. In one embodiment, the value D[V,0.90] of the form H' is in

- 25 046472 range from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of the H' form ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of form H' ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of the H' form ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of the H' form ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of the H' form ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of form H' ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of form H' ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of form H' ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of form H' ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of form H' is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of form H' is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of form H' is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of form H' is in the range of about 10 μm to about 30 μm.

In one embodiment, Form J is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form J is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form J is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form J is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form J is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form J is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form J is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form J is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 300 μm. In one embodiment, the shape value D[V,0.90] of shape J is in the range from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form J is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form J is in the range of about 10 μm to about 30 μm.

In one embodiment, Form K is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form K is in the range of about 0.5 μm to about 15 μm. In one embodiment, the shape value D[V,0.10] of shape K is in the range from about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form K is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form K is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form K is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form K is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form K is in the range of about 2 μm to about 15 μm.

- 26 046472

In one embodiment, the D[V,0.90] value of Form K ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form K ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form K ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form K is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form K is in the range of about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form K is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form K is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form K ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form K ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form K is in the range of about 10 μm to about 30 μm.

In one embodiment, Form L is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.50] value of Form L ranges from about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.50] value of Form L is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.50] value of Form L is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form L is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form L is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form L is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form L is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form L ranges from about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form L ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form L ranges from about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form L ranges from about 10 μm to about 30 μm.

In one embodiment, Form M is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form M is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form M is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form M is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form M is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form M is in the range of about 2 μm to about 25 μm. In one embodiment, the value of D[V,0.50]

- 27 046472 form M is in the range from about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form M is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form M is in the range of about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form M ranges from about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form M ranges from about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form M is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form M ranges from about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form M is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form M is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form M ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form M ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form M ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form M ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form M is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form M is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form M is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form M is in the range of about 10 μm to about 30 μm.

In one embodiment, Form N is characterized by one or more of the following particle sizes: D[V,0.10] in the range of about 0.5 μm to about 15 μm, D[V,0.50] in the range of about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of Form N is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of Form N is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of Form N is in the range of about 0.5 μm to about 5 μm.

In one embodiment, the D[V,0.50] value of Form N is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of Form N is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of Form N is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of Form N is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of Form N ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of Form N is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of Form N ranges from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of Form N ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of Form N ranges from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of Form N ranges from about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of Form N is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of Form N ranges from about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of Form N is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of Form N is in the range of about 10 μm to about 30 μm.

In one embodiment, the amorphous form is characterized by one or more of the following particle sizes: D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in the range from about 5 µm to about 200 µm.

In one embodiment, the D[V,0.10] value of the amorphous form is in the range of about 0.5 μm to about 15 μm. In one embodiment, the D[V,0.10] value of the amorphous form is in the range of about 0.5 μm to about 10 μm. In one embodiment, the D[V,0.10] value of the amorphous form is in the range of about 0.5 μm to about 5 μm.

- 28 046472

In one embodiment, the D[V,0.50] value of the amorphous form is in the range of about 2 μm to about 30 μm. In one embodiment, the D[V,0.50] value of the amorphous form is in the range of about 2 μm to about 25 μm. In one embodiment, the D[V,0.50] value of the amorphous form is in the range of about 2 μm to about 20 μm. In one embodiment, the D[V,0.50] value of the amorphous form is in the range of about 2 μm to about 15 μm.

In one embodiment, the D[V,0.90] value of the amorphous form ranges from about 8 μm to about 600 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 500 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 400 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 300 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 200 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 100 μm. In one embodiment, the D[V,0.90] value of the amorphous form is in the range of about 8 μm to about 75 μm.

In one embodiment, the D[4,3] value of the amorphous form is in the range from about 5 μm to about 200 μm. In one embodiment, the D[4,3] value of the amorphous form ranges from about 5 μm to about 150 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range from about 5 μm to about 100 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range of about 5 μm to about 75 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range of about 5 μm to about 50 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range of about 5 μm to about 25 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range of about 10 μm to about 50 μm. In one embodiment, the D[4,3] value of the amorphous form is in the range of about 10 μm to about 30 μm.

In one aspect, the present invention relates to a composition comprising a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2yl)amino)-N- ( 1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide which is characterized by one or more of the following particle size parameters: D[V,0.10] in the range of about 0.5 µm to about 15 µm, D[V,0.50] in the range from about 2 µm to about 30 µm, D[V,0.90] in the range from about 8 µm to about 600 µm or D[4,3] in ranging from about 5 µm to about 200 µm.

In one embodiment, the composition includes a crystalline or amorphous form of (^)-2-(((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-( 1-(2-methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with a particle size index value D[V,0.10] ranging from about 0.5 μm to about 15 μm . In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (^)-2-(((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-( 1 - (2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide with a particle size index value D[V,0.10] ranging from about 0.5 μm to about 10 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt (b)-2-(((b)-6.8-difluoro-1.2.3.4-tetrahydronaphthalene-2-yl)amino)-H-(1(2-methyl- 1-(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with a particle size index value D[V,0.10] ranging from about 0.5 μm to about 5 μm.

In one embodiment, the composition includes a crystalline or amorphous form of (^)-2-(((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-( 1-(2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a particle size index value D[V,0.50] ranging from about 2 μm to about 30 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (^)-2-(((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-( 1 - (2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide with a particle size index value D[V,0.50] ranging from about 2 μm to about 25 μm. In one embodiment, the composition includes a crystalline or amorphous form of (^)-2-(((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-( 1(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a particle size index value D[V,0.50] ranging from about 2 μm to about 20 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide with a particle size index value D[V,0.50] ranging from about 2 μm to about 15 μm.

In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-K-( 1-(2-methyl-1-29 046472 (neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 600 µm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 500 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)N(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 400 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1- (2-methyl-1-(neopentylamino)propan-2yl)-N-imidazol-4-yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 300 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 200 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)N(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 100 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1- (2-methyl-1-(neopentylamino)propan-2yl)-N-imidazol-4-yl)pentanamide with a particle size index value D[V,0.90] ranging from about 8 μm to about 75 μm.

In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 5 μm to about 200 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide with a D[4,3] particle size index value ranging from about 5 μm to about 150 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2methyl-1-(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 5 μm to about 100 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2-(((S)-6,8difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-( 1 - (2-methyl-1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 5 μm to about 75 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)N(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 5 μm to about 50 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1 -(2-methyl-1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 10 μm to about 50 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)N(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 10 μm to about 40 μm. In one embodiment, the composition includes a crystalline or amorphous form of the hydrobromide salt of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1-(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide with a D[4,3] particle size index value ranging from about 10 μm to about 30 μm.

In one embodiment, the hydrobromide salt of ^)-2-((^)-6.8-difluoro-1.2.3.4tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propane-2 -yl)-1H-imidazol-4yl)pentanamide, which is characterized by one or more particle size indices of D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50] in the range from about 2 μm to about 30 μm, D[V,0.90] in the range from about 8 μm to about 600 μm, or D[4,3] in the range from about 5 μm to about 200 μm, is in amorphous form. In one embodiment, the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N-(1-(2-methyl1-( neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide, which is characterized by one or more particle size indices of D[V,0.10] in the range from about 0.5 μm to about 15 μm,

- 30 046472

D[V,0.50] in the range of about 2 μm to about 30 μm, D[V,0.90] in the range of about 8 μm to about 600 μm, or D[4,3] in the range of about 5 μm to about 200 μm , presented in crystalline form. In one embodiment, the amorphous or crystalline hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2- methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide, which is characterized by one or more particle size indices of D[V,0.10] in the range from about 0.5 μm to about 15 μm , D[V,0.50] in the range from about 2 μm to about 30 μm, D[V,0.90] in the range from about 8 μm to about 600 μm, or D[4,3] in the range from about 5 μm to about 200 µm, is a compound of formula (I)

implementation of the hydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4 In one embodiment, tetrahydronaphthalene-2-yl)amino)-H-( 1 -(2-methyl-1 -( neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide, which is characterized by one or more particle size indices of D[V,0.10] in the range from about 0.5 μm to about 15 μm, D[V,0.50 ] in the range from about 2 μm to about 30 μm, D[V,0.90] in the range from about 8 μm to about 600 μm, or D[4,3] in the range from about 5 μm to about 200 μm, is a compound of formula (II)

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.

In some embodiments, the crystalline form is Form A, which is characterized by one or more particle size characteristics 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 of the present invention, the crystalline form is Form A, in which two or more particle size parameters are selected from the group consisting of D[V,0.10], D[V,0.50], D[V,0.90], and D[ 4.3].

Each of the embodiments described herein may be combined with any other embodiment described herein that is consistent with the embodiment with which it is combined.

In other embodiments of the present invention, the crystalline form is Form A, wherein the D[V,0.10] value is in the range of about 0.5 μm to about 15 μm; from about 0.5 μm to about 10 μm; from about 0.5 μm to about 5 μm; from about 1 μm to about 15 μm; from about 1 μm to about 10 μm; from about 1 μm to about 7.5 μm; from about 1 μm to about 5 μm; from about 2 μm to about 10 μm; from about 2 μm to about 7.5 μm; from about 2 μm to about 5 μm; from about 3 μm to about 10 μm; from about 3 μm to about 7.5 μm; or from about 3 μm to about 5 μm. In other embodiments of the present invention, the crystalline form is Form A, which has a D[V,0.10] value of less than 15 μm; less than 12.5 microns; less than 10 microns; less than 9 microns; less than 8 microns; less than 7 microns; less than 6 microns; less than 5 microns; less than 4 microns; or less than 3 microns.

In other embodiments of the present invention, the crystalline form is Form A, which has a D[V,0.50] value in the range of about 2 μm to about 30 μm; from about 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; from about 7.5 μm to about 15 μm; from about 7.5 μm to about 10 μm; from about 10 μm to about 30 μm; from about 10 μm to about 25 μm; from about 10 μm to about 20 μm; from about 10 μm to about 15 μm; from about 12 μm to about 15 μm; from about 15 μm to about 30 μm; from about 15 μm to about 25 μm; from about 15 μm to about 20 μm; from about 20 µm to about 30 µm. In other embodiments of the present invention, the crystalline form is

- 31 046472 form A, in which the D[V,0.50] value is less than 30 µm; less than 25 microns; less than 20 microns; less than 15 microns; less than 12.5 microns; or less than 10 microns.

In other embodiments of the present invention, the crystalline form is Form A, which has a D[V,0.90] value in the range of 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 175 μm; from about 8 μm to about 150 μm; from about 8 μm to about 125 μm; from about 8 μm to about 100 μm; from about 8 μm to about 75 μm; from about 8 μm to about 50 μm; from about 8 μm to about 40 μm; from about 8 μm to about 30 μm; from about 10 μm to about 600 μm; from about 10 μm to about 575 μm; from about 10 μm to about 550 μm; from about 10 μm to about 525 μm; from about 10 μm to about 500 μm; from about 10 μm to about 475 μm; from about 10 μm to about 450 μm; from about 10 μm to about 425 μm; from about 10 μm to about 400 μm; from about 10 μm to about 375 μm; from about 10 μm to about 350 μm; from about 10 μm to about 325 μm; from about 10 μm to about 300 μm; from about 10 μm to about 275 μm; from about 10 μm to about 250 μm; from about 10 μm to about 225 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 125 μm; from about 10 μm to about 100 μm; from about 10 μm to about 75 μm; from about 10 μm to about 60 μm; from about 10 μm to about 50 μm; from about 25 μm to about 600 μm; from about 25 μm to about 575 μm; from about 25 μm to about 550 μm; from about 25 μm to about 525 μm; from about 25 μm to about 500 μm; from about 25 μm to about 475 μm; from about 25 μm to about 450 μm; from about 25 μm to about 425 μm; from about 25 μm to about 400 μm; from about 25 μm to about 375 μm; from about 25 μm to about 350 μm; from about 25 μm to about 325 μm; from about 25 μm to about 300 μm; from about 25 μm to about 275 μm; from about 25 μm to about 250 μm; from about 25 μm to about 225 μm; from about 25 μm to about 200 μm; from about 25 μm to about 175 μm; from about 25 μm to about 150 μm; from about 25 μm to about 125 μm; from about 25 μm to about 100 μm; from about 25 μm to about 75 μm; from about 25 μm to about 50 μm; from about 40 μm to about 600 μm; from about 40 μm to about 575 μm; from about 40 μm to about 550 μm; from about 40 μm to about 525 μm; 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 50 μm to about 75 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 at

- 32 046472 approximately 600 microns; 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 150 μm to about 175 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

- 33046472 µm to approximately 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; from about 350 μm to about 575 μm; from about 350 μm to about 550 μm; from about 350 μm to about 525 μm; from about 350 μm to about 500 μm; from about 350 μm to about 475 μm; from about 350 μm to about 450 μm; from about 350 μm to about 425 μm; from about 350 μm to about 400 μm; from about 350 μm to about 375 μm; from about 375 μm to about 600 μm; from about 375 μm to about 575 μm; from about 375 μm to about 550 μm; from about 375 μm to about 525 μm; from about 375 μm to about 500 μm; from about 375 μm to about 475 μm; from about 375 μm to about 450 μm; from about 375 μm to about 425 μm; from about 375 μm to about 400 μm; from about 400 μm to about 600 μm; from about 400 μm to about 575 μm; from about 400 μm to about 550 μm; from about 400 μm to about 525 μm; from about 400 μm to about 500 μm; from about 400 μm to about 475 μm; from about 400 μm to about 450 μm; from about 400 μm to about 425 μm; from about 425 μm to about 600 μm; from about 425 μm to about 575 μm; from about 425 μm to about 550 μm; from about 425 μm to about 525 μm; from about 425 μm to about 500 μm; from about 425 μm to about 475 μm; from about 425 μm to about 450 μm; from about 450 μm to about 600 μm; from about 450 μm to about 575 μm; from about 450 μm to about 550 μm; from about 450 μm to about 525 μm; from about 450 μm to about 500 μm; from about 450 μm to about 475 μm; from about 475 μm to about 600 μm; from about 475 μm to about 575 μm; from about 475 μm to about 550 μm; from about 475 μm to about 525 μm; from about 450 μm to about 500 μm; from about 450 μm to about 475 μm; from about 500 μm to about 600 μm; from about 500 μm to about 575 μm; from about 500 μm to about 550 μm; from about 500 μm to about 525 μm; from about 550 μm to about 600 μm; from about 550 μm to about 575 μm; or from about 575 microns to about 600 microns. In other embodiments of the present invention, the crystalline form is Form A, the D[V,0.90] value of which is 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 microns, less than 400 microns, less than 375 microns, less than 350 microns, less than 325 microns, less than 300 microns, less than 275 microns, less than 250 microns, less than 225 microns, less than 200 microns, less than 175 microns; less than 150 microns; less than 125 microns; less than 100 microns; less than 75 microns; or less than 50 microns.

In other embodiments of the present invention, the crystalline form is Form A, wherein the D[4,3] value ranges from about 5 μm to about 200 μm; from about 5 μm to about 175 μm; from about 5 μm to about 150 μm; from about 5 μm to about 125 μm; from about 5 μm to about 100 μm; from about 5 μm to about 75 μm; from about 5 μm to about 50 μm; from about 5 μm to about 40 μm; from about 5 μm to about 25 μm; from about 10 μm to about 200 μm; from about 10 μm to about 175 μm; from about 10 μm to about 150 μm; from about 10 μm to about 125 μm; from about 10 μm to about 100 μm; from about 10 μm to about 75 μm; from about about 10 μm to about 50 μm; from about 10 μm to about 40 μm; from about 10 μm to about 25 μm; from about 15 μm to about 200 μm; from about 15 μm to about 175 μm; from about 15 μm to about 150 μm; from about 15 μm to about 125 μm; from about 15 μm to about 100 μm; from about 15 μm to about 75 μm; from about 15 μm to about 50 μm; from about 15 μm to about 40 μm; from about 15 μm to about 25 μm; from about 20 μm to about 200 μm; from about 20 μm to about 175 μm; from about 20 μm to about 150 μm; from about 20 μm to about 125 μm; from about 20 μm to about 100 μm; from about 20 μm to about 75 μm; from about 20 μm to about 50 μm; from about 25 μm to about 200 μm; from about 25 μm to about 175 μm; from about 25 μm to about 150 μm; from about 25 μm to about 125 μm; from about 25 μm to about 100 μm; from about 25 μm to about 75 μm; from about 25 μm to about 50 μm; from about 25 μm to about 40 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 50 μm to about 75 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 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 200 μm; from about 125 μm to about 175 μm; from about 125 μm to about 150 μm; from about 150 μm to about 200 μm; from about 150 μm to about 175 μm; or from about 175 microns to about 200 microns. In other embodiments of the present invention, the crystalline form is Form A, which has a D[4,3] value of less than 200 μm; less than 175 microns; less than 150 microns; less than 125 microns; less

- 34 046472

100 µm; less than 75 microns; 50 µm; less than 40 microns; less than 30 microns; or less than 25 microns.

The hydrobromide salt form of Compound 1 can be prepared based on the synthetic schemes described in US Pat. No. 7,795,447, which is incorporated herein by reference in its entirety. In some embodiments, the specific crystalline or amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-( 2-methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with the desired particle size is the product of the synthesis. In other embodiments of the present invention, the specific crystalline or amorphous hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2yl)amino)-L-(1-(2 -methyl-1-(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide with the desired particle size is prepared using additional processing steps after synthesis. Examples of such process steps include, but are not limited to, recrystallization and comminution, such as jet milling.

In some embodiments, particle size is determined using laser diffraction (eg, Sympatec Helos and QicPic) at a dispersion pressure of 3.0 bar (300 kPa).

Particle sizes of crystalline materials can be estimated using laser diffraction techniques. Laser diffraction is recognized by standards and governing bodies including ISO and ASTM and is widely used to determine particle size distribution. During the evaluation, the sample is passed through a laser beam, causing the laser light to be scattered at different angles. Detectors placed at fixed angles measure the intensity of light scattered at that position. A mathematical model (Mie or Fraunhoffer theory) is then applied to obtain the particle size distribution.

Particle size was analyzed using laser diffraction (or small angle light scattering) by dispersing a dry powder sample with compressed air. Specifically, particle size distribution analysis was carried out using a Sympatec HELOS RODOS system equipped with a Vibri dry powder feeder. The powder sample was dispersed at a dispersion pressure of 0.5 bar (50 kPa). In some cases, an Aspiros microdosing device was used and the powder sample was dispersed at a dispersion pressure of 0.2 bar (20 kPa). A suitable lens was selected to cover the particle size range of each sample.

When determining particle sizes, the median particle size is defined as the value where half the population has a particle size greater than this value and the other half of the population has a particle size less than this value. In a particle size distribution, the median is referred to as D50. D50 is the size in microns that divides the particle distribution population into half with a diameter greater than this diameter and half with a diameter less than this diameter. The abbreviation Dv50 or D[v,0.5] is sometimes used to indicate the median of the volume distribution.

The mode (or mode) represents the peak value of the frequency of the distribution. The particle distribution may include more than one mode, for example when the particles exist as primary particles and as agglomerations.

A range of values is sometimes used to measure the width of a distribution, which is defined as the ratio (D[v,0.9]- D[v,0.1])/D[v,0.5] or (D90-D10)/D50.

The distribution width can also be characterized by specifying one, two or preferably three values, usually some combination of D10, D50 and D90. D50, the median value, is defined above as the diameter that is the maximum for half the particles and the minimum for the other half of the particles. Likewise, 90 percent of the particles have a diameter below the D90 value, and 10 percent of the particles have a diameter below the D10 value.

The D[4,3] value refers to the median volume or median mass moment. Laser diffraction results are reported on a volume basis, and the median volume can be used to determine the center point of the distribution. The D[4,3] value is sensitive to the presence of large particles in the distribution.

IV. Pharmaceutical compositions.

Forms A-N and the amorphous form of the hydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-L-( 1 -(2-methyl-1 - (neopentylamino)propan-2-yl)-N-imidazol-4yl)pentanamide of formula (I) or (II) can be administered to subjects orally, parenterally (such as subcutaneous, intravenous, intramuscular, intrasternal route of administration and infusion), rectal, intranasal , topical or transdermal (for example, using a patch) methods. In one embodiment, crystalline Form A of the compound of formula (I) can be administered to subjects by oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion routes), rectal, intranasal, topical or transdermal (eg, patch) routes.

In one embodiment, the pharmaceutical composition includes crystalline form A of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1- (2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I). In one embodiment, it will be carried out

- 35 046472 the pharmaceutical composition is a tablet for oral administration, including one or more of the forms A-N and the amorphous form of the hydrobromide salt (S)-2-(((S)-6,8difluoro-1,2,3,4 -tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1-(neopentylamino)propan-2-yl)-shimidazol-4-yl)pentanamide of formula (I) or (II) and pharmaceutically acceptable carrier. In one embodiment, the tablet includes from about 25 mg to about 400 mg of one or more of Forms A-N and an amorphous hydrobromide salt form of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2 -yl)amino)-N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of formula (I) or (II). In one embodiment, the tablet includes 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 80 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 hydrobromide salt ^)-2-((^)-6,8-difluoro-1 ,2,3,4tetrahydronaphthalen-2-yl)amino)-N-( 1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-N-imidazol-4yl)pentanamide in one or more of the forms A-N or amorphous form. In one embodiment, the tablet includes about 50 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-(1-(2- methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of one or more of the forms A-N and the amorphous form of the hydrobromide salt (S)-2((^)-6,8-difluoro-1, 2,3,4-tetrahydronaphthalen-2-yl)amino)-H-(1-(2-methyl-1-(neopentylamino)propan-2yl)-III-imidazol-4-yl)pentanamide of formula (I) or ( II). In one embodiment, the tablet includes about 100 mg of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2yl)amino)-N-(1-(2- methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide in the form of one or more of the forms A-N and the amorphous form of the hydrobromide salt ^)-2-((^)-6,8- difluoro-1,2,3,4tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of formula (I) or (II). In one embodiment, the tablet includes about 150 mg of one or more of Forms A-N and an amorphous hydrobromide salt form of ^)-2-((^)-6,8-difluoro1,2,3,4-tetrahydronaphthalene-2-yl)amino) -H-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of formula (I) or (II).

Known carriers may be included in the pharmaceutical composition for oral administration. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, calcium hydrogen phosphate and glycine can be used along with various disintegrants such as starch (preferably corn, potato and tapioca starch), methylcellulose, alginic acid and certain silicate complexes, as well as granulation binders such as like polyvinylpyrrolidone, sucrose, gelatin and gum arabic, which may also be included in the tablet. In addition, tabletting often additionally uses lubricants such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type can also be filled into gelatin capsules. In this regard, preferred materials include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may also be combined with various sweeteners or flavoring agents, coloring agents or dyes and, if necessary, emulsifiers and/or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin and their various combinations.

For parenteral administration, solutions containing Compound 1 can be prepared in sesame or peanut oil, aqueous propylene glycol, sterile water or saline. If necessary, aqueous solutions must be suitably buffered (preferably pH greater than 8) and the liquid diluent must first be isotonized with sufficient saline or glucose. Such aqueous solutions are suitable for intravenous injection. Oil solutions are suitable for intra-articular, intramuscular and similar injections. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical methods well known to those skilled in the art.

V. Methods of treatment.

Forms A-N and the amorphous form of the hydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino)-N-( 1 -(2-methyl-1 - The (neopentylamino)propan-2-yl)-N-imidazol-4yl)pentanamide of formula (I) or (II) can be used to modulate or inhibit the Notch signaling pathway in organisms, including humans. The Notch signaling pathway is frequently activated in a variety of human tumors (including, but not limited to, breast, prostate, pancreatic, and T-cell progenitor acute lymphoblastic leukemia).

Accordingly, forms A-N and the amorphous form of the hydrobromide salt ^)-2-((^)-6,8-difluoro- 36 046472

1,2,3,4-tetrahydronaphthalen-2-yl)amino)-H-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of formula (I) or (ii) may be administered to treat a subject suffering from tumors or cancer, including, but not limited to, desmoid tumors, multiple myeloma, adenoid cystic carcinoma, and T-cell progenitor acute lymphoblastic leukemia. In one embodiment, crystalline Form A of a compound of formula (I) may be administered to treat a subject suffering from tumors or cancers, including, but not limited to, desmoid tumors, multiple myeloma, adenoid cystic carcinoma, and acute lymphoblastic T-cell progenitor leukemia. In one embodiment, crystalline Form A of a compound of formula (I) and a pharmaceutically acceptable carrier can be administered to treat a subject suffering from tumors or cancer, including, but not limited to, desmoid tumors, multiple myeloma, adenoid cystic carcinoma, and acute lymphoblastic T-cell progenitor leukemia. . In one embodiment, Forms A-N and the amorphous hydrobromide salt form of (S)2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-( 2-methyl-1-(neopentylamino)propan-2yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II) can be administered for the treatment of tumors, including desmoid tumors. In one embodiment, Forms A-N and the amorphous hydrobromide salt form of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-( 2-methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide of formula (I) or (II) can be administered for the treatment of cancer with a mutation in the Notch signaling pathway gene. In one embodiment, Forms A-N and the amorphous hydrobromide salt form ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)N(1-(2- Methyl 1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II) can be administered for the treatment of multiple myeloma. Forms A-N and the amorphous form of the hydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl- 1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide of formula (I) or (II) can be administered for the treatment of adenoid cystic carcinoma. Forms A-N and the amorphous form of hydrobromine salt (S)-2((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H-(1-(2-methyl- 1-(neopentylamino)propan-2yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II) can be administered for the treatment of acute lymphoblastic leukemia of T lymphocyte progenitor cells.

In one embodiment, one or more of the forms A-N and the amorphous hydrobromide salt form of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H- (1-(2-methyl-1(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide of formula (I) or (II) is administered in doses ranging from about 0.1 mg to about 1000 mg per day. In one embodiment, the subject is administered daily from about 50 mg to about 500 mg of one or more forms of A-N and an amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene -2-yl)amino)-N-(1-(2methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II). In another embodiment, the subject is administered daily from about 100 mg to about 400 mg of one or more of the forms A-N and the amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene- 2-yl)amino)-N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-III-imidazol-4yl)pentanamide of formula (I) or (II). In another embodiment, the subject is administered daily 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 of one or more of forms A-N and an amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino )-H-(1-(2-methyl-1(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II). The total daily dose may be given in a single dose or divided into several doses (1, 2, 3, or 4 doses per day). In one embodiment, the total daily dose is provided in two doses. For example, a total daily dose of 300 mg or 200 mg may be administered to a subject in two separate doses of 150 mg or 100 mg, respectively. In one embodiment, three tablets comprising 50 mg of one or more of Forms A-N and an amorphous hydrobromide salt form of ^)-2-((^)-6,8-difluoro-1,2,3,4tetrahydronaphthalene-2-yl)amino )-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-N-imidazol-4yl)pentanamide of formula (I) or (II) twice daily or 200 mg daily may be administered to the subject in the form of two tablets comprising 50 mg of one or more forms A-N and amorphous compound 1 of formula (I) or (II), twice daily.

In one aspect, the present invention relates to the use of one or more of the forms A-N or an amorphous form of the hydrobromide salt of ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2yl)amino)- N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide of formula (I) or (II) discussed above, for the treatment of tumors or cancer. In one embodiment, the present invention relates to the use of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-H- hydrobromide salt Form A (1-(2-methyl-1-(neopentylamino)propan-2-yl)-shimidazol-4-yl)pentanamide of formula (I) for the treatment of tumors or cancer. In one embodiment, the present invention relates to a pharmaceutical composition discussed above for the treatment of tumors or cancer. In one embodiment, the use is for use in the treatment of desmoid tumors. In one embodiment, the use is when

- 37 046472 change for the treatment of cancer selected from the group consisting of multiple myeloma, cancer with a mutation in the Notch signaling pathway gene, adenoid cystocarcinoma and acute lymphoblastic leukemia of T-cell progenitors.

In one aspect, the present invention provides one or more of Forms A-N or an amorphous form of the hydrobromide salt (D)-2-(((D)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2- yl)amino)N(1-(2-methyl-1-(neopentylamino)propan-2-yl)-III-imidazol-4-yl)pentanamide of formula (I) or (II) discussed above, for use in the method treatment of tumors or cancer. In one embodiment, the present invention provides crystalline Form A of (S)-2-(((S)6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-N(1) hydrobromide salt -(2-methyl-1 -(neopentylamino)propan-2-yl)-1Himidazol-4-yl)pentanamide of formula (I) for use in a method for treating tumors or cancer. In one embodiment, the present invention relates to a pharmaceutical composition discussed above for use in a method of treating tumors or cancer. In one embodiment, the use is for the treatment of desmoid tumors. In one embodiment, the use is for the treatment of a cancer selected from the group consisting of multiple myeloma, Notch signaling pathway mutated cancer, adenoid cystic carcinoma, and T cell progenitor acute lymphoblastic leukemia.

Examples

A. Abbreviations and acronyms.

NMR Nuclear magnetic resonance spectroscopy XRPD Powder X-ray diffraction PLM Polarized light microscopy TGA Thermogravimetric analysis DSC Differential scanning calorimetry TG-IR Thermogravimetric infrared analysis F.E. Fast evaporation S.E. Slow evaporation S/AS Solvent/anti-solvent SR Crash Precipitation LLD Liquid-liquid diffusion LVD Liquid-vapor diffusion S.C. Slow cooling F.C. Fast cooling SS Crush Cooling LIMS Laboratory information management system B/E Birefringence/extinction RT Room temperature/ambient temperature RH Relative humidity V.O. Vacuum oven ACN Acetonitrile SNS1 ₃ Chloroform dhm Dichloromethane DCE Dichloroethane DEE Diethyl ether DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide EtOAc Ethyl acetate EtOH Ethanol H ₂ O Water HFIPA Hexafluoroisopropanol IPA Isopropanol IPOAc Isopropyl acetate MSN Methylcyclohexane MeOH Methanol MEK Methyl ethyl ketone MIBK Methyl isobutyl ketone MTBE Methyl tert-butyl ether NMP M-methyl-2-pyrrolidone PG Propylene glycol TFE Trifluoroethanol THF Tetrahydrofuran

B. Experimental methods.

Example 1: approximated kinetic solubility.

- 38 046472

Weighed samples of material are treated with aliquots of specific solvents at ambient temperature. Typically, samples are sonicated between additions to facilitate dissolution. Complete dissolution is observed by visual inspection. Solubility is calculated based on the total amount of solvent added to achieve complete dissolution and may be greater than this value due to gradual solvent addition and intrinsic dissolution kinetics. If dissolution does not occur, the values are indicated with a less than sign. If dissolution occurs when the solvent is first added, the values are indicated with a greater than sign. In table Figure 1 shows the kinetic solubility of the dihydrobromide salt (S)-2((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-Na(1-(2-methyl-1- (neopentylamino)propan-2yl)-1H-imidazol-4-yl)pentanamide.

Table 1

Solvent Solubility rating (a) (mg/ml) Acetone <1 Acetone/SNS1 ₃ 50/50 <1 ACN <1 ACN/CHCI3 50/50 <1 ACN/EtOAc 50/50 <1 Chloroform <1 DCE <1 Dioxane '<1 DMA 8 DMF 18 DMF/ACN 30/70 <1 DMF/ACN 60/40 3 DMF/EYAc 50/50 <1 DMF/1RA 60/40 5 DMF/M1VK 80/20 4 DMSO 63 DMSO/MTBE 10/90 <1 Ethylene glycol 7 EYAs <1 E1ON <1 EtOH/DCM 50/50 <1 Heptane/SNS1 ₃ 30/70 <1 MEK/DMFA (b) 40/60 2 MeOH 19 MeOH/acetone5 0/5 0 6 MeOH/SHC1 ₃ 50/50 13 MeON/EYAc 50/50 2 MeON/MTBE 80/20 7 NMP 10 XMP/acetone85/15 7 NMP/EtOAc 57/43 1 PG(b) 2 TFE (anhydrous) 10

- 39 046472

TFE/MEK 70/30 2 THF(b) <1 THF/SHC13 50/50 1 THF/SHC1 ₃ 25/75 <1 THF/SHC13 (b) 85/15 <1 Toluene <1 Water 7 Acetone/NeO 30/70 14 ACN/ _H2O 50/50 36 Dioxane/H ₂ O (b) 50/50 19 DMF/N ₂ O 50/50 24 DMF/N ₂ O 30/70 17 EtOH/ _H2O 40/60 10 1RA/N ₂ O 50/50 15 MeOH/H ₂ O 20/80 9 THF/N ₂ O 80/20 24 THF/N ₂ O 90/10 4

(a) Solubility assessed visually by adding solvent to samples. Values are rounded to the nearest whole number and are indicated with a < sign if no dissolution was observed.

(b) Samples received without confirmation of compliance with cGMP - clinical Rules for the organization of production and quality control of medicinal products.

Example 2: Screening for stable form and hydrate.

Method a: rubbing experiments.

Samples of hydrobromide salt ^)-2-((^)-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 triturated at ambient temperature or at the indicated temperature in the indicated solvent systems. After approximately 24 hours, solids are removed by centrifugation using Eppendorf centrifuge tubes with a 0.45 μm nylon filter. Stirring is continued in the freshly distilled solvents for ~1 and 3 weeks, after which the solids are removed as described above, examined under polarized light, and analyzed by Xray powder diffraction (XRPD).

Method b: Equilibrium solubility testing.

The equilibrium solubility of the isolated solids is determined gravimetrically as follows. Measured aliquots of mother liquor solutions from 3-week suspensions are placed into pre-weighed aluminum TGA dishes. The solvents are then evaporated under ambient conditions or using vacuum. The remaining solids are weighed.

In table Figure 2 presents the results of screening the stable form and hydrates.

- 40 046472

table 2

Solvent system, conditions (a) Observations XRPD results Solubility (mg/ml) (b) DMA (anhydrous), 1 week Unknown morphology; B/E Form A - DMA (anhydrous), 3 weeks Unknown morphology; B/E Form A 27 DMF/ACN (65/35), 1 week Unknown morphology; B/E Form A - DMF/ACN (65/35), 3 weeks Unknown morphology; B/E Form A 10 DMF/1RA (60/40), 1 week Unknown morphology; B/E Form A - DMF/1RA (60/40), 3 weeks Unknown morphology; B/E Form A 13 DMF/M1VK (85/15), 1 week Unknown morphology; B/E Form A - DMF/M1VK (85/15), 3 weeks Unknown morphology; B/E Form A 19 DMSO/MTBE (anhydrous) (30/70), 1 day (s) Unknown morphology; B/E Form A - MEK/DMFA (20/80), 1 week Unknown morphology; B/E Form A - MEK/DMFA (20/80), 3 weeks Unknown morphology; B/E Form A 17 MeOH (anhydrous), 2-8°C (d), 1 week Unknown morphology, small particles; B/E Form A - MeOH (anhydrous), 2-8°C (d), 3 weeks Unknown morphology + some needle-like morphology; B/E Form A 13 MeOH/acetone (without aqueous) (50/50), 1 week Unknown morphology, small particles; B/E Form A - MeOH/acetone (anhydrous) (50/50), 3 weeks Unknown morphology, extremely small particles; B/E Form A 7 MeOH/SHC13 (anhydrous) (40/60), 1 week Unknown morphology; B/E Form A - MeOH/SHC13 (anhydrous) (40/60), 3 weeks Unknown morphology + some needle-like morphology; B/E Form A 22 MeOH/EAAc (anhydrous) (70/30), 1 week Unknown morphology, small particles; B/E Form A - MeOH/EtOAc (anhydrous) (70/30), 3 weeks Unknown morphology; B/E Form A 6

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MeOH/MTBE (anhydrous) (80/20), 1 week Unknown morphology, small particles; B/E Form A - MeOH/MTBE (anhydrous) (80/20), 3 weeks Unknown morphology + some needle-like morphology; B/E Form A 12 NMP (anhydrous), 1 week Unknown morphology; B/E Form A - NMP (anhydrous), 3 weeks Unknown morphology, very small particles; B/E Form A 50 MMP/acetone(anhydrous) (85/15), 1 week Unknown morphology, very small particles; B/E Form A - MMP/acetone(anhydrous) (85/15) 3 weeks Unknown morphology; B/E Form A 36 NMP/EtOAc (anhydrous) (80/20), 1 week Unknown morphology + small needles; B/E Form A - NMP/EtOAc (anhydrous) (80/20), 3 weeks Unknown morphology; B/E Form A 25 PG, 1 week Unknown morphology; B/E Form A - PG, 3 weeks Unknown morphology, extremely small particles; B/E Form A 8 TFE (anhydrous), 3 weeks Unknown morphology; B/E Form A - TFE/MEK (anhydrous) (85/15), 1 week Unknown morphology; B/E Form A - TFE/MEK (anhydrous) (85/15), 3 weeks Unknown morphology, extremely small particles; B/E Form A H2O, 1 week Unknown morphology; B/E Form A - N ₂ O, 3 weeks Very small needles; B/E Form A 14 Acetone/H ₂ O (50/50), 1 week Unknown morphology, very small particles; B/E Form A - Acetone/H ₂ O (50/50), 3 weeks Unknown morphology, extremely small particles; B/E Form A 43

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Dioxane/N ₂ O (70/30), 1 week Unknown morphology, small particles; B/E Form A - Dioxane/N ₂ O (70/30), 3 weeks Unknown morphology + some number of needles; B/E Form A 24 1RA/N ₂ O (60/40), 1 week Unknown morphology, very small particles; B/E Form A - 1RA/N ₂ O (60/40), 3 weeks Unknown morphology, extremely small particles; B/E Form A 26 EtOH/H ₂ O (60/40), 1 week Unknown morphology; B/E Form A - EYUN/N ₂ O (60/40), 3 weeks Extremely small needles; B/E Form A 36 EtOH/H ₂ O (60/40), 2-8°C (d), 1 week Unknown morphology, small particles; B/E Form A - EtOH/H ₂ O (60/40), 2-8°C (s), 3 weeks Unknown morphology, extremely small particles; B/E Form A 33 MeOH/H ₂ O (20/80), 1 week Unknown morphology, small particles; B/E Form A - MeOH/H ₂ O (20/80), 3 weeks Extremely small needles; B/E Form A 17 THF/N ₂ O (85/15), 1 week Unknown morphology; B/E Form A - THF/N ₂ O (85/15), 3 weeks Unknown morphology, extremely small particles; B/E Form A 25

(a) Experiments are carried out for ∼1 week and ∼3 weeks, both with solvent changes after suspension for ∼1 day. Solvent ratios (v/v) and experimental times are approximate. Experiments are performed under ambient conditions unless otherwise stated.

(b) Solubility determined gravimetrically.

(c) After the initial solvent change, the amount of solids is insufficient for further use as a suspension.

(d) Conducted in a cold room.

(e) Samples without confirmation of cGMP compliance.

Example 3: polymorph screening.

Unless otherwise stated, dihydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene2-yl)amino)-N(1-(2-methyl-1-( neopentylamino)propan-2-yl)-N-imidazol-4-yl)pentanamide is used as the starting material. The materials obtained in the study are used for selected experiments.

The starting materials are subjected to crystallization by the methods presented below. Solids are typically isolated by vacuum filtration, observed under polarized light, and analyzed by XRPD.

Method a: Grinding experiments.

The solids are mixed with small amounts of solvent and transferred to an agate container for grinding. Add the agate ball and connect the container to the Retsch mill. The sample is ground for one twenty-minute cycle at 30 Hz or transferred and the cycle is repeated for an additional 20 minutes.

Method b: suspension experiments.

The solids are suspended in the specified solvents. After this, the suspensions are mixed

- 43 046472 at ambient temperature or at set temperature. After a certain time, the solids are released.

Method c: solvent/antisolvent precipitation.

Starting solutions are prepared at ambient or elevated temperature and filtered using 0.2 µm nylon filters. They are then mixed with suitable anti-solvents at elevated temperatures. If precipitation of solid particles is not observed, the solutions are cooled to ambient or below room temperature or other crystallization methods are used.

Method d: Crash deposition.

Solutions of starting material are prepared at elevated temperature in specific solvents and hot filtered through 0.2 μm nylon filters into suitable antisolvents precooled in a dry ice/acetone or water/ice bath. If solid particles precipitate, they are immediately separated by vacuum filtration in a cold state. If the solution remains clear, store the sample below room temperature or use additional crystallization methods.

Method e: cooling experiments.

Solutions of the starting material are prepared in the indicated solvents at elevated temperatures using a heating plate. Solutions are subjected to hot filtration through a nylon filter with a pore size of 0.2 μm into vials for warm administration. The vials are either quickly transferred to a bath at a temperature below ambient temperature (usually dry ice/acetone) for crash cooling (CC), removed from a warm location for rapid cooling (FC), or the heating is turned off to allow slow cooling ( slow cooling - SC). If precipitation of solid particles occurs, they are separated from the cooled solution by vacuum filtration. If the solution remains clear, store the sample below ambient temperature or use additional crystallization methods.

Method f: evaporation experiments.

The starting material solutions are partially evaporated or evaporated to dryness at ambient or elevated temperature from open fast evaporation (FE) vials or from pinhole-coated aluminum foil vials for slow evaporation (SE). Before evaporation, solutions are filtered at ambient or elevated temperature using nylon filters with a pore size of 0.2 μm.

Method g: liquid-vapor diffusion experiments.

Starting material solutions are prepared at ambient temperature and filtered through 0.2 μm nylon filters into receiver vials. The opened vials are then placed into secondary containers with appropriate antisolvents. The containers are hermetically sealed and left undisturbed under ambient conditions.

Method h: steam stress experiments.

Solids from the starting material are transferred to uncapped vials and placed in secondary containers with suitable antisolvents. Secondary containers are sealed and left undisturbed at ambient or below-ambient temperatures.

Method i: Low relative humidity stress experiments.

The solid particles of the starting material are transferred to a vial, which is placed open in an RH container containing P2O5. The container is stored at ambient temperature for a certain period of time.

Method j: drying experiments.

The solid particles of the starting material are dried at ambient temperature or under reduced pressure at a specified temperature for a specified period of time.

In table Table 3 presents the results of screening polymorphs of the hydrobromide salt (S)-2-(((S)-6,8difluoro-1,2,3,4-tetragcdronaphthalene-2-yl)amino)-H-(1-(2-methyl- 1-(neopentylamino)propan-2-yl)-shimidazol-4-yl)pentanamide.

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Table 3

Solvent system Condition(s) Observations XRPD results ACN Suspension, 45°C, 2 days Unknown morphology; B/E Form A DCE Suspension, 45°C, 2 days Unknown morphology; B/E Form A DMA/DMSO (89/11) Try FC from 44°C to RT (clear). Transfer to the freezer for 13 days. Ultrasonication, FE followed by SE and then FE at RT (small needles present in solution). Transfer back to freezer, 13 days Insufficient particulate matter - DMF Try FC from 44°C to RT (clear). Transfer to the freezer for 13 days. Ultrasonication, FE followed by SE and then FE at RT (solids). Transfer back to freezer, 13 days. Unknown morphology; B/E Form A DMF/M1VK (80/20) Try SC, 45°C to RT for 2 days. Transfer to the freezer for 8 days. Ultrasonication, FE followed by SE and then FE at RT (small needles present in solution). Transfer back to freezer, 13 days. Insufficient particulate matter - DMSO/MTBE (30/70) Uterine fluid; F.E. Unknown morphology; B/E Form A EYAs Suspension, 45°C, 2 days Unknown morphology; B/E Form A H ₂ O Suspension, RT, 4 days Unknown morphology; B/E Form A HFIPA S.E. Unknown morphology; B/E Form F S.E. Unknown morphology + small needles; B/E Shape J MeOH (anhydrous) 2-8°C (b) Uterine fluid; F.E. B/E particles in a transparent matrix Form B, unordered

- 45 046472

MeOH/acetone (anhydrous) (50/50) Uterine fluid; F.E. Opaque particles; not B/E Form C MeOH/acetone (50/50) FE, 40°С Unknown morphology + small needles; B/E Form B, disordered FE, RT Unknown morphology + semi-transparent particles; B/E Form B, disordered MeOH/ACN S/AS try, adding AS at 45°C (clear); volume reduction with FE at 45°C (gel-like solids). Add AS at 45°C, transfer to freezer, 1 month. Unknown morphology; B/E Form A, disordered MeOH/SHC1 ₃ (anhydrous) (40/60) Uterine fluid; F.E. Unknown morphology; B/E Disordered, with Form A peaks MeOH/EtOAc (anhydrous) (70/30) Uterine fluid; F.E. Glass - MeOH/MTBE Try CP 45°C/below RT, ice bath (viscous solids). Ice bath, 2 hours, then at RT 20 days. Unknown morphology + small needles; B/E Form A - Viscous solids from 6094-34-04. Addition of Heptane to Viscous Solids, FE at RT Unknown morphology+glass ide particles; B/E Form B, disordered NMP/EtOAc (70/30) Try SC, 45°C to RT for 2 days. Transfer to the freezer for 8 days. Ultrasonication followed by FE at RT. No particulate matter - TFE/MEK (anhydrous) (85/15) Uterine fluid; F.E. Unknown morphology+glass; B/E Form A TFE/MEK (anhydrous) Try CP 45°C/below RT (ice bath). Transfer to the freezer for 7 days. Releases hard white cooled particles Unknown morphology; B/E Form A

- 46 046472

Acetone/H ₂ O (50/50) Uterine fluid; F.E. Glass+some B/E particles Form B, disordered DMSO/H ₂ O (4/96) SS attempt from 44°C to below RT (ice/H ₂ O bath, clear). Store in the refrigerator for 13 days (clear). Ultrasonication FE at RT (some particulate matter). Transfer back to the refrigerator, -5 months Insufficient particulate matter - Dioxane/H ₂ O (70/30) AIatomic liquid; F.E. Unknown morphology + needles; B/E Form A, possibly with x-ray amorphous contents Dioxane/H ₂ O (50/50) FE, 45°С Unknown morphology + small dendritic spines; B/E Form B, disordered Lyophilization, -35°C - X-ray amorphous Lyophilization, -50°C - X-ray amorphous 1RA/N ₂ O (60/40) AIatomic liquid; F.E. Rosettes in a glassy matrix of unknown morphology; B/E Form A, possibly with X-ray amorphous material 1RA/N ₂ O (50/50) FE, 45°С Unknown morphology; B/E Form B, disordered EtOH/ _H2O (60/40) Uterine fluid; F.E. Needles+unknown morphology; B/E Disordered, with Form A peaks EtOH/ _H2O (60/40) FE, 45°С Unknown morphology; B/E Shape D+peaks EtOH/H ₂ O (60/40) 2-8°C (b) Uterine fluid; F.E. Unknown morphology + needles; B/E Form B, disordered MeOH/H ₂ O (20/80) Uterine fluid; F.E. Unknown morphology+glass; B/E Form B, disordered THF/N ₂ O (85/15) Uterine fluid; F.E. Unknown morphology; some B/E Form B, disordered

(a) Solvent ratios (v/v), temperatures, and experimental times are approximate. Refrigerator temperature and low room temperature: 2-8°C; Freezer temperature: -10 to -25°C.

(b) Mother liquor is obtained from the suspension at 2-8°C. Evaporation is carried out at ambient temperature.

(c) Samples without confirmation of cGMP compliance.

In table Table 4 presents the results of screening polymorphs of the dihydrobromide salt (S)-2-(((S)-6,8difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-^( 1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1Nimidazol-4-yl)pentanamide, based on X-ray amorphous material.

- 47 046472

Table 4

Solvent system Conditions (b) Observations XRPD results SNS13/heptane 43/57 (anhydrous) EUN MEK/heptane 62/38 (anhydrous) Toluene dhm MeOH/acetone (anhydrous) Dioxane (anhydrous) IPOAc DCE Stirring, SHC13, RT, 3 days (viscous solids). Add heptane at RT (small, finely divided solids); suspension, 1 day. Suspension, RT, 3 days Mixing, MEK, RT, 3 days (viscous solids). Add heptane at RT (small, fine solids + some viscous particles); suspension, 1 day. Steam stress, RT, 6 days Steam stress, freezer, 6 days LVD, RT Grinding; 1 cycle, 30 Hz, 20 minutes Grinding; 1 cycle, 30 Hz, 20 minutes FE, 30°C, then cool to RT and transfer to freezer Unknown morphology, extremely small particles; B/E Unknown morphology, very small particles; B/E Unknown morphology+certain amount of viscous particles; B/E Opaque particles + a few particles with B/E Unknown morphology; B/E Solvent present. Unknown morphology + needles; B/E Unknown morphology + some semi-transparent particles; B/E Unknown morphology + small needles; B/E Unknown morphology; no suitable crystals for structure determination Form E, crystalline with disorder Form A Form G, disordered X-ray amorphous Form H, disordered, possible presence Forms A Form A Form B, disordered, possible presence Shape G Form A, disordered Disordered Aceto n/MeOH/MSN 14/17/69 S/AS, add AS at 30°C. Store at 30°C for 3-4 hours, then cool to RT Very fine needles; B/E Form A SNS1 ₃ Saturated solution, stored at RT for 1 day. Transfer to freezer, ~5 months Insufficient particulate matter -

(a) All samples received from LIMS 386797 are not cGMP certified.

(b) Solvent ratio (v/v), temperature and duration of experiments are approximate. Refrigerator temperature and low room temperature: 2-8°C; Freezer temperature: -10 to -25°C.

Example 4: obtaining X-ray amorphous material.

A solution of the starting material is prepared in a mixture of dioxane/water (50/50) at ambient temperature and filtered into a round bottom flask.

The flask is cooled in a dry ice/acetone bath to freeze the solution. Once frozen, it is placed in a freeze dryer at approximately -50°C and kept under these conditions for two days.

Example 5: Receiving selected materials.

In table 5 presents the conditions for obtaining the selected materials.

- 48 046472

Table 5

Target material Solvent system Condition(s) Observations XRPD results Form B MeOH FE, RT Unknown morphology; B/E Form B, disordered F.E., R.T. Store solids in the freezer Unknown morphology; B/E Form B, disordered SE, RT. Solids are stored in the freezer - Analyze wet. Form D From 6094-34-02. Steam stress, RT. Solids are stored in the freezer Unknown morphology; B/E Form A Prepare a saturated solution at 45°C, then SC to RT. Transfer to the freezer No particulate matter - MeOH /acetone 50/50 FE, 45°C. Solids are stored in the freezer. Unknown morphology, B/E particles encapsulated in solvent Form D MeOH /acetone A saturated solution is obtained in MeOH at 45°C; acetone is added at elevated temperatures. SC to RT (turbidity). Small needles; B/E Form A MeOH /HFIPA 60/40 SE, RT. Solids are stored in the freezer - Analyze in a wet state. Shape M Acetone/IEO 50/50 SE then FE RT. Steklov idnaya - SC, 50°C to RT Transfer to freezer. No particulate matter -

- 49 046472

MeOH /MTBE LVD, RT. The solids are air dried Unknown morphology + glassy; B/E Form B, disordered Shape C MeOH/a cetone (anhydrous) 50/50 F.E. 45°C Unknown morphology; B/E + a certain amount of unidentified particles Form C MeOH/a cetone (anhydrous) 50/50 FE, 45°C. Solids are stored in the freezer - Form C+small peaks - From 6141-67- 02. VO, RT, 1 day. - Form C+small peaks MeOH/a cetone (anhydrous) 50/50 Suspension, RT, 1 day; solid particles are centrifuged, FE mother liquor. Solids are stored in the freezer Unknown morphology, small particles; some amount of B/E Form C+small peaks Form D EtOH/ _H2O 60/40 FE, 45°С Unknown morphology + small needles; B/E Form D+peaks, may also contain Form A

- 50 046472

FE, 45°C. Store in the freezer - Analyze wet. Disordered, contains Form D SC, 45°C to RT, then FE. RT. Glass - Suspension, RT Unknown morphology, small particles; B/E Form A MeOH/H ₂ O 35/65 Suspension, RT Unknown morphology; B/E Form A Form E (b) SNS1 ₃ /g eptane (anhydrous) 43/57 Suspension, RT, 7 days; add heptane, transfer to the freezer, 10 days. Add heptane, then SE at ambient temperature. Solids are stored in the freezer Unknown morphology+glass-like structure; some B/E X-ray amorphous SNS1 ₃ /g eptane (anhydrous) (33/67) Suspension, SNS1 ₃ , RT, 5 days (viscous). Heptane is added. Suspension, RT, 7 days. Unknown morphology; B/E Form E, improved crystallinity

- 51 046472

Shape H (b) dhm Suspension, RT, 7 days; add DCM, transfer to freezer, 10 days, then SE at ambient temperature. Solid product is stored in the freezer Unknown morphology; B/E Form K, disordered Steam stress, freezer, 13 days. Unknown morphology; B/E Similar H shape, disordered Form G (b) MEK/heptan (anhydrous) 58/42 SC from 45°C; transfer to freezer, 14 days, then SE at ambient temperature Viscous - MEK/GE ptan (anhydrous) (43/57) Suspension, MEK, RT, 5 days (viscous). Heptane is added. Suspension, RT, 7 days Unknown morphology+and eyes; B/E Form A Shape F (b) HFIPA S.E. Unknown morphology; B/E Similar Form F

- 52 046472

Shape J HFIPA SE. Solids are stored in the freezer Unknown morphology; B/E Shape L Steam stress Solids dissolved - From 6141-5302. SE, RT. Solids are stored in the freezer Unknown morphology; B/E Form F+peaks; weakly crystalline Grinding; 2 cycles, 30 Hz, 20 minutes Unknown morphology, small particles; B/E Form A+peaks, reduced crystallinity

(a) Solvent ratio (v/v), temperature and duration of experiments are approximate. Refrigerator temperature and low room temperature: 2-8°C; Freezer temperature: -10 to -25°C.

(b) X-ray amorphous material is used as a starting material. The material is not certified to comply with cGMP.

(c) Samples are not cGMP certified.

In table 6 shows the drying conditions for selected materials.

Table 6

Raw material Condition(s) XRPD results Similar to Form F VO, 45°C, 1 day Complies with Form F Form F VO, 77°C, 1 day Complies with Form F; weakly crystalline Form D VO, 75°C, 1 day Complies with Form D Dried on Р2О5, RT, 17 days RH upon receipt: 3% RH after storage: 43% Corresponds to Shape D, selected peaks with weak shifts Shape M Air drying, 1 day Similar to Form F Form E 120°C, 8 hours Disordered, similar to Form B

(a) Temperature, RH and duration of experiments are approximate.

Example 6: Interconversion Experiments/

The starting materials, with the exception of Form A, are dried in a vacuum oven at 45°C for approximately 1 day. Prepare saturated solutions of Form A in specific solvent systems and seed crystals of the dried materials and Form A. Mix samples in sealed vials at ambient temperature for approximately one week.

In table Figure 7 presents the results of interconversion experiments.

Table 7

Source material(s) Conditions (b) XRPD results Germs Form A, Form D, Form B, Form E, Form F, Form G, Form J MeOH suspension, RT, 1 week Form A MEK/DMFA 50/50, suspension, RT, 1 week Form A Germs Form A, Form D, Form B. Form C, Form E, Form F, Form G, Form J EtOH/FEO 60/40 suspension, RT, 1 week Form A

(a) All materials except Form A were vacuum dried at 45°C for ~1 day before experiments.

- 53 046472 (b) Experimental temperatures and durations are approximate.

Example 7: single crystal growth experiments.

Samples of Form A are processed using the crystallization methods described below. To induce crystallization, Form A seed crystals were added in separate experiments.

Method a: Evaporation/volume reduction experiments.

Starting material solutions are partially evaporated or evaporated to dryness at ambient or elevated temperature from open fast evaporation (FE) vials or from loosely capped or pinhole-lined aluminum foil slow evaporation (SE) vials. Before evaporation, solutions are filtered at ambient or elevated temperature using a 0.2 µm nylon filter.

Method b: Liquid-vapor and liquid-liquid diffusion experiments.

Solutions of the starting material are prepared in specific solvents at ambient temperature and filtered conventionally through a 0.2 μm nylon filter. For liquid vapor diffusion (LVD), vials of filtered solutions are placed in secondary containers with suitable antisolvents and left alone at or below ambient temperature. For liquid-liquid diffusion (LLD), solutions of the test material are carefully brought into contact with specific solvents and left alone at or below ambient temperature.

Method c: cooling experiments.

Starting material solutions are prepared at elevated temperature using a hotplate for heating. The solutions are then hot filtered using a 0.2 µm nylon filter, left on the heating source and slowly cooled to the set temperature (SC). After a certain period of time, the solutions are further cooled to a temperature below ambient temperature.

In table Figure 8 shows the results of growing single crystals of form A.

Table 8

Solvent system Condition(s) Observations XRPD results DMF/DEE LLD; Store in refrigerator, 6 weeks No suitable crystals - DMF/EAAc LVD There are no suitable crystals; unknown morphology; B/E Form A DMF/1RA LVD, after 15 days transfer to freezer, ~5 months No particulate matter - DMF/MEK LVD, 5 days There are no suitable crystals; unknown morphology + small needles; B/E Form A DMF/THF LVD, after 5 days, transfer to freezer, -5 months No particulate matter - MeOH/acetone (64/36) SE, 45°C, using seed There are no suitable crystals; unknown morphology, B/E - MeOH/acetone (50/50) S.E. There are no suitable crystals; small needle-like particles; B/E Form B, disordered MeOH/SHC1 ₃ (50/50) S.E. Unknown morphology; B/E Form B, disordered MeOH/cyclohexanone LLD No particulate matter -

- 54 046472

MeOH/DEE LLD; Store in refrigerator, 6 weeks - - McOH/heptane LLD - - MeOH/heptane LLD, below room temperature (freezer) No particulate matter - MeOH/MTBE (80/20) S.E. There are no suitable crystals; unknown morphology; B/E Form B, disordered NMP Try SC, 45°C to 30°C; seed Form A; 30°C, And days. Transfer to the freezer for 16 days. No particulate matter - FE from elevated temperature (40°C to 30°C), then cooled to RT and transferred to freezer. Needles + small particles, unknown morphology; B/E Form N, may contain Form C PG SC, 45°C to 30°C; seed Form A; 30°C, 11 days, then transferred to the freezer, 16 days. No particulate matter -

(a) Solvent ratio (v/v), temperature and duration of experiments are approximate. Refrigerator temperature and low room temperature: 2-8°C; Freezer temperature: -10 to -25°C.

(b) Samples without confirmation of cGMP compliance.

Example 8: X-ray Powder Diffraction (XRPD).

Method a: transmission geometry.

Powder X-ray diffraction (XRD) patterns are obtained on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation obtained using an Optix long-focus fine-focusing source. A multilayer mirror with an elliptical graduation is used to focus CuKa X-rays through the sample onto the detector. Prior to analysis, a silicon sample (NIST SRM 640d or 640e) is examined to verify the position of the Si 111 peak according to NIST certification. The sample preparation is clamped between 3 μm thick films and analyzed for transmission geometry. To minimize the background created by air, a beam absorber, a short anti-scatter extension and an anti-scatter knife collimator are used. To minimize broadening due to axial divergence, Soller slits are used for the incident and diffracted beams. Diffraction patterns are obtained using a scanning position-sensitive detector (X'Celerator), located at a distance of 240 mm from the sample, and Data Collector software v.2.2b.

Method b. reflection geometry.

XRDG is obtained on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of CuKa radiation obtained using a long-focus fine-focusing source and a nickel filter. A diffractometer with a configuration obtained using symmetrical Bragg-Brentano geometry is used. Prior to analysis, a silicon sample (NIST SRM 640d or 640e) is examined to verify the position of the Si 111 peak according to NIST certification. The sample preparation is obtained as a thin circular sheet centered on a silicon substrate with zero background. To minimize the background created by air, antiscatter slits (SS) are used. To minimize broadening due to axial divergence, anti-scattering Soller slits (SS) are used for the incident and diffracted beams. Diffraction patterns are recorded using a scanning position-sensitive detector (X'Celerator) located at a distance of 240 mm from the sample and Data Collector software v. 2.2b.

Example 9: Thermogravimetric Analysis (TGA).

TGA analysis is carried out using a TA Instruments 2050 apparatus or a Discovery thermogravimetric analyzer. Temperature calibration is performed using nickel and Alumel™. Each sample is placed in an aluminum or platinum cup and placed in a TG oven. The furnace is heated in a nitrogen stream. The method code on the thermogram briefly indicates the initial and final temperatures and heating rate; for example, 25-350-10 means 25°C to 350°C at 10°C/min.

Example 10: Differential Scanning Calorimetry DSC.

-

Claims (28)

DSC analysis is performed using a TA Instruments Q2000 differential scanning calorimeter. Temperature calibration is performed using NIST calibrated indium metal. The sample is placed in an aluminum DSC cup (T0C), capped, and the mass is determined accurately. A weighed aluminum cup is placed on the control side of the cell as a control sample. The method code on the thermogram abbreviates the initial and final temperatures and heating rates; for example, for example -30-250-10 means -30°C to 250°C at 10°C/min. Examples 11: Thermogravimetric analysis with infrared spectroscopy (TG-IR). Thermogravimetric analysis with infrared spectroscopy (TG-IR) is performed on a TA Instruments model 2050 thermogravimetric (TG) analyzer coupled to a Magna-IR 560® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with a mid/far IR sensor -band (Ever-Glo), a beam splitter based on potassium bromide (KBr) and a mercury cadmium telluride detector (MCT-A). FT-IR wavelength verification is performed using polystyrene, and TG calibration standards are nickel and Alumel™. The sample is placed in a platinum sample cup and placed in a TG oven. The TG device is turned on first, immediately after that the FTIR spectrometer. The TG instrument operates in a helium flow at 90 and 10 cm ³ /min for purge and balance, respectively. The furnace is heated in a helium atmosphere at a rate of 20°C/min to a final temperature of 250°C. IR spectra were recorded approximately every 32 s for approximately 13 min. Each IR spectrum is a superposition of 16 scans with a spectral resolution of 4 cm ^-1 . Volatiles are identified using the High Resolution Nicolet Vapor Phase spectral library database. Searches of this database are considered not to be cGMP compliant. Example 12: Polarized Light Microscopy (PLM). Optical microscopy studies are performed using a Leica DM LP microscope equipped with a SPOT Insight™ color digital camera. Each sample is placed on a glass slide, covered with a coverslip, and a drop of mineral oil is added to cover the sample by capillarity. Each sample is examined using a 0.8-10.0x objective with crossed polarizers and a first order red compensator. Example 14: Computational Methods (Indexing). Successful PRDG indexing indicates that the sample consists primarily of a single crystalline phase. The correspondence of the positions of the resolved peaks with the positions of the observed peaks indicates a reliable determination of the unit cell. Indexing is carried out using X'Pert High Score Plus 2.2a (2.2.1) and TRIADS™. No molecular packaging is attempted to confirm pre-indexing in this work. CLAIM 1. Crystalline form of hydrobromide salt ^)-2-((^)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)amino)-U-(1-(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4yl)pentanamide of formula (I) selected from crystalline Form A, wherein Form A is characterized by a powder X-ray diffraction pattern (XRD) containing peaks at 8.8 ± 0.2, 9.8±0.2, and 23.3±0.2° two theta. 2. The crystalline form according to claim 1, wherein crystalline form A is anhydrous. 3. The crystalline form of claim 1 or 2, wherein the melting point of crystalline form A is about 254°C. 4. Crystalline form according to any one of claims 1 to 3, where form A is characterized by a PRDH containing 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° two theta. 5. Crystalline form according to any one of claims 1 to 4, where form A is characterized by a PRDH containing 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° two theta. 6. A crystalline form according to any one of claims 1 to 5, wherein Form A is characterized by a PDH essentially as shown in FIG. 1. 7. A crystalline form according to any one of claims 1 to 6, wherein Form A is characterized by a TGA profile substantially as shown in FIG. 2. 8. A crystalline form according to any one of claims 1 to 7, wherein Form A is characterized by a DSC profile substantially as shown in FIG. 3. - 56 046472 9. The crystalline form according to any one of claims 1 to 8, wherein form A has a unit cell that is indexed as primitive monoclinic. 10. The crystalline form of any one of claims 1 to 9, wherein Form A has a unit cell wherein the a value is about 10.035 A, the b value is about 7.532 A, and the c value is about 20.092 A. 11. The crystalline form of any one of claims 1 to 10, wherein Form A has a unit cell with a volume of approximately 1518.1 LA ³ . 12. A crystalline form according to any one of claims 1 to 11, wherein Form A has a particle size D[V,0.50] in the range of from about 2 μm to about 30 μm. 13. A pharmaceutical composition containing a crystalline form according to any one of claims 1 to 12 and a pharmaceutically acceptable carrier. 14. The pharmaceutical composition according to claim 13, where the pharmaceutical composition is a tablet. 15. The pharmaceutical composition according to claim 13 or 14, wherein said composition contains from about 25 mg to about 400 mg of the hydrobromide salt of (8)-2-(((8)-6,8-difluoro-1,2,3,4 -tetrahydronaphthalene-2yl)amino)-N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 16. The pharmaceutical composition according to any one of claims 13 to 15, wherein said composition contains approximately 50 mg of hydrobromide salt (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)amino)-H(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 17. The pharmaceutical composition according to any one of claims 13 to 15, wherein said composition contains approximately 100 mg of hydrobromide salt (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)amino)N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 18. The pharmaceutical composition according to any one of claims 13 to 15, wherein said composition contains approximately 150 mg of hydrobromide salt (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)amino)N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 19. A method of treating tumors or cancer, comprising administering to a subject in need of such treatment a pharmaceutical composition according to any one of claims 13 to 18. 20. The method of claim 19, wherein the tumors are desmoid tumors. 21. The method of claim 19, wherein the cancer is selected from the group consisting of multiple myeloma, cancer with a mutation in the Notch signaling pathway gene, adenoid cystic carcinoma and T-cell acute lymphoblastic leukemia. 22. The method of any one of claims 19 to 21, wherein the subject is administered daily from about 50 mg to about 500 mg of the hydrobromide salt of (8)-2-(((8)-6,8-difluoro-1,2,3 ,4-tetrahydronaphthalene-2-yl)amino)N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 23. The method according to any one of claims 19 to 22, wherein the subject is administered daily from about 100 mg to about 400 mg of the hydrobromide salt of (8)-2-(((8)-6,8-difluoro-1,2,3 ,4-tetrahydronaphthalene-2-yl)amino)N-(1 -(2-methyl-1 -(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 24. The method according to any one of claims 19 to 23, wherein the subject is administered daily about 300 mg of (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-hydrobromide salt 2-yl)amino)-H-(1-(2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 25. The method according to any one of claims 19 to 23, wherein the subject is administered daily about 200 mg of (8)-2-(((8)-6,8-difluoro-1,2,3,4-tetrahydronaphthalene-hydrobromide salt 2-yl)amino)-H-(1-(2-methyl-1(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide. 26. The method according to any one of claims 19 to 25, wherein the total daily dose is provided in two separate doses. 27. The method of claim 19 or 26, wherein the total daily dose is provided in two separate doses of about 150 mg. 28. The method of claim 19 or 26, wherein the total daily dose is provided in two separate doses of about 100 mg. -