WO2021168341A1

WO2021168341A1 - Solid forms of 1-(5-(3-(7-(3-fluorophenyl)-3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-n,n-dimethylmethanamine

Info

Publication number: WO2021168341A1
Application number: PCT/US2021/018896
Authority: WO
Inventors: Sunil Kumar Kc
Original assignee: Samumed LLC
Current assignee: Biosplice Therapeutics Inc
Priority date: 2020-02-21
Filing date: 2021-02-19
Publication date: 2021-08-26
Anticipated expiration: 2022-08-21

Abstract

The present application relates to two crystalline polymorphic forms, crystalline methanol, ethanol and tetrahydrofuran solvates and a crystalline hydrate of the compound l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3- yl)-N,N-dimethylmethanamine (Ipivivint), to a pharmaceutical composition comprising them and their medical use for the treatment of disorders characterized by the activation of of the Wnt signaling pathway selected from cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis. Also claimed is a process for the preparation of compounds of Formula (I) by reacting a starting material of Formula (A1) with a compound of Formula (A2).

Description

SOLID FORMS OF 1-(5-(3-(7-(3-FLUOROPHENYL)-3H-IMIDAZO[4,5-C]PYRlDlN-2- YL)-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)PYRIDIN-3-YL)-N,N- DIMETHYLMETHANAMINE

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of United States Provisional Application 62/979,462, filed on February 21, 2020, which is incorporated herein by reference in its entirety.

BACKGROUND

Technical Field

[001] This disclosure features solid forms of 1-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine as well as methods of making and using the same.

Background

[002] The Wnt growth factor family includes more than 10 genes identified in the mouse and at least 19 genes identified in the human. Members of the Wnt family of signaling molecules mediate many short-and long-range patterning processes during invertebrate and vertebrate development. The Wnt signaling pathway is known for its role in the inductive interactions that regulate growth and differentiation, and it also plays roles in the homeostatic maintenance of post-embryonic tissue integrity. Wnt stabilizes cytoplasmic β-catenin, which stimulates the expression of genes including c-myc, c jun, fta-1, and cyclin Dl. In addition, misregulation of Wnt signaling can cause developmental defects and is implicated in the genesis of several human cancers. The Wnt pathway has also been implicated in the maintenance of stem or progenitor cells in a growing list of adult tissues including skin, blood, gut, prostate, muscle, and the nervous system.

[003] US 2013/0296302 and WO 2013/166396 disclose compounds that are active on Wnt proteins. One such compound disclosed in US 2013/0296302 and WO 2013/166396 is l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine, which has the structure shown below (referred to as compound 18 in US 2013/0296302 and WO 2013/166396):

SUMMARY

[004] This disclosure features solid forms of 1-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine as well as methods of making and using the same. In some embodiments, said solid forms exhibit enhanced stability, and as such, can have improved suitability for bulk handling and formulation.

[005] Other features and advantages of the compositions, methods and uses provided herein will be apparent from the following detailed description and figures, and from the claims.

[006] In one aspect, this invention features a crystalline polymorph of 1-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylm: ethanamine

wherein the polymorph is Form A and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 20 that occurs at about 6.4. For ease of exposition, the aforementioned polymorph is referred to herein as “Form A.”

[007] The X-ray powder diffraction pattern of Form A can also include one or more additional characteristic peaks. [008] In embodiments, the X-ray powder diffraction pattern of Form A can also include one or more of the following additional characteristic peaks, which can also be used to identify Form A (e.g., in a sample).

[009] For example, the X-ray powder diffraction pattern of Form A also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 24.7.

[010] As another example, the X-ray powder diffraction pattern of Form A also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 22.1.

[011] As another example, the X-ray powder diffraction pattern of Form A also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 2.2.

[012] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form A.

[013] In certain embodiments, Form A can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 6.4 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 2.2; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 22.1; or (iii) the characteristic peak expressed in degrees 2Θ that occurs at about 24.7.

[014] In other embodiments, Form A can be identified using the characteristic peaks expressed in degrees 2Θ that occur at about 6.4, about 22.1, and about 24.7.

[015] In other embodiments, Form A can be identified using the characteristic peaks expressed in degrees 2Θ that occur at about 2.2, about 6.4, about 22.1, and about 24.7.

[016] The X-ray powder diffraction pattern of Form A can also include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[017] For example, the X-ray powder diffraction pattern of Form A can also include from

1-13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) of the following additional characteristic peaks expressed in degrees 2Θ: about 2.4, about 2.7, about 11.7, about 13.0, about 16.0, about 18.7, about 20.1, about 20.8, about 21.9, about 23.2, about 28.3, about 29.0, and about 30.2.

[018] For example, the X-ray powder diffraction pattern of Form A also comprises from 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) of the following additional characteristic peaks expressed in degrees 2Θ: about 2.4, about 2.7, about 11.7, about 12.2, about 12.8, about 13.0, about 16.0, about 16.4, about 16.6, about 17.7, about 18.7, about 20.1, about 20.8, about 21.9, about 23.2, about 24.0, about 28.3, about 28.6, about 29.0, and about 30.2.

[019] As a further example, the X-ray powder diffraction pattern of Form A can be substantially the same as that shown in FIG. 4.

[020] Form A can also have one or more of the following characteristics.

[021] Form A can have a differential scanning calorimetry pattern comprising a melting onset of about 343°C.

[022] Form A can have a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 5.

[023] In some embodiments, Form A can be in substantially pure form.

[024] In another aspect, this invention features a crystalline methanol solvate of l-(5-(3-

(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3- yl)-N,N-dimethylmethanamine:

wherein the solvate is Form B and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.4. For ease of exposition, this solid form is referred to herein as “Form B.”

[025] The X-ray powder diffraction pattern of Form B can also include one or more additional characteristic peaks.

[026] In embodiments, the X-ray powder diffraction pattern of Form B can also include one or more of the following additional characteristic peaks, which can also be used to identify Form B (e.g., in a sample).

[027] For example, the X-ray powder diffraction pattern of Form B also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 17.6.

[028] As another example, the X-ray powder diffraction patter of Form B also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 25.6. [029] As another example, the X-ray powder diffraction pattern of Form B also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 25.8.

[030] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form B.

[031] In certain embodiments, Form B can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 6.4 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 17.6; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 25.6; or (iii) the characteristic peak expressed in degrees 2Θ that occurs at about 25.8.

[032] In other embodiments, Form B can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 6.4, about 17.6, and about 25.6.

[033] In other embodiments, Form B can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 6.4, about 17.6, about 25.6, and about 25.8.

[034] The X-ray powder diffraction pattern of Form B can also include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[035] For example, the X-ray powder diffraction pattern of Form B can also include from 1-13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) of the following additional characteristic peaks expressed in degrees 2Θ: about 7.8, about 14.3, about 14.8, about 15.6, about 18.2, about 19.0, about 19.2, about 19.8, about 20.8, about 22.1, about 22.7, about 23.7, and about 29.6.

[036] For example, the X-ray powder diffraction pattern of Form B also comprises from 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) of the following additional characteristic peaks expressed in degrees 2Θ: about 7.8, about 12.0, about 14.3, about 14.8, about 15.6, about 18.2, about 19.0, about 19.2, about 19.8, about 20.6, about 20.8, about 22.1, about 22.7, about 23.7, about 25.4, about 27.1, about 27.5, about 29.4, about 29.6, and about 29.9.

[037] As a further example, the X-ray powder diffraction pattern of Form B can be substantially the same as that shown in FIG. 27.

[038] Form B can also have one or more of the following characteristics.

[039] Form B can have a differential scanning calorimetry pattern comprising one or more melting onsets selected from the group consisting of: 130.5°C, 179.4°C, 194.4°C, 231.7°C, and 269.6°C. [040] Form B can have a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 7.

[041] Form B can have a thermogravimetric analysis pattern comprising a weight loss of about 7.0% at about 188°C.

[042] Form B can have a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 8.

[043] In some embodiments, Form B can be in substantially pure form.

[044] In another aspect, this invention features a crystalline ethanol solvate of l-(5-(3-(7- (3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine:

wherein the solvate is Form C and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.1. For ease of exposition, this solid form is referred to herein as “Form C.”

[045] The X-ray powder diffraction pattern of Form C can also include one or more additional characteristic peaks.

[046] In embodiments, the X-ray powder diffraction pattern of Form C can also include one or more of the following additional characteristic peaks, which can also be used to identify Form C (e.g., in a sample).

[047] For example, the X-ray powder diffraction pattern of Form C also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 15.5.

[048] As another example, the X-ray powder diffraction pattern of Form C also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 7.8.

[049] As another example, the X-ray powder diffraction pattern of Form C also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 16.9. [050] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form C.

[051] In certain embodiments, Form C can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 6.1 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 7.8; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 15.5; or (iii) the characteristic peak expressed in degrees 2Θ that occurs at about 16.9.

[052] In other embodiments, Form C can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 6.1, about 7.8, and about 15.5.

[053] In other embodiments, Form C can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 6.1, about 7.8, about 15.5, and about 16.9.

[054] The X-ray powder diffraction pattern of Form C can also include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[055] For example, the X-ray powder diffraction pattern of Form C can also include from 1-13 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) of the following additional characteristic peaks expressed in degrees 2Θ: about 2.5, about 9.4, about 12.3, about 14.2, about 14.7, about 18.4, about 20.0, about 21.1, about 22.3, about 22.7, about 25.2, about 25.9, and about 27.8.

[056] For example, the X-ray powder diffraction pattern of Form C also comprises from 1-20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) of the following additional characteristic peaks expressed in degrees 2Θ: about 2.5, about 9.4, about 12.3, about 14.2, about 14.7, about 18.4, about 19.0, about 20.0, about21.1, about 22.3, about 22.7, about 23.4, about 24.5, about 25.2, about 25.9, about 26.8, about 27.8, about 28.6, and about 31.1.

[057] As a further example, the X-ray powder diffraction pattern of Form C can be substantially the same as that shown in FIG. 28.

[058] Form C can also have one or more of the following characteristics.

[059] Form C can have a differential scanning calorimetry pattern comprising one or more melting onsets selected from the group consisting of: 129.5°C, 170.8°C, 194.3°C, 231.1°C, and 270.7°C. [060] Form C can have a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 10.

[061] Form C can have a thermogravimetric analysis pattern comprising a weight loss of about 8.6% at about 177°C.

[062] Form C can have a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 11.

[063] In some embodiments, Form C can be in substantially pure form.

[064] In another aspect, this invention features a crystalline hydrate of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine:

wherein the hydrate is Form D and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 3.6. For ease of exposition, this solid form is referred to herein as “Form D.”

[065] The X-ray powder diffraction pattern of Form D can also include one or more additional characteristic peaks.

[066] In embodiments, the X-ray powder diffraction pattern of Form D can also include one or more of the following additional characteristic peaks, which can also be used to identify Form D (e.g., in a sample).

[067] For example, the X-ray powder diffraction pattern of Form D also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 2.2.

[068] As another example, the X-ray powder diffraction pattern of Form D also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 5.6.

[069] As another example, the X-ray powder diffraction pattern of Form D also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 14.7. [070] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form D. [071] In certain embodiments, Form D can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 3.6 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 2.2; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 5.6; or (iii) the characteristic peak expressed in degrees 2Θ that occurs at about 14.7.

[072] In other embodiments, Form D can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 2.2, about 3.6, and about 5.6.

[073] In other embodiments, Form D can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 2.2, about 3.6, about 5.6, and about 14.7.

[074] The X-ray powder diffraction pattern of Form D can also include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[075] For example, the X-ray powder diffraction pattern of Form D can also include from 1-6 (e.g., 1, 2, 3, 4, 5, or 6) of the following additional characteristic peaks expressed in degrees 2Θ: about 7.3, about 10.2, about 16.8, about 19.8, about 21.7, about 24.2.

[076] For example, the X-ray powder diffraction pattern of Form D also comprises from 1-9 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) of the following additional characteristic peaks expressed in degrees 2Θ: about 7.3, about 10.2, about 11.0, about 16.8, about 17.3, about 19.8, about21.7, about 24.2, and about 27.3.

[077] As a further example, the X-ray powder diffraction pattern of Form D can be substantially the same as that shown in FIG. 29.

[078] Form D can also have one or more of the following characteristics.

[079] Form D can have a differential scanning calorimetry patter comprising a melting onset of about 125.2°C.

[080] Form D can have a differential scanning calorimetry patter that is substantially the same as that shown in FIG. 13. [081] Form D can have a thermogravimetric analysis pattern comprising a weight loss of about 3.9% at about 150°C.

[082] Form D can have a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 14.

[083] In some embodiments, Form D can be in substantially pure form.

[084] In another aspect, this invention features a crystalline tetrahydrofuran solvate of 1- (5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- y l)pyridin-3 -yl)-N,N-dimethylmethanamine :

wherein the solvate is Form E and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.5. For ease of exposition, this solid form is referred to herein as “Form E.”

[085] The X-ray powder diffraction pattern of Form E can also include one or more additional characteristic peaks.

[086] In embodiments, the X-ray powder diffraction pattern of Form E can also include one or more of the following additional characteristic peaks, which can also be used to identify Form E (e.g., in a sample).

[087] For example, the X-ray powder diffraction pattern of Form E also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 8.0.

[088] As another example, the X-ray powder diffraction pattern of Form E also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 3.3.

[089] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form E.

[090] In certain embodiments, Form E can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 3.3 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 6.5; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 8.0.

[091J In other embodiments, Form E can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 6.5 and about 8.0.

[092] In other embodiments, Form E can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 3.3, about 6.5, and about 8.0.

[093] The X-ray powder diffraction pattern of F orm E can al so include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[094] For example, the X-ray powder diffraction pattern of Form E can also include from 1-7 (e.g., 1, 2, 3, 4, 5, 6, or 7) of the following additional characteristic peaks expressed in degrees 2Θ: about 4.0, about 7.3, about 14.8, about 16.1, about 18.6, about 19.6, and about 20.1.

[095] For example, the X-ray powder diffraction pattern of Form E also comprises from 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following additional characteristic peaks expressed in degrees 2Θ: about 16.1, about 4.0, about 20.1, about 14.8, about 18.6, about 7.3, about 19.6, about 15.4, about 18.2, and about 25.6.

[096] As a further example, the X-ray powder diffraction pattern of Form B can be substantially the same as that shown in FIG. 30.

[097] Form E can also have one or more of the following characteristics.

[098] Form E can have a differential scanning calorimetry pattern comprising one or both melting onsets selected from the group consisting of: about 270.4°C and 344.6°C.

[099] Form E can have a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 16.

[0100] Form E can have a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 17.

[0101] In some embodiments, Form E can be in substantially pure form.

[0102] In another aspect, this invention features a crystalline polymorph of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine :

wherein the polymorph is Form F and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 8.0. For ease of exposition, the aforementioned polymorph is referred to herein as “Form F.”

[0103J The X-ray powder diffraction pattern of Form F can also include one or more additional characteristic peaks.

[0104] In embodiments, the X-ray powder diffraction pattern of Form F can also include one or more of the following additional characteristic peaks, which can also be used to identify Form F (e.g., in a sample).

[0105] For example, the X-ray powder diffraction pattern of Form F also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 2.3.

[0106] As another example, the X-ray powder diffraction pattern of Form F also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 7.2.

[0107] As another example, the X-ray powder diffraction pattern of Form F also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 16.1.

[0108] Any one of the aforementioned characteristic peaks alone, or in combination, can be used to identify Form F.

[0109] In certain embodiments, Form F can be identified using the characteristic peak expressed in degrees 2Θ that occurs at about 2.3 and one of the following: (i) the characteristic peak expressed in degrees 2Θ that occurs at about 7.2; or (ii) the characteristic peak expressed in degrees 2Θ that occurs at about 8.0; or (iii) the characteristic peak expressed in degrees 2Θ that occurs at about 16.1.

[0110] In other embodiments, Form F can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 2.3, about 7.2, and about 8.0.

[0111] In other embodiments, Form F can be identified using the characteristic peaks expressed in degrees 2Θ that occurs at about 2.3, about 7.2, about 8.0, and about 16.1. [0112] The X-ray powder diffraction pattern of Form F can also include one or more lower intensity characteristic peaks. The relative intensities of these additional peak(s) are, in general, lower than the relative intensities associated with the four characteristic peaks described above.

[0113] For example, the X-ray powder diffraction pattern of Form F can also include from 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) of the following additional characteristic peaks expressed in degrees 2Θ: about 3.7, about 3.9, about 14.8, about 15.3, about 18.1, about 18.8, about 19.4, about 20.0, about 25.1, about 28.5.

[0114] For example, the X-ray powder diffraction patter of Form F also comprises from 1-15 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) of the following additional characteristic peaks expressed in degrees 2Θ: about 3.3, about 3.7, about 3.9, about 14.8, about 15.3, about 18.1, about 18.8, about 19.4, about 20.0, about21.1, about 23.7, about 25.1, about 26.1, about 28.5, and about 29.9.

[0115] As a further example, the X-ray powder diffraction pattern of Form F can be substantially the same as that shown in FIG. 31.

[0116] Form F can also have one or more of the following characteristics.

[0117] Form F can have a differential scanning calorimetry pattern comprising one or more melting onsets selected from the group consisting of: 270.4°C and 344.6°C.

[0118] Form F can have a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 19.

[0119] Form F can have a thermogravimetric analysis pattern comprising a weight loss of about 1.1% at about 180°C.

[0120] Form F can have a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 20.

[0121] In some embodiments, Form F can be in substantially pure form.

[0122] The skilled artisan will recognize that the relative intensities of X-ray powder diffraction pattern peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedure, and the particular instrument employed. Accordingly, depending on the type of the instrument and settings employed (including filters), new peaks may be observed in subsequently obtained patterns; or peaks observed in previously obtained patterns may have a negligible relative intensities (and hence may not be observed) in subsequently obtained patterns. As such, the absence of one or more of the lower relative intensity peaks described herein may not, in and of itself, establish that a particular solid Form is not present (e.g., in a sample). However, the presence of the lower relative intensity peaks described above can, in general, be used to further establish the presence of a particular solid Form in a sample.

[0123] In one aspect, this invention features a composition (e.g., a pharmaceutical composition, a pharmaceutical formulation, or a colloidal composition) that includes at least about 0.5 weight percent (e.g., at least about 1.0 weight percent, at least about 2 weight percent, 5 weight percent, at least about 10 weight percent, at least about 20 weight percent, at least about 30 weight percent, at least about 40 weight percent, at least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 90 weight percent, at least about 95 weight percent, at least about 99 weight percent) of Form A, Form B, Form C, Form D, Form E, Form F, or any combination thereof (e.g., any two, three, four, five, or six of Forms A, B, C, D, E, or F in combination, e.g., the composition can include a mixture of

Form A and Form F).

[0124] The compositions can include one or more of the following features.

[0125] The compositions can include one or more pharmaceutically acceptable carriers.

[0126] The compositions can include one or more one or more other therapeutic agent(s).

[0127] In another aspect, this invention features a pharmaceutical composition that includes Form A and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0128] In a further aspect, this invention features a pharmaceutical composition that includes Form B and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0129] In another aspect, this invention features a pharmaceutical composition that includes Form C and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0130] In a further aspect, this invention features a pharmaceutical composition that includes Form D and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0131 J In a further aspect, this invention features a pharmaceutical composition that includes Form E and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0132] In a further aspect, this invention features a pharmaceutical composition that includes Form F and one or more pharmaceutically acceptable carriers. In embodiments, the pharmaceutical compositions can further include one or more one or more other therapeutic agent(s).

[0133] In another aspect, this invention features a colloidal composition that includes Form A and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0134] In a further aspect, this invention features a colloidal composition that includes Form B and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0135] In another aspect, this invention features a colloidal composition that includes Form C and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0136] In a further aspect, this invention features a colloidal composition that includes Form D and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0137] In a further aspect, this invention features a colloidal composition that includes Form E and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0138] In a further aspect, this invention features a colloidal composition that includes Form F and one or more pharmaceutically acceptable carriers. In embodiments, the colloidal compositions can further include one or more one or more other therapeutic agent(s).

[0139] In some embodiments of the compositions and formulations described herein (e.g., pharmaceutical compositions, pharmaceutical formulations, and/or colloidal compositions) that include any of Forms A, B, C, D, E, and/or F, the pharmaceutically acceptable carrier is selected from the group consisting of: water, a surfactant, an acid, a sugar alcohol, and mixtures thereof. In certain of these embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of: sterile water, tyloxapol, hydrochloric acid, a sugar alcohol, and mixtures thereof.

[0140] In some embodiments of the compositions and formulations described herein (e.g., pharmaceutical compositions, pharmaceutical formulations, and/or colloidal compositions) that include any of Forms A, B, C, D, E, and/or F, the composition is a liquid composition.

[0141] In some embodiments of the compositions and formulations described herein (e.g., pharmaceutical compositions, pharmaceutical formulations, and/or colloidal compositions) that include any of Forms A, B, C, D, E, and/or F, the composition is an emulsion.

[0142] In some embodiments of the compositions and formulations described herein (e.g., pharmaceutical compositions, pharmaceutical formulations, and/or colloidal compositions) that include any of Forms A, B, C, D, E, and/or F, the composition is a colloidal solution.

[0143] In some embodiments of the compositions and formulations described herein (e.g., pharmaceutical compositions, pharmaceutical formulations, and/or colloidal compositions) that include any of Forms A, B, C, D, E, and/or F, the composition is formulated for respiratory delivery.

[0144] In one aspect, this invention features a method for preparing Form A, which includes:

(a) recrystallizing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine from a solution comprising N,N-dimethylacetamide and ethanol to provide a first solid;

(b) recrystallizing the first solid from a solution comprising N-methylpyrrolidinone and methanol to provide a second solid;

(c) combining the second solid with methanol to provide a third solid; and

(d) combining the third solid with a solution comprising acetone and methyl tert-butyl ether to provide the polymorph.

[0145] In one aspect, this invention features a method for preparing Form A, which includes anti-solvent addition of ethyl acetate to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine in N-methyl pyrrolidinone. [0146] In one aspect, this invention features a method for preparing Form A, which includes agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: ethyl acetate, acetone, methyl ethyl ketone, t-butyl methyl ether, acetonitrile, tetrahydrofuran, dimethylsulfoxide, a 95:5 v/v solution of ethyl acetate:dimethylsulfoxide, and N,N-dimethylformamide.

[0147] In one aspect, this invention features a method for preparing Form B, which includes anti-solvent addition of methanol to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine in N-methyl pyrrolidinone.

[0148] In one aspect, this invention features a method for preparing Form B, which includes agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: methanol and a 95:5 v/v solution of methanol :N- methylpyrrolidinone.

[0149] In one aspect, this invention features a method for preparing Form C, which includes agitating the compound of Formula I for about 1 week at about 50°C in ethanol.

[0150] In one aspect, this invention features a method for preparing Form D, which includes agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: isopropyl acetate, a 1:1 v/v solution of acetone:water, and a 1:1 v/v solution of acetonitrile:water.

[0151] In one aspect, this invention features a method for preparing Form E, which includes agitating the compound of Formula I for about 1 week at about 25°C in tetrahydrofuran.

[0152] In one aspect, this invention features a method for preparing Form F, which includes agitating the compound of Formula I for about 1 week at about 50°C in tetrahydrofuran.

[0153] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, the method including administering to a subject in need thereof an effective amount of Form A, Form B, Form C, Form D, Form E, Form F, or any combination thereof (as described herein) or a composition that includes an effective amount of Form A, Form B, Form C, Form D, Form E, Form F, or any combination thereof (such as any of the compositions or formulations described herein).

[0154] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form A or a composition that includes an effective amount of Form A (such as any of the compositions or formulations described herein).

[0155J In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form A or a composition that includes an effective amount of Form A (such as any of the compositions or formulations described herein).

[0156] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form B or a composition that includes an effective amount of Form B (such as any of the compositions or formulations described herein).

[0157] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form C or a composition that includes an effective amount of Form C (such as any of the compositions or formulations described herein).

[0158] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form D or a composition that includes an effective amount of Form D (such as any of the compositions or formulations described herein).

[0159] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form E or a composition that includes an effective amount of Form E (such as any of the compositions or formulations described herein).

[0160] In another aspect, this invention features a method for treating a disorder characterized by the activation of the Wnt signaling pathway, which includes administering to a subject in need thereof an effective amount of Form F or a composition that includes an effective amount of Form F (such as any of the compositions or formulations described herein).

[0161] In embodiments, the disorder is selected from pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis).

[0162] In embodiments, the disorder is cancer in a patient, wherein the cancer is selected from: hepatocellular carcinoma, colon cancer, colorectal cancer, breast cancer, pancreatic cancer, leukemia, lymphoma, sarcoma, ovarian cancer, lung cancer, melanoma, squamous cell carcinoma, and adenocarcinoma. For example, the cancer is hepatocellular carcinoma. For example, the cancer is colon cancer. For example, the cancer is colorectal cancer. For example, the cancer is breast cancer. For example, the cancer is pancreatic cancer. For example, the cancer is leukemia. For example, the cancer is lymphoma. For example, the cancer is sarcoma. For example, the cancer is ovarian cancer. For example, the cancer is lung cancer (e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma). As a non-limiting example of the foregoing, the cancer is squamous cell carcinoma. As a further non-limiting example of the foregoing, the cancer is adenocarcinoma.

[0163] In embodiments, the disorder is a bone or cartilage disorder such as osteoarthritis.

[0164] In embodiments, the disorder is selected from osteochondrodysplasia.

[0165] In embodiments, the disorder is a fibrotic disorder selected from the group consisting of: skin fibrosis; scleroderma; progressive systemic fibrosis; muscle fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver; liver fibrosis; adhesions occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonary fibrosis; idiopathic pulmonary fibrosis (IPF); fibrosis and scarring associated with difluse/interstitial lung disease; central nervous system fibrosis; fibrosis following stroke; fibrosis associated with neuro-degenerative disorders selected from the group consisting of Alzheimer's Disease and multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease; and radiation fibrosis. For example, the fibrotic disorder is skin fibrosis. For example, the fibrotic disorder is scleroderma. For example, the fibrotic disorder is pulmonary fibrosis. For example, the fibrotic disorder is renal fibrosis. For example, the fibrotic disorder is idiopathic pulmonary fibrosis (IPF). For example, the fibrotic disorder is cirrhosis of the liver. For example, the fibrotic disorder is liver fibrosis.

[0166] In embodiments, the disorder is selected from cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis. For example, the disorder is idiopathic pulmonary fibrosis.

[0167] Forms A, B, C, D, E, and F, and the compositions that include the aforementioned solid forms, and the methods of making and using the aforementioned solid forms can include any one or more of the features delineated in the detailed description and/or the claims. [0168] This disclosure also features a method of making a compound of Formula I or a pharmaceutically acceptable salt thereof:

the process comprising reacting a starting material Al,

wherein:

R² is independently selected from the group consisting of H and -(C1-9 alkyl)nN(R⁹)2; each R⁹ is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)ncarbocyclyl and -(C1.9 alkyl)N(R¹⁶)2; each R¹⁶ is independently selected from the group consisting of H and lower alkyl;

P¹ is a nitrogen protecting group; each q is independently an integer of 1 or 2; and each n is independently an integer of 0 or 1; with a starting material A2:

wherein:

R⁴ is independently selected from the group consisting of -aryl(R¹³)q, -furyl(R¹⁵)q, and - thiophenyl(R¹⁵)_q; each R⁸ is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, and -CM alkyl; each R¹³ is 1-2 substituents each attached to the aryl ring and independently selected from the group consisting of H, halide, -(CM alkyl)nheterocyclyl(R⁸)q, -(Ci-9 alkyl)nN(R⁹)2 and -(Ci-9 alkyl)nNHS0₂R¹⁸; each R¹⁵ is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, and -C(=0)(Ci-3 alkyl); and each R¹⁸ is a lower alkyl; wherein any N-H moieties in the compound are optionally protected.

[0169] In some embodiments, P¹ is tetrahy dropyrany 1.

[0170] In some embodiments, the process comprises: reacting A1 and A2 to form a compound of Formula (Γ)

treating the compound of Formula (Γ) with an acid (e.g., trifluoroacetic acid) to provide the compound of Formula (I).

[0171] In some embodiments, the process comprises reacting a compound of Formula A3

with bis(pinacolato)diboron to form a compound of Formula A3-1

then reacting the compound of Formula A3-1 with a compound of Formula A4

to form the compound of Formula Al; wherein each occurrence of X is independently selected from iodo, bromo, or chloro (e.g., bromo).

[0172] In some embodiments, the R⁴ aryl is phenyl.

[0173] In some embodiments, the R¹³ heterocyclyl is selected from the group consisting of azetidinyl(R⁸)q, pyrrolidinyl(R⁸)q, piperidinyl(R⁸)q, piperazinyl(R⁸)q, and morpholinyl(R⁸)q.

[0174] In some embodiments, R² is H.

[0175] In some embodiments, R² is -(C1-9 alkyl)nN(R⁹)2.

[0176] In some embodiments, R² is -CHzN(R⁹)2 or -N(R⁹)2.

[0177] In some embodiments, R⁹ is independently selected from the group consisting of

H, Me, Et, n-propyl, isopropyl, and -Cfkcarbocyclyl.

[0178] In some embodiments, R⁴ is phenyl(R¹³)q.

[0179] In some embodiments, R⁴ is -furyl(R¹⁵)q.

[0180] In some embodiments, R⁴ is -thiophenyl(R¹⁵)q.

[0181] In some embodiments, R¹³ is one substituent attached to the phenyl ring and the substituent is a fluorine atom.

[0182] In some embodiments (when R¹³ is one substituent attached to the phenyl ring and the substituent is a fluorine atom), R¹³ is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and -N(R⁹)2. wherein R⁹ is independently selected from the group consisting of H and -CH2CH2N(R¹⁶)2, and wherein R¹⁶ is independently selected from the group consisting of H, Me, and Et.

[0183] In some embodiments (when R¹³ is one substituent attached to the phenyl ring and the substituent is a fluorine atom), R¹³ is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and -(CH2)nNHSO2R¹⁸, wherein R⁹ is independently selected from the group consisting of Me and Et.

[0184] In some embodiments (when R⁴ is -fmyl(R¹⁵)q or -thiophenyl(R¹⁵)q), R¹⁵ is one substituent attached to the thiophenyl ring and the substituents are selected from the group consisting of H, F, Me, and -C(=0)Me. [0185] In some embodiments, the compound of Formula (I) has a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound of Formula (I) has a structure selected from the group consisting of: HI

NHt

9 9 9

9 , , p y acceptable salt thereof.

[0187] In some embodiments, the compound of Formula (I) has the following structure: or a pharmaceutically acceptable salt thereof.

DESCRIPTION OF DRAWINGS

[0188] FIG. 1 is an X-ray powder diffractogram of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyiidin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmeth an amine as obtained after synthesis. [0189] FIG. 2 is a differential scanning calorimetry thermogram of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine as obtained after synthesis.

[0190] FIG. 3 is a thermogravimetric analysis thermogram of l-(5-(3-(7-(3-fluorophenyl)- 3H-imidazo[4, 5-c]pyridin-2-yl)- lH-pyrazolo[3 ,4-b]pyridin-5 -yl)pyri din-3 -y 1)-N, N- dimethylmethanamine as obtained after synthesis.

[0191] FIG. 4 is an X-ray powder diffractogram of Form A obtained using the conditions set forth in method 1.

[0192] FIG. 5 is a differential scanning calorimetry thermogram of Form A.

[0193] FIG. 6 is an X-ray powder diffractogram of Form A, Form B, Form C, Form D,

Form E, and Form F.

[0194] FIG. 7 is a differential scanning calorimetry thermogram of Form B.

[0195] FIG. 8 is a thermogravimetric analysis thermogram of Form B.

[0196] FIG. 9 is a ¹H NMR spectrum of Form B.

[0197] FIG. 10 is a differential scanning calorimetry thermogram of Form C.

[0198] FIG. 11 is a thermogravimetric analysis thermogram of Form C.

[0199] FIG. 12 is a ¹H NMR spectrum of Form C.

[0200] FIG. 13 is a differential scanning calorimetry thermogram of Form D.

[0201] FIG. 14 is a thermogravimetric analysis thermogram of Form D.

[0202] FIG. 15 is a ¹H NMR spectrum of Form D.

[0203] FIG. 16 is a differential scanning calorimetry thermogram of Form E.

[0204] FIG. 17 is a thermogravimetric analysis thermogram of Form E.

[0205] FIG. 18 is a ¹H NMR spectrum of Form E.

[0206] FIG. 19 is a differential scanning calorimetry thermogram of Form F.

[0207] FIG. 20 is a thermogravimetric analysis thermogram of Form F.

[0208] FIG. 21 is a ¹H NMR spectrum of Form F.

[0209] FIG. 22 is an overlay of XRPD scans of products obtained from water activity experiments.

[0210] FIG. 23 is an overlay of XRPD scans of products obtained from competitive slurry experiments. [0211] FIG. 24 is an overlay of XRPD scans of products obtained from equilibration experiments at 25°C.

[0212] FIG. 25 is an overlay of XRPD scans of products obtained from equilibration experiments at 50°C.

[0213] FIG. 26 is an overlay of XRPD scans of products obtained from precipitation by addition of anti-solvent experiments.

[0214] FIG. 27 is an X-ray powder diffractogram of Form B.

[0215] FIG. 28 is an X-ray powder diffractogram of Form C.

[0216] FIG. 29 is an X-ray powder diffractogram of Form D.

[0217] FIG. 30 is an X-ray powder diffractogram of Form E.

[0218] FIG. 31 is an X-ray powder diffractogram of Form F.

[0219] FIG. 32 is a polarized light microscope scan of amorphous l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine as obtained after synthesis.

[0220] FIG. 33 is a polarized light microscope scan of Form A.

[0221] FIG. 34 is an X-ray powder diffractogram of Form A obtained using the conditions set forth in method 2.

DETAILED DESCRIPTION

[0222] This disclosure features solid forms of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine as well as methods of making and using the same. In some embodiments, said solid forms exhibit enhanced stability, and as such, can have improved suitability for bulk handling and formulation.

Definitions

[0223] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0224] The skilled artisan will recognize that the relative intensities of X-ray powder diffraction pattern peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedure, and the particular instrument and settings employed (including filters). Thus, the term “about” when used in conjunction with defining a position of a characteristic peak in an X-ray powder diffraction pattern is intended to mean the stated degree 2Θ value ± 0.2 degrees 2Θ.

[0225] As used herein, the term “l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin- 2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine” when not used in conjunction with modifiers such as “polymorph," “solvate,” or “amorphous" refers to any form of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- yl)pyridin-3-yl)-N,N-dimethylmethanamine that is currently available to those in the art including, but not limited to, any form disclosed in US 2013/0296302 and/or WO 2013/166396.

[0226] The term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. A “nitrogen protecting group" is a substituent attached to a nitrogen atom that blocks or protects the nitrogen functionality in the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. An "alcohol or hydroxyl protecting group" is a substituent attached to an OH group that blocks or protects the OH functionality in the compound.

[0227] Examples of “nitrogen protecting group" (e.g., “amino-protecting group") includes tetrahydropyrany 1.

[0228] Examples of “nitrogen protecting group” (e.g., “amino-protecting group”) include carbamate protecting groups. Non-limiting examples of carbamate protecting groups include benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, P- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxy carbonyl, 2,4- dimethoxybenzyloxy carbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxy carbonyl, 3 ,4, 5-trimethoxybenzyloxy carbonyl, l-(p-biphenylyl)-l- methylethoxy carbonyl, dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (*Boc), diisopropylmethoxycarbonyl, isopropyloxy carbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxy-carbonyl (Troc), phenoxy carbonyl, 4- nitro-phenoxy carbonyl, cyclopentyloxy carbonyl, adamantyloxycarbonyl, cyclohexyloxy carbonyl, or phenylthiocarbonyl.

[0229J Examples of “nitrogen protecting group” (e.g., “amino-protecting group”) include sulfonyl protecting groups. Non-limiting examples of sulfonyl protecting groups include methanesulfonyl, benzenesulfonyl, toluenesulfonyl, nitro-benzenesulfonyl, 2-[(4-nitrophenyl)- ethyl] sulfonyl, ally 1 sulfonyl, 2-formylbenzenesulfonyl, and N,N-dialkylaminosulfonyl.

[0230] Examples of “nitrogen protecting group” (e.g., “amino-protecting group”) include amide protecting groups. Non-limiting examples include formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, tricMoroacetyl, phthalyl, o- nitrophenoxyacetyl, benzoyl, 4-cMorobenzoyl, 4-bromobenzoyl, and 4-nitrobenzoyl.

[0231] Examples of “nitrogen protecting group” (e.g., “amino-protecting group”) include silyl protecting groups. Non-limiting examples include TBS, TBDPS, TES, TMS, and TIPS.

[0232] The term “administration” or “administering” refers to a method of providing a dosage of a compound or pharmaceutical composition to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian, where the method is, e.g., orally, subcutaneously, intravenously, intralymphatic, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, ontologically, neuro-otologically, intraocularly, subconjuctivally, via anterior eye chamber injection, intravitreally, intraperitoneally, intrathecally, intracystically, intrapleurally, via wound irrigation, intrabuccally, intra-abdominally, intra-articularly, intra-aurally, intrabronchially, intracapsularly, intrameningeally, via inhalation, via endotracheal or endobronchial instillation, via direct instillation into pulmonary cavities, intraspinally, intrasynovially, intrathoracically, via thoracostomy irrigation, epidurally, intratympanically, intradstemally, intravascularly, intraventriculariy, intraosseously, via irrigation of infected bone, or via application as part of any admixture with a prosthetic device. The method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, the site of the disease, the disease involved, and the severity of the disease.

[0233] The term “mammal” is used in its usual biological sense. Thus, it specifically includes humans, cattle, horses, monkeys, dogs, cats, mice, rats, cows, sheep, pigs, goats, and nonhuman primates, but also includes many other species. [0234] The terai “pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, isotonic and absorption delaying agents and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Brunton et al. (Eds.) (2017); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 13th Ed.. The McGraw-Hill Companies.

[0235] The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and, which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Many such salts are known in the art, for example, as described in WO 87/05297. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. [0236] “Patient” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate, or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate. In some embodiments, the patient is a human.

[0237] A “therapeutically effective amount” of a compound as provided herein is one which is sufficient to achieve the desired physiological effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. “Therapeutically effective amount” is also intended to include one or more of the compounds of Formula I, in combination with one or more other agents that are effective to treat the diseases and/or conditions described herein. The combination of compounds can be a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22, 27-55, occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. It will be appreciated that different concentrations may be employed for prophylaxis than for treatment of an active disease. This amount can further depend upon the patient’s height, weight, sex, age and medical history.

[0238] A therapeutic effect relieves, to some extent, one or more of the symptoms of the disease.

[0239] “Treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition as provided herein for therapeutic purposes. The term “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease thus causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying metabolic causes of symptoms, postponing or preventing the further development of a disorder, and/or reducing the severity of symptoms that will or are expected to develop.

[0240] “Subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0241] As used herein, the term “polymorph,” refers to a compound, which when present as a solid, exists in different forms. [0242] The term “anhydrous,” as used herein, refers to a crystal form of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-

Ν,Ν-dimethylmethanamine that includes 1% or less by weight of water. For example, 0.5% or less, 0.25% or less, or 0.1% or less by weight of water.

[0243] The term “solvate” as used herein refers to a crystalline form of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-

Ν,Ν-dimethylmethanamine, such as a polymorph form of the compound, where the crystal lattice comprises one or more solvents of crystallization. In some embodiments, a solvate is a hydrate.

[0244] In some embodiments the % water by weight in a crystal form, such as a non- stoichiometric hydrate, is determined by the Karl Fischer titration method. In some embodiments, the crystal form is dried prior to Karl Fischer titration.

[0245] “Purity,” unless otherwise indicated, when used in reference to a composition including a solid form of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3 ,4-b]pyridin-5-yl)pyri din-3 -y l)-N,N-dimethylmethanamine, refers to the percentage of one specific solid form relative to another solid form or an amorphous form of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine in the referenced composition. For example, a composition comprising solid Form A having a purity of 90% would comprise 90 weight parts Form A and 10 weight parts of other solid and/or amorphous forms of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin- 2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine.

[0246] As used herein, a compound or composition is “substantially free of’ one or more other components if the compound or composition contains no significant amount of such other components. Such components can include starting materials, residual solvents, or any other impurities that can result from the preparation of and/or isolation of the compounds and compositions provided herein. In some embodiments, a polymorph form provided herein is substantially free of other polymorph forms. In some embodiments, a particular polymorph of 1- (5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- yl)pyridin-3-yl)-N,N-dimethylmethanamine is “substantially free” of other polymorphs if the particular polymorph constitutes at least about 95% by weight of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine present. In some embodiments, a particular polymorph of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine is “substantially free” of other polymorphs if the particular polymorph constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine present. Such solid forms are sometimes referred to herein as being “substantially pure.”

[0247] “Room temperature” or “RT” refers to the ambient temperature of a typical laboratory, which is typically around 25 °C.

Solid Forms

[0248] Methods for preparing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine can be found, e.g., in US 2013/0296302 and/or WO 2013/166396 which are herein incorporated by reference in their entireties.

[0249] In other embodiments, one solid form (e.g., amorphous) can be used to prepare another solid form (e.g., Form A, B, C, D, E, or F). For example, Form F can be used to prepare Form A.

[0250] In some embodiments, provided herein is Form A that exhibits an endotherm between about 337-362°C as measured by differential scanning calorimetry (DSC) with a peak temperature of about 351.8°C. In some embodiments, the endotherm is observed when using a scan rate of 10°C per minute.

[0251] Provided herein are methods of preparing Form A. In some embodiments, the method comprises (a) recrystallizing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine from a solution comprising Ν,Ν-dimethylacetamide and ethanol to provide a first solid;

(c) combining the second solid with methanol to provide a third solid; and

(d) combining the third solid with a solution comprising acetone and methyl tert-butyl ether to provide the polymorph. [0252] In some embodiments, Form A can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form A. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is selected from the group consisting of acetone, a 5:95 v/v solution of dimethylsulfoxide (DMSO): ethyl acetate, and DMSO. In some of these embodiments (when the organic solvent is acetone), Form A and Form F are produced. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is selected from the group consisting of ethyl acetate, acetone, methyl ethyl ketone, t-butyl methyl ether, acetonitrile, tetrahydrofuran, dimethylsulfoxide, a 95:5 v/v solution of ethyl acetate:dimethylsulfoxide, and N,N- dimethylformamide.

[0253] In some embodiments, Form A can be prepared by addition of ethyl acetate to a soluti on of 1 -(5-(3 -(7-(3 -fluoropheny l)-3 H-imidazo[4,5-c]pyri din-2-yl)- 1 H-py razolo[3 ,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine in N-methyl pyrrolidinone, and filtration of the resulting precipitate.

Methods of Characterization and Identification

[0254] Characterization of solid forms A, B, C, D, E, and F described herein and distinguishing these solid forms from the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin- 2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as obtained directly after synthesis can be accomplished using conventional analytical techniques known to those of skill in the art.

[0255] Verification of the gross chemical structure of solid forms A, B, C, D, E, and F (i.e., verification that solid forms A, B, C, D, E, and F have the same chemical formula/connectivity as that of the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as directly obtained after synthesis can be carried out using techniques including (but not limited to) melting point, infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), mass spectral analysis (MS), combustion analysis, Raman spectroscopy, elemental analysis, and chromatography including high performance liquid chromatography.

[0256] Other techniques including Powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), polarized light microscopy (PLM), dynamic vapor sorption (DVS), and gravimetric vapor sorption (GVS) and are particularly useful in identifying the solid forms A, B, C, D, E, and F.

Powder X-ray diffraction [0257] The Powder X-ray diffraction patterns shown in FIGS. 1, 4, 6, and 22-31 were obtained on a Bruker D8 Advance X-Ray Powder Diffractometer. A copper x-ray tube (λ=1.54179Α) scanning at 10 degrees/minute from 2 to 40 degree 2-theta with a sample rotation speed of 15 rpm was used as the x-ray source. The generator had the following parameters: Voltage: 40 kV; Current: 40 mA. The Powder X-ray diffraction pattern shown in FIG. 34 was obtained using the conditions set forth in method 2.

Differential Scanning Calorimetry

[0258] The DSC data shown in FIGS. 5, 7, 10, 13, 16, and 19 were collected using a DISCOVERY DSC-2500. Typically, 1-2 mg of sample were used in a hermetically sealed aluminum pan with a pinhole. The sample was heated from 25°C to 400°C at a ramp rate of 10°C/min under 50 mL/min of N2.

[0259] The location of DSC peak may be slightly shifted depending on the particle size distribution, type of machine, and the heating rate. The presence of impurities may also change the peak location.

Thermogravimetric Analysis

[0260] The TGA data shown in FIGS. 3, 8, 11, 14, 17, and 20 were collected using a DISCOVERY TGA 5500. Typically, 3-5 mg of sample was deposited on an open platinum pan and heated from 30°C to 300°C at 10°C/min under a 25 mL/min N2 flow.

[0261] The location of TGA peaks may be shifted depending on the particle size distribution, type of machine, type and flow rate of purge gas, and the heating rate. The presence of impurities may also change the peak location. Methods of Preparing Forms A, B. C. D. E, and F

Starting Materials:

[0262] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine can be used as a starting material for the preparation of Solid Forms A, B, C, D, E, and F.

[0263] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine can be prepared as described in US 2013/0296302 and/or WO 2013/166396 (see Example 2 and compound 18). The l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- yl)pyridin-3-yl)-N,N-dimethylmethanamine that is obtained in this fashion can be used either in crude or purified form, and is typically an amorphous solid.

[0264] As can be appreciated by the skilled artisan, further methods of synthesizing l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3 -yl)-N,N-dimethylmethanamine will be evident to those of ordinary skill in the art. Synthetic chemistiy transformations and protecting group methodologies (protection and deprotection) useful in synthesizing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0265] In other embodiments, one solid form (e g., 1 -(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine as obtained immediately after its preparation) can be used to prepare another solid form (e.g., Form A, Form B, Form C, Form D, Form E, and/or Form F). For example, Form F can be used to obtain Form A. Form A

[0266] In some embodiments, Form A can be prepared by a method consisting of:

(a) recrystallizing 1 -(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-l H- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine from a solution comprising Ν,Ν-dimethylacetamide and ethanol to provide a first solid;

(c) combining the second solid with methanol to provide a third solid; and

[0267] In certain embodiments, the v/v ratio of Ν,Ν-dimethylacetamide to ethanol is about 15:11.25. In certain embodiments, the v/v ratio of N-methylpyrrolidinone to methanol is about 1 :2. In certain embodiments, the v/v ratio of acetone to methyl tert-butyl ether about 2:1.

[0268] In certain embodiments, step (a) is performed under nitrogen. In certain embodiments, step (b) is performed under nitrogen. In certain embodiments, step (c) is performed under nitrogen.

[0269] In certain embodiments, step (a) further comprises adding a small amount of Form A to the solution to facilitate recrystallization. In certain embodiments, step (b) further comprises adding a small amount of Form A to the solution to facilitate recrystallization.

[0270] In certain embodiments, step (a) further comprises (al) dissolving l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine in Ν,Ν-dimethylacetamide under nitrogen to form a first solution, (a2) adding a small amount of Form A to the first solution, (a3) adding ethanol to the first solution to form a second solution, and (a4) cooling the second solution to form the first solid. In certain of these embodiments, step (a2) further comprises cooling the first solution to 23-28°C after adding the small amount of Form A. In certain of these embodiments, the step (a3) addition of ethanol is performed dropwise. For example, the step (a3) addition of ethanol is performed dropwise through a cartridge filter, e.g., by means of a peristaltic pump. In certain of these embodiments, cooling the second solution in step (a4) comprises cooling the second solution to 5-15°C. In certain of these embodiments, cooling the second solution in step (a4) comprises forming a slurry, then filtering the slurry to form the first solid. For example, filtering the slurry to form the first solid is performed by means of centrifugation. For example, filtering the slurry to form the first solid further comprises washing the first solid with a 1 :5 v/v solution of N,N-dimethylacetamide:ethanol then optionally washing with ethanol.

[0271] In certain embodiments, step (b) further comprises (b 1) adding methanol to a small amount of Form A to form a suspension, (b2) dissolving the first solid in N-methylpyrrolidinone to form a third solution, (b3) adding the third solution to the suspension generated in step (bl) to form a fourth solution, and (b4) cooling the fourth solution to form the second solid. In certain of these embodiments, step (bl) further comprises cooling the suspension to 10-20°C. In certain of these embodiments, the step (b3) addition of the third solution is performed dropwise. For example, the step (b3) addition of the third solution is performed dropwise through a cartridge filter, e.g., by means of a peristaltic pump. In certain of these embodiments, cooling the fourth solution in step (b4) comprises cooling the fourth solution to 10-20°C. In certain of these embodiments, cooling the fourth solution in step (b4) comprises forming a slurry, then filtering the slurry to form the second solid. For example, filtering the slurry to form the second solid is performed by means of centrifugation. For example, filtering the slurry to form the second solid further comprises washing the second solid with methanol.

[0272] In certain embodiments, step (c) further comprises agitating (e.g., stirring) the second solid in methanol. In certain of these embodiments, the agitating is performed at 10-20°C.

[0273] In certain embodiments, step (d) further comprises agitating (e.g., stirring) the second solid in 2:1 acetone and methyl tert-butyl ether. In certain of these embodiments, the agitating is performed at 23-28°C.

[0274] In some embodiments, Form A can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form A. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is selected from the group consisting of acetone, a 5:95 v/v solution of dimethylsulfoxide (DMSO): ethyl acetate, and DMSO. In some of these embodiments (when the organic solvent is acetone), Form A and Form F are produced. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is selected from the group consisting of ethyl acetate, acetone, methyl ethyl ketone, t-butyl methyl ether, acetonitrile, tetrahydrofuran, dimethylsulfoxide, a 95:5 v/v solution of ethyl acetate:dimethylsulfoxide, and N,N- dimethylform amide.

[0275] In some embodiments, Form A can be prepared by addition of ethyl acetate to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine in N-methyl pyrrolidinone, and filtration of the resulting precipitate.

Form B

[0276] In some embodiments, Form B can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3 -yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form B. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is selected from the group consisting of methanol and a 95:5 v/v solution of methanol :N-methylpyrrolidinone. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is selected from the group consisting of methanol and a 95:5 v/v solution of methanol :N-methylpyrrolidinone.

[0277] In some embodiments, Form B can be prepared by addition of methanol to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine in N-methyl pyrrolidinone, and filtration of the resulting precipitate.

Form C

[0278] In some embodiments, Form C can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form C. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is ethanol. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is ethanol.

Form D

[0279] In some embodiments, Form D can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form D. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, /-butyl methyl ether, and a 1:1 v/v solution of acetone: water. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is selected from the group consisting of isopropyl acetate, a 1:1 v/v solution of acetone: water, and a 1:1 v/v solution of acetonitrile:water.

Form E

[0280J In some embodiments, Form E can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3 -yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form E. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is tetrahydrofuran. In some of these embodiments, both Form E and Form F are obtained. Form F

[0281] In some embodiments, Form F can be prepared by agitating a suspension of l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (crude or purified) in an organic solvent, then filtering the suspended solid to provide Form F. In some embodiments, the agitation is performed using an Eppendorf shaker. In some embodiments, the agitation is performed for 1 week. In some embodiments, the agitation is performed at 25°C. In some embodiments (when the agitation is performed for 1 week at 25°C), the organic solvent is selected from the group consisting of acetone and tetrahydrofuran. In some of these embodiments (when the oiganic solvent is acetone), Form A and Form F are produced. In some other of these embodiments (when the oiganic solvent is tetrahydrofuran), Form E and Form F are produced. In some embodiments, the agitation is performed at 50°C. In some embodiments (when the agitation is performed for 1 week at 50°C), the organic solvent is selected from the group consisting of 2-propanol and tetrahydrofuran.

Compositions/Formulations. Combination Therapy, and Administration of Forms A. B, C. D. E, and F and Methods of Use Thereof

[0282] In some embodiments, each of Forms A, B, C, D, E, or F (or any combination thereof, e.g., any two, three, four, five, or six of Forms A, B, C, D, E, or F in combination) can be in the form of a composition (e.g., a pharmaceutical composition or a pharmaceutical formulation).

[0283] In certain embodiments, the compositions can include one or more pharmaceutically acceptable carriers, which can include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- a-tocopherol poly ethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β- , and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3 -hy droxypropyl-P-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0284] The compounds of this invention may also be useful in combination (administered together or sequentially) with other known agents.

[0285] Non-limiting examples of diseases which can be treated with l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and other known agents are colorectal cancer, ovarian cancer, retinitis pigmentosa, macular degeneration, idiopathic pulmonary fibrosis and osteoarthritis.

[0286] In some embodiments, colorectal cancer can be treated with l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and one or more of the following drugs: 5-Fluorouracil (5-FU), which is often given with the vitamin-like drug leucovorin (also called folinic acid); Capecitabine (Xeloda^®), Irinotecan (Camptosar^®), Oxaliplatin (Eloxatin^®). Examples of combinations of these drugs which could be further combined with l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) are FOLFOX (5-FU, leucovorin, and oxaliplatin), FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU, oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin). For rectal cancer, chemo with 5-FU or capecitabine combined with radiation may be given before surgery (neoadjuvant treatment).

[0287] In some embodiments, ovarian cancer can be treated with l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and one or more of the following drugs: Topotecan, Liposomal doxorubicin (Doxil⁸), Gemcitabine (Gemzar^®), Cyclophosphamide (Cytoxan^®), Vinorelbine (Navelbine^®), Ifosfamide (Ifex^®), Etoposide (VP- 16), Altretamine (Hexalen^®), Capecitabine (Xeloda^®), Irinotecan (CPT-11, Camptosar^®), Melphalan, Pemetrexed (Alimta^®) and Albumin bound paclitaxel (nab-paclitaxel, Abraxane^®). Examples of combinations of these drugs which could be further combined with l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) are TIP (paclitaxel [Taxol], ifosfamide, and cisplatin), VelP (vinblastine, ifosfamide, and cisplatin) and VIP (etoposide [VP- 16], ifosfamide, and cisplatin).

[0288J In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) can be used to treat cancer in combination with any of the following methods: (a) Hormone therapy such as aromatase inhibitors, LHRH [luteinizing hormone-releasing hormone] analogs and inhibitors, and others; (b) Ablation or embolization procedures such as radiofrequency ablation (RFA), ethanol (alcohol) ablation, microwave thermotherapy and ciyosurgery (cryotherapy); (c) Chemotherapy using alkylating agents such as cisplatin and carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy using anti-metabolites such as azathioprine and mercaptopurine; (e) Chemotherapy using plant alkaloids and terpenoids such as vinca alkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) and taxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposide and docetaxel; (g) Chemotherapy using topoisomerase inhibitors such as irinotecan, topotecan, amsaciine, etoposide, etoposide phosphate, and teniposide; (h) Chemotherapy using cytotoxic antibiotics such as actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i) Chemotherapy using tyrosine- kinase inhibitors such as Imatinib mesylate (deevec^®, also known as STI-571), Gefitinib (Iressa, also known as ZD1839), Erlotinib (marketed as Tarceva^®), Bortezomib (Velcade^®) , tamoxifen , tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax in clinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib, Olaparib in clinical trials), PI3K inhibitors (eg. perifosine in a phase ΙΠ trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152, (AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818), MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g. PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy using monoclonal antibodies such as Rituximab (marketed as MabThera^® or Rituxan^®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab (marketed as Erbitux^®) and Bevacizumab (marketed as Avastin^®); and (k) radiation therapy.

[0289] In some embodiments, idiopathic pulmonary fibrosis can be treated with l-(5-(3-

(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3- yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and one or more of the following drugs: pirfenidone (pirfenidone was approved for use in 2011 in Europe under the brand name Esbriet^®), prednisone, azathioprine, N-acetylcysteine, interferon-γ lb, bosentan (bosentan is currentiy being studied in patients with IFF, [The American Journal of Respiratory and Critical Care Medicine (2011), 184(1), 92-9]), Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal of Pharmacology (2011), 163(1), 141-172], and anti-inflammatory agents such as corticosteroids.

[0290] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) can be used to treat idiopathic pulmonary fibrosis in combination with any of the following methods: oxygen therapy, pulmonary rehabilitation and surgery.

[0291] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyiidin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) can be used to treat osteoarthritis in combination with any of the following methods: (a) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, aspirin and acetaminophen; (b) physical therapy; (c) injections of corticosteroid medications; (d) injections of hyaluronic acid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine; (f) in combination with braces and/or shoe inserts or any device that can immobilize or support your joint to help you keep pressure off it (e.g., splints, braces, shoe inserts or other medical devices); (g) realigning bones (osteotomy); (h) joint replacement (arthroplasty); and (i) in combination with a chronic pain class.

[0292] In some embodiments, macular degeneration can be treated with a combination of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyri din-5- yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and one or more of the following drugs: Bevacizumab (Avastin^®), Ranibizumab (Lucentis^®), Pegaptanib (Macugen), Aflibercept (Eylea^®), verteporfin (Visudyne^®) in combination with photodynamic therapy (PDT) or with any of the following methods: (a) in combination with laser to destroy abnormal blood vessels (photocoagulation); and (b) in combination with increased vitamin intake of antioxidant vitamins and zinc.

[0293] In some embodiments, retinitis pigmentosa can be treated with a combination of 1 - (5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) and one or more of the following drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurin or with any of the following methods: (a) with the Argus^® Π retinal implant; and (b) with stem cell and/or gene therapy.

[0294J Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. Pharmaceutical compositions as provided herein may be formulated as solids, semi solids, liquids, solutions, colloidals, liposomes, emulsions, suspensions, complexes, coacervates, or aerosols. Dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, implants, controlled release or the like are also provided herein. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, milling, grinding, supercritical fluid processing, coacervation, complex coacervation, encapsulation, emulsification, complexation, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills (tablets and or capsules), transdermal (including electrotransport) patches, implants and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. Preferably, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0295] The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like. The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxy alkylcyclodextrins, including 2- and 3- hydroxypropyl-b-cyclodextrins, or other solubilized derivatives can also be advantageously used to enhance deliveiy of compounds described herein. Dosage forms or compositions containing a compound as described herein in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. The contemplated compositions may contain 0.001%-100% active ingredient, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^nd Edition (Pharmaceutical Press, London, UK. 2012).

[0296] In one preferred embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g. , in propylene carbonate, vegetable oils, PEG’S, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which the two active ingredients are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0297] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g. , water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution, colloid, liposome, emulsion, complexes, coacervate or suspension. If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, co-solvents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like).

[0298] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 0.25 mg/Kg to 50 mg/Kg in humans.

[0299] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 0.25 mg/Kg to 20 mg/Kg in humans.

[0300] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 0.50 mg/Kg to 19 mg/Kg in humans.

[0301] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 0.75 mg/Kg to 18 mg/Kg in humans.

[0302] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 1.0 mg/Kg to 17 mg/Kg in humans.

[0303] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 1.25 mg/Kg to 16 mg/Kg in humans.

[0304] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 1.50 mg/Kg to 15 mg/Kg in humans.

[0305] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyiidin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 1.75 mg/Kg to 14 mg/Kg in humans.

[0306] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 2.0 mg/Kg to 13 mg/Kg in humans. [0307] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 3.0 mg/Kg to 12 mg/Kg in humans.

[0308] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyiidin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 4.0 mg/Kg to 11 mg/Kg in humans.

[0309] In some embodiments, the unit dosage of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) is 5.0 mg/Kg to 10 mg/Kg in humans.

[0310] In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0311] In some embodiments, the compositions are provided in unit dosage forms suitable for twice a day administration of a precise dose.

[0312] In some embodiments, the compositions are provided in unit dosage forms suitable for three times a day administration of a precise dose.

[0313] Injectables can be prepared in conventional forms, either as liquid solutions, colloid, liposomes, complexes, coacervate or suspensions, as emulsions, or in solid forms suitable for reconstitution in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable and could be higher if the composition is a solid or suspension, which could be subsequently diluted to the above percentages.

[0314] In some embodiments, the composition will comprise 0.1-10% of the active agent in solution.

[0315] In some embodiments, the composition will comprise 0.1-5% of the active agent in solution.

[0316] In some embodiments, the composition will comprise 0.1-4% of the active agent in solution. [0317] In some embodiments, the composition will comprise 0.15-3% of the active agent in solution.

[0318] In some embodiments, the composition will comprise 0.2-2% of the active agent in solution.

[0319] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-96 hours.

[0320] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-72 hours.

[0321] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-48 hours.

[0322] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-24 hours.

[0323] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infUsion over a period of 1-12 hours.

[0324] In some embodiments, the compositions are provided in dosage forms suitable for continuous dosage by intravenous infusion over a period of 1-6 hours.

[0325] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m² to 300 mg/m².

[0326] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m² to 200 mg/m².

[0327] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 5 mg/m² to 100 mg/m².

[0328] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 10 mg/m² to 50 mg/m².

[0329] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 50 mg/m² to 200 mg/m².

[0330] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 75 mg/m² to 175 mg/m².

[0331] In some embodiments, these compositions can be administered by intravenous infusion to humans at doses of 100 mg/m² to 150 mg/m². [0332] It is to be noted that concentrations and dosage values may also vary depending on the specific compound and the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0333] In one preferred embodiment, the compositions can be administered to the respiratory tract (including nasal and pulmonary) e.g., through a nebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powder inhaler, insufflator, liquid instillation or other suitable device or technique.

[0334] In some embodiments, aerosols intended for delivery to the nasal mucosa are provided for inhalation through the nose. For optimal delivery to the nasal cavities, inhaled particle sizes of about 5 to about 100 microns are useful, with particle sizes of about 10 to about 60 microns being preferred. For nasal delivery, a larger inhaled particle size is desired to maximize impaction on the nasal mucosa and to minimize or prevent pulmonary deposition of the administered formulation. In some embodiments, aerosols intended for delivery to the lung are provided for inhalation through the nose or the mouth. For optimal delivery to the lung, inhaled aerodynamic particle sizes of about less than 10 pm are useful, with an aerodynamic particle size of about 1 to about 10 microns being preferred. Inhaled particles may be defined as liquid droplets containing dissolved drug, liquid droplets containing suspended drug particles (in cases where the drug is insoluble in the suspending medium), dry particles of pure drug substance, drug substance incorporated with excipients, liposomes, emulsions, colloidal systems, coacervates, aggregates of drug nanoparticles, or dry particles of a diluent which contain embedded drug nanoparticles.

[0335] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) disclosed herein intended for respiratory delivery (either systemic or local) can be administered as aqueous formulations, as non-aqueous solutions or suspensions, as suspensions or solutions in halogenated hydrocarbon propellants with or without alcohol, as a colloidal system, as emulsions, coacervates or as dry powders. Aqueous formulations may be aerosolized by liquid nebulizers employing either hydraulic or ultrasonic atomization or by modified micropump systems (like the soft mist inhalers, the Aerodose^® or the AERx^® systems). Propellant-based systems may use suitable pressurized metered-dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs), which are capable of dispersing the drug substance effectively. A desired particle size and distribution may be obtained by choosing an appropriate device.

[0336] In some embodiments, the compositions of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) disclosed herein can be administered to the ear by various methods. For example, a round window catheter (e.g., U.S. Pat.

Nos. 6,440,102 and 6,648,873) can be used. [0337] Altematively, formulations can be incorporated into a wick for use between the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) or absorbed to collagen sponge or other solid support (e.g., U.S. Pat. No. 4,164,559).

[0338] If desired, formulations of the invention can be incorporated into a gel formulation

(e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

[0339] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) disclosed herein intended for delivery to the ear can be administered via an implanted pump and delivery system through a needle directly into the middle or inner ear (cochlea) or through a cochlear implant stylet electrode channel or alternative prepared drug delivery channel such as but not limited to a needle through temporal bone into the cochlea.

[0340] Other options include delivery via a pump through a thin film coated onto a multichannel electrode or electrode with a specially imbedded drug delivery channel (pathways) carved into the thin film for this purpose. In other embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine (including Form A, B, C, D, E, and/or F) can be delivered from the reservoir of an external or internal implanted pumping system.

[0341] Formulations of the invention also can be administered to the ear by intratympanic injection into the middle ear, inner ear, or cochlea (e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815). [0342] Intratympanic injection of therapeutic agents is the technique of injecting a therapeutic agent behind the tympanic membrane into the middle and/or inner ear. In one embodiment, the formulations described herein are administered directly onto the round window membrane via transtympanic injection. In another embodiment, the ion channel modulating agent auris-acceptable formulations described herein are administered onto the round window membrane via a non-transtympanic approach to the inner ear. In additional embodiments, the formulation described herein is administered onto the round window membrane via a surgical approach to the round window membrane comprising modification of the crista fenestrae cochleae.

[0343] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) is formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), and the like.

[0344] Suppositories for rectal administration of the drug (either as a solution, colloid, suspension or a complex) can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt or erode/dissolve in the rectum and release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0345] Solid compositions can be provided in various different types of dosage forms, depending on the physicochemical properties of the drug, the desired dissolution rate, cost considerations, and other criteria. In one of the embodiments, the solid composition is a single unit. This implies that one-unit dose of the drug is comprised in a single, physically shaped solid form or article. In other words, the solid composition is coherent, which is in contrast to a multiple unit dosage form, in which the units are incoherent.

[0346] Examples of single units which may be used as dosage forms for the solid composition include tablets, such as compressed tablets, film-like units, foil-like units, wafers, lyophilized matrix units, and the like. In a preferred embodiment, the solid composition is a highly porous lyophilized form. Such lyophilizates, sometimes also called wafers or lyophilized tablets, are particularly useful for their rapid disintegration, which also enables the rapid dissolution of the active compound.

[0347] On the other hand, for some applications the solid composition may also be formed as a multiple unit dosage form as defined above. Examples of multiple units are powders, granules, microparticles, pellets, mini-tablets, beads, lyophilized powders, and the like. In one embodiment, the solid composition is a lyophilized powder. Such a dispersed lyophilized system comprises a multitude of powder particles, and due to the lyophilization process used in the formation of the powder, each particle has an irregular, porous microstructure through which the powder is capable of absorbing water very rapidly, resulting in quick dissolution. Effervescent compositions are also contemplated to aid the quick dispersion and absorption of the compound.

[0348] Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water-soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles. In this type of system, the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.

[0349] In some embodiments, the formulations can be in any form that is suitable for oral administration (e.g., any conventional oral dosage forms including, but not limited to, solid dosage forms such as a tablet, a pill, a hard or soft capsule, a dragee, a lozenge, a cachet, a sachet, a powder (e.g., dispensable powder), granules; and liquid preparations such as syrups, slurries, gels, elixirs, emulsions and aqueous suspensions, dispersions, solutions, and concentrated drops, or any other form reasonably adapted for oral administration).

[0350] In some embodiments, the formulations can be in the form of a discrete, solid dosage unit (e.g. a capsule, a tablet, or a dragee) containing a predetermined amount of the active ingredient, one or more surfactants, and optionally containing one or more other pharmaceutically - acceptable diluent(s), binders), disintegrant(s), glidant(s), lubricant(s), stabilizers), and/or agent(s) for adjusting pH. [0351] In some embodiments, the formulations can be encapsulated in a suitable capsule shell. Non-limiting examples of capsules include: a hydroxypropyl methylcellulose (HPMC) hard shell capsule, hard gelatine capsule, or a soft gelatin capsule.

[0352] In certain embodiments, the formulations (e.g., in granule or powder form) can be encapsulated in a hard (e.g., two piece) capsule made of HPMC. An exemplary, but nonlimiting example of an HPMC capsule is manufactured by Qualicap and has the following specifications (#0 Capsule; opaque reddish-brown cap and body; weight of 100 capsules is about from 8.1 g - 9.9 g):

Table 1

Composition of HPMC Capsule Shell

Ingredient (%)

Carrageenan 0.33

Potassium Chloride 0.51

Titanium Dioxide 1.00

Synthetic Iron Oxide Red 5.00

Hydroxypropyl Methylcellulose 88.16 (Hypromellose)

Water 5.00

[0353] In other embodiments, the formulations can be encapsulated in a push-fit capsule made of gelatin, or a soft, sealed capsule made of gelatin and a plasticizer, such as glycerol or sorbitol.

[0354] For example, the capsules can contain, in solid form, the active ingredients described herein in admixture with one or more surfactants and optionally containing one or more other pharmaceutically-acceptable diluent(s), binders), disintegrant(s), glidant(s), lubricants), stabilizers), and/or agent(s) for adjusting pH. In soft capsules, the active ingredients) themselves can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.

[0355] In some embodiments, the formulations can be in the form of a tablet or pill. Such forms can be shaped and dimensioned as desired. In certain embodiments, the formulations can be in the form of a tablet that is capsule-shaped. In certain embodiments, the formulations can be in the form of a tablet having a thickness of from about 2.0 to about 5.0 millimeters (mm) (e.g., about 3.0 mm or about 4.0 mm). In certain embodiments, the formulations can be in the form of a tablet having a length of from about 10.0 to about 16.0 millimeters (mm) (e.g., about 12.5 mm or about 14.5 mm). In certain embodiments, the formulations can be in the form of a tablet having a width of from about 4.0 to about 7.0 millimeters (mm) (e.g., about 5.0 mm or about 5.5 mm). In embodiments, the formulations can be in the form of a tablet having one, two, or three of the dimensions delineated above.

[0356] In certain embodiments, the formulations can be in the form of a “compressed tablet,” which as used herein refers to a plain, uncoated tablet for oral ingestion. Compressed tablet is typically prepared by a single compression or by pre-compaction tapping followed by a final compression (e.g., using a Carver press). The tablets can be scored and/or debossed with desired identifier markings. In some embodiments, the tablets can have a hardness of from about 7.0 to about 10.0 kp (e.g., about 8.1 kp or 9 kp).

[0357] In certain embodiments, the tablet can be a coated tablet.

[0358] For example, the coating may be prepared from one or more film-formers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose; one or more plasticizers such as polyethylene glycols, dibutyl sebacate, triethyl citrate; and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments, fillers and others.

[0359] As another example, tablets, pills and the like additionally can be prepared with enteric coatings, e.g., to provide a dosage form affording the advantage of prolonged action. The tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0360] As a further example, tablets can also be coated with a conventional coating material such as Opadry™ White YS-1-18027A (or another color).

[0361] In certain embodiments, the tablet can be a “suspension tablet,” which as used herein refers to compressed tablets which rapidly disintegrate after they are placed in water and are readily dispersible to form a suspension containing a precise dose of the active ingredient. In other embodiments, the tablet can be in the form of a rapidly disintegrating chewable tablet, lozenge, troche or swallowable tablet.

[0362J In some embodiments, the formulations can be in the form of a dragee cores, provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active ingredient doses.

[0363] The formulations can be prepared so as to provide quick, sustained or delayed release of the compositions after administration to the patient by employing procedures known in the art.

[0364J In general, the formulations can be prepared by any suitable and conventional method of pharmacy known in the art, which includes the step of bringing into association the active ingredient(s), one or more surfactants, and optionally and one or more other pharmaceutically-acceptable diluent(s), binders), disintegrant(s), glidant(s), lubricant(s), stabilizers), and/or agent(s) for adjusting pH. Methods of preparation can include one or a combination of methods including: (1) dry mixing, (2) direct compression, (3) milling, (4) diy or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986).

[0365] In some embodiments, the formulations can be obtained, for example, by performing one or more of the following steps: (i) combining (e g., uniformly and intimately admixing so as to disperse the active ingredient evenly throughout the composition, e.g., to facilitate subdivision of the formulation into unit dosage forms) the active ingredient, surfactant(s), and any other component(s) described herein to provide a mixture; (ii) screening, seiving, grinding, and/or milling the resulting mixture; (iii) processing the mixture of granules, after adding suitable auxiliaries, if desired; (iv) shaping and optionally coating the product to obtain tablets or dragee cores; or (v) adding the processed formulation to a vessel suitable for oral administration, such as a capsule.

[0366] In certain embodiments, the formulations can be prepared using wet granulation techniques known in the art, which can include the steps of milling and sieving of the ingredients, dry powder mixing, wet massing, granulation and final grinding. In some embodiments, the wet granulation techniques can better accommodate the micronized active ingredients and can result in formulations having enhanced powder flow (for encapsulation) and dissolution properties.

[0367J In other embodiments, the formulations can be prepared using dry granulation techniques known in the art, which involves compressing a powder mixture into a rough tablet or "slug" on a heavy-duty rotary tablet press. The slugs can then be broken up into granular particles by a grinding operation, usually by passage through an oscillation granulator. The individual steps include mixing of the powders, compressing (slugging) and grinding (slug reduction or granulation). Typically, no wet binder or moisture is involved in any of the steps.

[0368] In certain embodiments, compressed tablets can be prepared by compressing, in a suitable machine, the formulation in a free-flowing form, such as a powder or granules. Molded tablets can be made by molding, in a suitable machine, the powdered formulation moistened with an inert liquid diluent.

[0369] Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such formulations can also include, for example, wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[0370] Also provided herein are kits. Typically, a kit includes one or more compounds or compositions as described herein. In certain embodiments, a kit can include one or more delivery systems, e.g., for delivering or administering a compound as provided above, and directions for use of the kit (e.g., instructions for treating a patient). In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with cancer. In another embodiment, the kit can include a compound or composition as described herein and a label that indicates that the contents are to be administered to a patient with one or more of hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, rheumatoid arthritis, scleroderma, mycotic and viral infections, bone and cartilage diseases, Alzheimer’s disease, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Mullerian-duct regression and virilization, SERKAL syndrome, type Π diabetes, Fuhrmann syndrome, Al- Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha- thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome [0371] The actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

Methods of Treatment

[0372] The compounds and compositions provided herein can be used as inhibitors and/or modulators of one or more members of the Wnt pathway, which may include one or more Wnt proteins, and thus can be used to treat a variety of disorders and diseases in which aberrant Wnt signaling is implicated, such as cancer and other diseases associated with abnormal angiogenesis, cellular proliferation, and cell cycling. Accordingly, the compounds and compositions provided herein can be used to treat cancer, to reduce or inhibit angiogenesis, to reduce or inhibit cellular proliferation, to correct a genetic disorder, and/or to treat a neurological condition/disorder/disease due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Non-limiting examples of diseases which can be treated with the compounds and compositions provided herein include a variety of cancers, diabetic retinopathy, idiopathic pulmonaiy fibrosis (IFF), pulmonaiy fibrosis, rheumatoid arthritis, scleroderma, sarcoidosis, mycotic and viral infections, bone and cartilage diseases, neurological conditions/diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), motor neuron disease, Down’s syndrome, frontotemporal dementia (FTDP-17), Pick’s disease, surpanuclear palsy, corticobasal degeneration, multiple sclerosis or autism, lung disease, osteoarthritis, polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, retinal tumors, early coronary disease, tetra-amelia, Mxillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Nome disease and Rett syndrome.

[0373] With respect to cancer, the Wnt pathway is known to be constitutively activated in a variety of cancers including, for example, colon cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer , pancreatic cancer and leukemias such as CML, CLL, T-ALL, myelodysplastic syndromes and Mantle Cell Lympohomas. The constitutive activation is due to constitutively active β-catenin, perhaps due to its stabilization by interacting factors or inhibition of the degradation pathway. Accordingly, the compounds and compositions described herein may be used to treat these cancers in which the Wnt pathway is constitutively activated. In certain embodiments, the cancer is chosen from hepatocellular carcinoma, colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

[0374] Other cancers can also be treated with the compounds and compositions described herein.

[0375] More particularly, cancers that may be treated by the compound, compositions and methods described herein include, but are not limited to, the following:

[0376] 1) Breast cancers, including, for example ER⁺ breast cancer, ER^' breast cancer, her2^* breast cancer, her2⁺ breast cancer, stromal tumors such as fibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumors such as large duct papillomas; carcinomas of the breast including in situ (noninvasive) carcinoma that includes ductal carcinoma in situ (including Paget's disease) and lobular carcinoma in situ, and invasive (infiltrating) carcinoma including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, medullaiy carcinoma, colloid (mucinous) carcinoma, tubular carcinoma, and invasive papillary carcinoma; and miscellaneous malignant neoplasms. Further examples of breast cancers can include luminal A, luminal B, basal A, basal B, and triple negative breast cancer, which is estrogen receptor negative (ER^*), progesterone receptor negative, and hei2 negative (her2^'). In some embodiments, the breast cancer may have a high risk Oncotype score.

[0377] 2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma; fibroma; lipoma and teratoma. [0378] 3) Lung cancers, including, for example, bronchogenic carcinoma, e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

[0379] 4) Gastrointestinal cancer, including, for example, cancers of the esophagus, e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large bowel, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma.

[0380] 5) Genitourinary tract cancers, including, for example, cancers of the kidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, and leukemia; cancers of the bladder and urethra, e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, and lipoma.

[0381] 6) Liver cancers, including, for example, hepatoma, e.g., hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hepatocellular adenoma; and hemangioma.

[0382] 7) Bone cancers, including, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors.

[0383] 8) Nervous system cancers, including, for example, cancers of the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, e.g., meningioma, meningiosarcoma, and gliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors; and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma, and sarcoma. [0384] 9) Gynecological cancers, including, for example, cancers of the uterus, e.g., endometrial carcinoma; cancers of the cervix, e.g., cervical carcinoma, and pre tumor cervical dysplasia; cancers of the ovaries, e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors, Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma; cancers of the vulva, e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of the vagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embiyonal rhabdomyosarcoma; and cancers of the fallopian tubes, e.g., carcinoma.

[0385] 10) Hematologic cancers, including, for example, cancers of the blood, e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin's lymphoma, non-Hodgkin’s lymphoma (malignant lymphoma) and Waldenstrom's macroglobulinemia.

[0386] 11) Skin cancers and skin disorders, including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, desmoid tumors, and scleroderma.

[0387] 12) Adrenal gland cancers, including, for example, neuroblastoma.

[0388] Cancers may be solid tumors that may or may not be metastatic. Cancers may also occur, as in leukemia, as a diffuse tissue. Thus, the term “tumor cell,” as provided herein, includes a cell afflicted by any one of the above identified disorders.

[0389] A method of treating cancer using a compound or composition as described herein may be combined with existing methods of treating cancers, for example by chemotherapy, irradiation, or surgery (e.g., oophorectomy). In some embodiments, a compound or composition can be administered before, during, or after another anticancer agent or treatment.

[0390] The compounds and compositions described herein can be used as antiangiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer and other diseases associated with cellular proliferation mediated by protein kinases. Accordingly, provided herein is a method of treating cancer or preventing or reducing angiogenesis through kinase inhibition.

[0391] In addition, and including treatment of cancer, the compounds and compositions described herein can function as cell-cycle control agents for treating proliferative disorders in a patient. Disorders associated with excessive proliferation include, for example, cancers, scleroderma, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells

[0392] Diseases or disorders associated with uncontrolled or abnormal cellular proliferation include, but are not limited to, the following:

• a variety of cancers, including, but not limited to, carcinoma, hematopoietic tumors of lymphoid lineage, hematopoietic tumors of myeloid lineage, tumors of mesenchymal origin, tumors of the central and peripheral nervous system and other tumors including melanoma, seminoma and Kaposi's sarcoma.

• a disease process which features abnormal cellular proliferation, e.g., benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, atherosclerosis, arthritis, glomerulonephritis, restenosis following angioplasty or vascular surgery, inflammatory bowel disease, transplantation rejection, endotoxic shock, and fungal infections. Fibrotic disorders such as skin fibrosis; scleroderma; progressive systemic fibrosis; lung fibrosis; muscle fibrosis; kidney fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic scar formation; uterine fibrosis; renal fibrosis; cirrhosis of the liver, liver fibrosis; adhesions, such as those occurring in the abdomen, pelvis, spine or tendons; chronic obstructive pulmonary disease; fibrosis following myocardial infarction; pulmonaiy fibrosis; idiopathic pulmonaiy fibrosis (IFF); fibrosis and scarring associated with diffuse/interstitial lung disease; central nervous system fibrosis, such as fibrosis following stroke; fibrosis associated with neuro-degenerative disorders such as Alzheimer's Disease or multiple sclerosis; fibrosis associated with proliferative vitreoretinopathy (PVR); restenosis; endometriosis; ischemic disease and radiation fibrosis.

• defective apoptosis-associated conditions, such as cancers (including but not limited to those types mentioned herein), viral infections (including but not limited to herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), prevention of AIDS development in HTV-infected individuals, autoimmune diseases (including but not limited to systemic lupus eiythematosus, rheumatoid arthritis, scleroderma, autoimmune mediated glomerulonephritis, inflammatory bowel disease and autoimmune diabetes mellitus), neurodegenerative disorders (including but not limited to Alzheimer’s disease, lung disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's disease, AIDS-related dementia, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndromes, aplastic anemia, ischemic injury associated with myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

• genetic diseases due to mutations in Wnt signaling components, such as polyposis coli, bone density and vascular defects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia, Miillerian-duct regression and virilization, SERKAL syndrome, type II diabetes, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto- onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith- Wiedemann Syndrome and Rett syndrome.

[0393] Furthermore, the compounds and compositions described herein can be used to treat neurological conditions, disorders and/or diseases caused by dysfunction in the Wnt signaling pathway. Non-limiting examples of neurological conditions/disorders/diseases which can be treated with the compounds and compositions provided herein include Alzheimer's disease, aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attention deficit hyperactivity disorder, auditory processing disorder, autism, alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury, Canavan disease, carpal tunnel syndrome, causalgia, central pain syndrome, central pontine myelinolysis, centronuclear myopathy, cephalic disorder, cerebral aneurysm, cerebral arteriosclerosis, cerebral atrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis, cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiari malformation, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowry syndrome, complex regional pain syndrome, compression neuropathy, congenital facial diplegia, corticobasal degeneration, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulative trauma disorder, Cushing's syndrome, cytomegalic inclusion body disease (CIBD), Dandy-Walker syndrome, Dawson disease, De Morsieris syndrome, Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phase syndrome, dementia, dermatomyositis, developmental dyspraxia, diabetic neuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia, dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome, encephalitis, encephalocele, encephalotrigeminal angiomatosis, encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor, Fabiy's disease, Fahr's syndrome, familial spastic paralysis, febrile seizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville's syndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis, giant cell inclusion disease, globoid cell leukodystrophy, gray matter heterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy, Hallervorden-Spatz disease, hemifacial spasm, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis, herpes zoster oticus, herpes zoster, Hirayama syndrome, holoprosencephaly, Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism, hypoxia, immune-mediated encephalomyelitis, inclusion body myositis, incontinentia pigmenti, infantile phytanic acid storage disease, infantile Refsum disease, infantile spasms, inflammatory myopathy, intracranial cyst, intracranial hypertension, Joubert syndrome, Karak syndrome, Keams-Sayre syndrome, Kennedy disease, Kinsboume syndrome, Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru, Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffner syndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease, Lennox-Gastaut syndrome, Lesch- Nyhan syndrome, leukodystrophy, Lewy body dementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease, lumbar disc disease, lumbar spinal stenosis, Lyme disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly, macropsia, megalencephaly, Melkersson- Rosenthal syndrome, Menieres disease, meningitis, Menkes disease, etachromatic leukodystrophy, microcephaly, micropsia, Miller Fisher syndrome, misophonia, mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motor neurone disease, motor skills disorder, Moyamoya disease, mucopolysaccharidoses, multi-infarct dementia, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, muscular dystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclastic diffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus, myopathy, myotubular myopathy, myotonia congenital, narcolepsy, neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus, neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease, O'Sullivan-McLeod syndrome, occipital Neuralgia, occult Spinal Dysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy, opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension, palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita, paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome, Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy, photic sneeze reflex, phytanic acid storage disease, Pick's disease, polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome, postherpetic neuralgia (PHN), postural hypotension, Prader- Willi syndrome, primary lateral sclerosis, prion diseases, progressive hemifacial atrophy, progressive multifocal leukoencephalopathy, progressive supranuclear palsy, pseudotumor cerebri, Ramsay Hunt syndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome type III, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsum disease, restless legs syndrome, retrovirus-associated myelopathy, Rett syndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome, Saint Vitus dance, SandhofF disease, schizophrenia, Schilder's disease, schizencephaly, sensory integration dysfunction, septo-optic dysplasia, Shy- Drager syndrome, Sjogren's syndrome, snatiation, Sotos syndrome, spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy, spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome, Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacute sclerosing panencephalitis, subcortical arteriosclerotic encephalopathy, superficial siderosis, Sydenham's chorea, syncope, synesthesia, syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardive dysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus, tethered spinal cord syndrome, Thomsen disease, thoracic outlet syndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxic encephalopathy, transient ischemic attack, transmissible spongiform encephalopathies, transverse myelitis, tremor, trigeminal neuralgia, tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis, ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis (VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome, Williams syndrome, Wilson's disease and Zellweger syndrome.

[0394] The compounds and compositions may also be useful in the inhibition of the development of invasive cancer, tumor angiogenesis and metastasis.

[0395] In some embodiment, the invention provides a method for treating a disease or disorder associated with aberrant cellular proliferation by administering to a patient in need of such treatment an effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-l H- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine, in combination

(simultaneously or sequentially) with at least one other agent.

[0396J In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0397] In some embodiments, the method of treats a disorder or disease in which aberrant Wnt signaling is implicated in a patient, the method comprises administering to the patient a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine, or a pharmaceutically acceptable salt thereof.

[0398] In some embodiments, the disorder or disease is cancer.

[0399] In some embodiments, the disorder or disease is diabetic retinopathy.

[0400] In some embodiments, the disorder or disease is pulmonary fibrosis.

[0401] In some embodiments, the disorder or disease is idiopathic pulmonary fibrosis

(IFF).

[0402] In some embodiments, the disorder or disease is rheumatoid arthritis.

[0403] In some embodiments, the disorder or disease is scleroderma.

[0404] In some embodiments, the disorder or disease is a mycotic or viral infection.

[0405] In some embodiments, the disorder or disease is a bone or cartilage disease.

[0406] In some embodiments, the disorder or disease is Alzheimer's disease.

[0407] In some embodiments, the disorder or disease is dementia.

[0408] In some embodiments, the disorder or disease is Parkinson's disease.

[0409] In some embodiments, the disorder or disease is osteoarthritis.

[0410] In some embodiments, the disorder or disease is lung disease

[0411] In some embodiments, the disorder or disease is a genetic disease caused by mutations in Wnt signaling components, wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Mullerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas- Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split- hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha- thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader- Willi syndrome, Beckwith- Wiedemann Syndrome, Norrie disease and Rett syndrome.

[0412] In some embodiments, the patient is a human.

[0413] In some embodiments, the cancer is chosen from: hepatocellular carcinoma, colon cancer, breast cancer, pancreatic cancer, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

[0414] In some embodiments, the cancer is chosen from: lung cancer - non-small cell, lung cancer - small cell, multiple myeloma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer - basal and squamous cell, skin cancer - melanoma, small intestine cancer, stomach cancers, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestational trophoblastic disease, gastrointestinal stromal tumor, gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer, cervical cancer, brain or spinal cord tumor, bone metastasis, bone cancer, bladder cancer, bile duct cancer, anal cancer and adrenal cortical cancer.

[0415] In some embodiments, the cancer is hepatocellular carcinoma.

[0416] In some embodiments, the cancer is colon cancer.

[0417] In some embodiments, the cancer is breast cancer.

[0418] In some embodiments, the cancer is pancreatic cancer.

[0419] In some embodiments, the cancer is chronic myeloid leukemia (CML).

[0420] In some embodiments, the cancer is chronic myelomonocytic leukemia.

[0421] In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

[0422] In some embodiments, the cancer is acute myeloid leukemia.

[0423] In some embodiments, the cancer is acute lymphocytic leukemia.

[0424] In some embodiments, the cancer is Hodgkin lymphoma.

[0425] In some embodiments, the cancer is lymphoma.

[0426] In some embodiments, the cancer is sarcoma. [0427] In some embodiments, the cancer is ovarian cancer.

[0428] In some embodiments, the cancer is lung cancer - non-small cell.

[0429] In some embodiments, the cancer is lung cancer - small cell.

[0430] In some embodiments, the cancer is multiple myeloma.

[0431] In some embodiments, the cancer is nasopharyngeal cancer.

[0432] In some embodiments, the cancer is neuroblastoma.

[0433] In some embodiments, the cancer is osteosarcoma.

[0434] In some embodiments, the cancer is penile cancer.

[0435] In some embodiments, the cancer is pituitary tumors.

[0436] In some embodiments, the cancer is prostate cancer.

[0437] In some embodiments, the cancer is retinoblastoma.

[0438] In some embodiments, the cancer is rhabdomyosarcoma.

[0439] In some embodiments, the cancer is salivary gland cancer.

[0440] In some embodiments, the cancer is skin cancer - basal and squamous cell.

[0441] In some embodiments, the cancer is skin cancer - melanoma.

[0442] In some embodiments, the cancer is small intestine cancer.

[0443] In some embodiments, the cancer is stomach cancers.

[0444] In some embodiments, the cancer is testicular cancer.

[0445] In some embodiments, the cancer is thymus cancer.

[0446] In some embodiments, the cancer is thyroid cancer.

[0447] In some embodiments, the cancer is uterine sarcoma.

[0448] In some embodiments, the cancer is vaginal cancer.

[0449] In some embodiments, the cancer is vulvar cancer.

[0450] In some embodiments, the cancer is Wilms tumor.

[0451] In some embodiments, the cancer is laiyngeal or hypopharyngeal cancer.

[0452] In some embodiments, the cancer is kidney cancer.

[0453] In some embodiments, the cancer is Kaposi sarcoma.

[0454] In some embodiments, the cancer is gestational trophoblastic disease.

[0455] In some embodiments, the cancer is gastrointestinal stromal tumor.

[0456] In some embodiments, the cancer is gastrointestinal carcinoid tumor.

[0457] In some embodiments, the cancer is gallbladder cancer. [0458] In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

[0459] In some embodiments, the cancer is Ewing tumor.

[0460] In some embodiments, the cancer is esophagus cancer.

[0461] In some embodiments, the cancer is endometrial cancer.

[0462] In some embodiments, the cancer is colorectal cancer.

[0463] In some embodiments, the cancer is cervical cancer.

[0464] In some embodiments, the cancer is brain or spinal cord tumor.

[0465] In some embodiments, the cancer is bone metastasis.

[0466] In some embodiments, the cancer is bone cancer.

[0467] In some embodiments, the cancer is bladder cancer.

[0468] In some embodiments, the cancer is bile duct cancer.

[0469] In some embodiments, the cancer is anal cancer.

[0470] In some embodiments, the cancer is adrenal cortical cancer.

[0471] In some embodiments, the disorder or disease is a neurological condition, disorder or disease, wherein the neurological condition/disorder/disease is selected from: Alzheimer's disease, frontotemporal dementias, dementia with lewy bodies, prion diseases, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, amyotrophic lateral sclerosis (ALS), inclusion body myositis, autism, degenerative myopathies, diabetic neuropathy, other metabolic neuropathies, endocrine neuropathies, orthostatic hypotension, multiple sclerosis and Charcot-Marie-Tooth disease.

[0472] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) inhibits one or more proteins in the Wnt pathway.

[0473] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethan amine (including Form A, B, C, D, E, and/or F) inhibits signaling induced by one or more Wnt proteins.

[0474] In some embodiments, the Wnt proteins are chosen from: WNT 1 , WNT2, WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16. [0475] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F) inhibits a kinase activity.

[0476] In some embodiments, the method of treats a disease or disorder mediated by the Wnt pathway in a patient, the method comprises administering to the patient a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0477] In some embodiments, l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A,

B, C, D, E, and/or F) inhibits one or more Wnt proteins.

[0478] In some embodiments, the method of treats a disease or disorder mediated by kinase activity in a patient, the method comprises administering to the patient a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0479] In some embodiments, the disease or disorder comprises tumor growth, cell proliferation, or angiogenesis.

[0480] In some embodiments, the method of inhibits the activity of a protein kinase receptor, the method comprises contacting the receptor with an effective amount of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine (including Form A, B, C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the method treats a disease or disorder associated with aberrant cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B,

C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the method prevents or reduces angiogenesis in a patient; the method comprises administering to the patient a therapeutically effective amount of l-(5-(3- (7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3- yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the method prevents or reduces abnormal cellular proliferation in a patient; the method comprises administering to the patient a therapeutically effective amount of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (including Form A, B, C, D, E, and/or F), or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the method of treats a disease or disorder associated with aberrant cellular proliferation in a patient, the method comprising administering to the patient a pharmaceutical composition comprising one or more polymorphs or solvates of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine (including Form A, B, C, D, E, and/or F) in combination with a pharmaceutically acceptable carrier and one or more other agents

[0485] Moreover, the compounds and compositions, for example, as inhibitors of the cyclin-dependent kinases (CDKs), can modulate the level of cellular RNA and DNA synthesis and therefore are expected to be useful in the treatment of viral infections such as HTV, human papilloma virus, herpes virus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and the like.

[0486] Compounds and compositions described herein can inhibit the kinase activity of, for example, CDK/cyclin complexes, such as those active in the G.o, G.i or mitotic stage of the cell cycle, e.g., CDK1, CDK2, CDK4, and/or CDK6 complexes.

Evaluation of Biological Activity

[0487] The biological activity of the compounds described herein can be tested using any suitable assay known to those of skill in the art, e.g., WO 2001/053268 or WO 2005/009997. For example, the activity of a compound may be tested using one or more of the test methods outlined below.

[0488] In one example, tumor cells may be screened for Wnt independent growth. In such a method, tumor cells of interest are contacted with a compound (i.e. inhibitor) of interest, and the proliferation of the cells, e.g. by uptake of tritiated thymidine, is monitored. In some embodiments, tumor cells may be isolated from a candidate patient who has been screened for the presence of a cancer that is associated with a mutation in the Wnt signaling pathway. Candidate cancers include, without limitation, those listed above. [0489] In another example, one may utilize in vitro assays for Wnt biological activity, e.g. stabilization of β-catenin and promoting growth of stem cells. Assays for biological activity of Wnt include stabilization of β-catenin, which can be measured, for example, by serial dilutions of a candidate inhibitor composition. An exemplary assay for Wnt biological activity contacts a Wnt composition in the presence of a candidate inhibitor with cells, e.g. mouse L cells. The cells are cultured for a period of time sufficient to stabilize β-catenin, usually at least about 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, then transferred to nitrocellulose and probed with antibodies specific for β-catenin. [0490] In a further example, the activity of a candidate compound can be measured in a Xenopus secondary axis bioassay (Leyns, L. etal. Cell (1997), 88(6), 747-756). [0491] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. Variations of these examples within the scope of the claims are within the purview⁷ of one skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.

EXAMPLES

Example 1 Manufacturing Process for Preparation of Amorphous 1-(5-(3-{7-{3- -3H-imidazof4.5-clpvridm-2-vI)-1H-pvrazoIo[3,4-b]pvridii-5-yI)pvridm-3-yI)-

Ν,Ν-dimethyImethanamine.

Abbreviations:

~ = to aq. or aq === aqueous

CDI = carbonyldiimidazole

CSTR = continuous stirred tank reactor

DCM = dichloromethane E A = ethyl acetate EtOH = ethanol h = hours

IP Ac = isopropyl acetate

KF = moisture content of solvent, solution, or mixture KOAc = potassium acetate 2-MeTHF = 2-methyltetrahydrofuran min = minutes

MTBE = methyl tert-butyl ether NMP = N-methylpyrrolidinone Pd/C = palladium on carbon

Pd(dppf)Ch = (l,l'-Bis(diphenylphosphino)fenocene)palladium(II) di chloride R = reactor T = tank pTsOH · H2O = para-toluene sulfonic acid monohydrate TEA = tri ethyl amine THF = tetrahydrofuran X = weight equivalents

[0492] The manufacturing process of l-(5-(3-(7-(3-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine is based on a convergent synthetic strategy involving three key intermediates: compound 4, compound 9, and compound 15. Compound 4 was prepared from 1 in two steps reaction as shown in Scheme 1. Compound 9 was prepared from compound 5 using three steps chemical transformation as shown in Scheme 2. Compound 15 was prepared from compound 10 using a 4-step chemical transformation. Then Compound 15 was reacted with compound 4 to obtain intermediate compound 16. Compound 16 was further reacted with intermediate compound 9 to obtain compound 17. Finally, the deprotection of compound 17 gave amorphous form of compound 18 as shown in Scheme 3.

[0493] Scheme 1. Preparation of Compound 4.

Scheme 2. Preparation of Compound 9.

[0494] Scheme 3. Preparation of 1 -(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- 1H- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine (18).

STEP 1:

STEP 2:

STEP 3:

STEP 4:

STEP 5:

STEP 6:

STEP 7

STEP 8

STEP 9

STEP 10

STEP 11

STEP 12

H

[0495] Off-white solid (39 mg, 0.08 mmol, 76.4% yield). ¹H NMR (DMSO-d6, 500 MHz) δ ppm 2.25 (s, 6H), 3.58 (s, 2H), 7.31 (t, J=8Ηz, 1H), 7.61 (q, J=7Ηz, 1H), 8.12 (s, 1H), 8.20 (d, J=8Hz, 1H), 8.37 (d, J=10Hz, 1H), 8.60 (s, 1H), 8.76 (s, 1H), 8.89 (s, 1H), 8.98 (s, 1H), 9.10 (s, 2H), 13.91 (s, 1H), 14.61 (s, 1H); ESIMS found C26H21FN8 m/z 465.3 (M+H).

[0496] As can be appreciated by the skilled artisan, further methods of synthesizing 1-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fiesefs Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

Example 2: Polymorph screen

[0497] A polymorph screen was performed on l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine to determine solubility, polymorphism, and thermodynamic stability.

Materials and Methods

[0498] Samples were run on XRPD using the methods below:

[0499] X-ray Powder Diffractometer (XRPD) Method 1 Details

[0500] Tube: Cu: K- Alpha (λ=1.54179λ).

[0501] Generator: Voltage: 40 kV; Current: 40 mA.

[0502] Scan Scope: 2 to 40 deg.

[0503] Sample rotation speed: 15 rpm.

[0504] Scanning rate: 10°/min or others.

[0505] X-ray Powder Diffractometer (XRPD) Method 2 Details

[0506] Tube: Cu: K- Alpha (λ=1.54059Α).

[0507] Generator: Voltage: 40 kV; Current: 40 mA.

[0508] Scan range: 1.00 to 39.99° 2Θ.

[0509] Step size: 0.017° 2Θ

[0510] Collection time: 722 s

[0511] Scan speed: 3.2°/min [0512] Revolution time: 1.0 s [0513] Unless otherwise indicated, all XRPD data was obtained using method 1.

[0514] Differential Scanning Calorimetric (DSC)

[0515] Details of the DSC method used in the characterization of forms obtained from the experiments:

[0516] Samples (1~ 2 mg) were tested using a hermetic aluminum pan with pinhole and heated from 25°C to 250°C at a rate of 10°C/min under 50 mL/min of N2.

Thermal Gravimetric Analysis (TGA)

[0517] Details of the TGA method used in the characterization of forms obtained from the experiments:

[0518] Samples (3 ~ 5 mg) were placed in an open platinum pan and heated from 30°C to 300°C or weight % < 80% at a rate of 10°C/min under 25 mL/min ofNz.

Polarized Light Microscope (PLM)

[0519] Details of polarized light microscope method used in the characterization of forms obtained from the experiments:

[0520] Nikon LVIOOPOL equipped with 5 megapixel CCD.

[0521] Physical Lens: 10X/20X.

Analysis of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c] pyridin-2-yI)-lH-pyrazolo[3,4- b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine obtained directly after its synthesis

[0522] X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) scans of the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5- c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine indicated that it was amorphous. FIG. 1 is an X-ray powder diffractogram of the l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- Ν,Ν-dimethylmethanamine. FIG. 2 is a differential scanning calorimetry thermogram of the l-(5- (3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin- 3-yl)-N,N-dimethylmethanamine . FIG. 3 is a thermogravimetric analysis thermogram of the 1- (5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5- yl)pyridin-3 -yl)-N,N-dimethylmethanamine .

B. Test Conditions

[0523J Approximate solubility at 25X! and 50"C

[0524] About 2 mg of the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as directly obtained after synthesis was weighed and dissolved with a minimal amount of solvent to determine solubility at 25°C and 50°C. The experiments were performed by manual dilution combined with visual observation.

Equilibration with solvents at 25X1 for 1 week

[0525] About 50 mg of drug substance was equilibrated in 0.5-2.0 mL of solvent at 25°C for 1 week with a stirring plate or an Eppendorf shaker. Obtained suspensions were filtered. The filtered solid was investigated by XRPD. When differences were observed, additional investigation was performed (by means of, e.g., DSC, TGA, and *13 NMR).

Equilibration with solvents at 50°C for 1 week

[0526] The procedure was the same as that used in “Equilibration with solvents at 25°C for 1 week” except the temperature at which the experiment was performed was 50°C.

Photostability experiment and data:

[0527] Approximately 100 mg each of amorphous l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine as directly obtained after synthesis and Form A were placed in Suprasil EPR tubes (Wilmad Lab glass 727-SQ-100M, 100 mm length, 4.0 mm OD, 2.4 mm±0.2 ID- Suprasil cut-off wavelength is 190 nm) providing for two tubes containing the amorphous lot and two tubes containing Form A. The tubes were capped with a plastic cap provided with each tube. Before exposing the tubes, one of the tubes in each lot was covered with aluminum foil to be used as a control. The tubes were placed in a photostability chamber. The chamber contained both visible and UV lamps. The UV spectrum ranges from 320-400 nm, with maximum energy near 350 nm wavelength. Exposure was confirmed by actinometry using a 2% (w/v) aqueous quinine monohydrochloride solution. The tubes with the control and test samples remained in the chamber until the actinometer indicated that the International Conference on Harmonization (ICH) requirements for both 1.2 million lux hours as well as an integrated 200 W hours/m² for UV exposure were met. Then the purity and impurity profiles of the samples were analyzed by HPLC.

Precipitation by addition of anti-solvent

[0528J About 50 mg of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as directly obtained after synthesis was dissolved in a solvent in which its solubility is high. To the obtained solutions were added solvents in which the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyiidin-3-yl)-N,N-dimethylmethanamine is insoluble or is of low solubility. Precipitates were collected by filtration and analyzed.

C. Forms Obtained.

[0529J The table below includes some properties of some of the Forms obtained.

[0530] The table below lists XRPD’s, thermograms, and ¹H NMR spectra of Forms A-F.

[0531] The table below lists polarized light microscopy scans of l-(5-(3-(7-(3- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3- yl)-N,N-dimethylmethanamine as obtained after synthesis and Form A.

[0532] The table below lists peaks and associated information in the XRPD of Form A

(method 1).

[0533] The table below lists peaks and associated information in the XRPD of Form A

(method 2).

[0534] The table below lists some higher intensity peaks and associated information in the XRPD of Form A (method 2).

[0535] The table below lists peaks and associated information in the XRPD of Form B

(method 1).

[0536J The table below lists peaks and associated information in the XRPD of Form C

(method 1).

[0537] The table below lists peaks and associated information in the XRPD of Form D

(method 1).

[0538] The table below lists peaks and associated information in the XRPD of Form E

(method 1).

[0539] The table below lists peaks and associated information in the XRPD of Form F

(method 1).

E. Experimental Results.

[0540] Approximate solubility at 25°C and 50°C.

[0541] The results of the solubility screen are shown in Table 2. The l-(5-(3-(7-(3- fluorophenyl)-3H-iniidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)- N,N-dimethylmethanamine as directly obtained after synthesis exhibited high solubility in DMSO and NMP, and low solubility in all other solvents screened.

Table 2 Approximate solubility measurement at 25°C and 50°C

[0542] Equilibration with solvents at 25°C and 50 °Cfor 1 week [0543] Table 3 depicts the outcome of equilibration experiments at 25°C and 50°C. The results suggest that high temperature accelerates the crystallization from amorphous form to crystalline form. Pattern D could be a hydrate containing about 2% water from Ή NMR and TGA.

Table 3 Equilibration with solvents at 25°C and 50°C for 1 week

Precipitation by addition of anti-solvent

[0544] The results of precipitation of the l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5- c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as direcdy obtained after synthesis by anti-solvent are shown in Table 4. Table 4 Precipitation by addition of anti-solvent

Competitive slurry experiments

[0545J Three experiments were performed separately in three solvent systems to understand relative stability of Form A and Form F (Table 5). A mixture of Form A and Form F (1:1, w/w) was suspended in the solvent of each experiment and stirred at 50°C. The solids were filtered and analyzed by XRPD (method 1). Complete conversion to Form A was observed in DMSO over 2 days while a mixture of Form A and Form F were observed in isopropyl alcohol (IPA) and DMSO/EA binary mixture over 4 days. Slower conversion may due to relatively low solubility and slow conversion kinetics. The results indicate that Form A is thermodynamically more stable than Form F.

Table 5 Competitive slurry experiments (50 °C) Form A and F

Stability data:

[0546] Form A was stored at ambient room temperature and humidity, then tested for purity after 1 year and after 4.5 years of the storage. Form A did not show any appreciable changes in the purity and impurities profiles after 1 year and 4.5 years of storage (Table 6). RRT = relative retention time.

[0547] Table 6: Comparison of Purity of Form A After 1 and 4.5 Years of Bulk

Storage

[0548] The amorphous form of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine as directly obtained after synthesis was stored at ambient room temperature and humidity and was retested after 1 year, after 2 years, and after 3 years of storage. Unlike Form A, this amorphous form showed an increase in the amount of two impurities at RRT 0.97 and 1.06 (see Table 7).

[0549] Table 7: Comparison of Purity of Amorphous l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo [4,5-c] pyridin-2-yl}-l H-pyrazolo [3,4-b] pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine After 1 Year, 2 Years, and 3 Years in Storage.

Photostability experiment and data:

[0550] The results of the experiment are shown in Table 8, which demonstrates that the amorphous form degraded significantly when exposed to light while the change in the impurity profile of Form A is insignificant.

[0551] Table 8: Results of Photo Degradation Study of Form A.

Water activity experiments

[0552] Table 9 shows the results of water activity experiments of Form A and Form D in Acetone/HzO. The results showed that hydrate Form D is more stable in acetone/water mixtures where water activity is >0.5 at both 25°C and 50°C. This suggests that the exposure to water should be carefully controlled during manufacturing.

Table 9 Water activity experiments (Forms A and D)

Example 3: Manufacturing Protocol for Preparation of Form A

[0553] Abbreviations:

DMAc = Ν,Ν-dimethylacetaxnide EtOH = ethanol h = hour(s)

R1 = Reactor 1 R2 = Reactor 2

X = weight equivalents

[0554J Manufacturing Protocol:

1. Washed R1 with EtOH.

2. Adjusted temperature of R1 to 45-55°C under nitrogen.

3. Charged l.OX of amorphous l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine into R1.

4. Charged 14.1-14.2X of DMAc into R1 through a cartridge filter (Cartridge filter).

5. Adjusted R1 to 45-55°C under nitrogen.

6. Stirred R1 for from 5-120 min at 45-55°C until all the solid was dissolved under nitrogen.

7. Charged 0.001-0.010X of Form A crystal seeds into R1 under nitrogen.

8. Stirred R1 at 45-55°C for 20-30 min under nitrogen.

9. Cooled R1 to 23-28°C over 2.0-3.0 h under nitrogen.

10. Added 8.8-9.0X of EtOH dropwise to R1 over 5-6 h through a cartridge filter with peristaltic pump under nitrogen.

11. Cooled R1 to 5-15°C over 3-4 h under nitrogen.

12. Stirred R1 at 5-15°C for 5-7 h under nitrogen.

13. Filtered material of R1 using centrifuge.

14. Charged 3.2-3.3 X of DMAc/EtOH (1:5) solution through Cartridge filter to wash the wet cake inside centrifuge

15. Charged 3.1-3.2X of EtOH through Cartridge filter to the centrifuge and spin 30-50 min to wash the cake inside the centrifuge. 16. Charged 3.1-3.2X ofEtOH again through Cartridge filter to wash the cake over 30-50 min.

17. Took sample of wet cake for purity and XRPD.

18. Took sample of mother liquor for Q residual test.

19. Dried wet product under vacuum at 45-50°C for 16-24 h under a flow of nitrogen.

20. Cleaned R1 with MeOH.

21. Charged 9.75-9.95 X of MeOH into R1 through Cartridge filter.

22. Adjusted R1 to 10-20°C under nitrogen.

23. Charged 0.001-0.010X of Form A crystal seeds into R1 under nitrogen.

24. Cleaned R2 with NMP.

25. Charged 1/3 part of solids from Step 19 into R2.

26. Charged 6.2-6.3X of NMP into R2 through Cartridge filter.

27. Adjusted R2 to 30-45°C under nitrogen.

28. Stirred R2 at 30-45°C until all solids dissolved completely.

29. Transferred the 30-45°C solution of R2 drop-wise into R1 through Cartridge filter.

30. Charged 0.1-1.0 X of NMP into R2 through Cartridge filter.

31. Adj usted R2 to 30-45°C under nitrogen.

32. Transferred the 30-45°C solution dropwise into R1 through Cartridge filter.

33. Stirred R1 at 10-20°C for 4-8 h under nitrogen.

34. Sampled the reaction mixture separate solids and check XRPD of the solid.

35. Filtered material of R1 by centrifuge.

36. Charged 0.79-0.80X of MeOH through Cartridge filter into centrifuge and spin 30-50 min to wash the cake inside the centrifuge.

37. Charged 0.79-0.80X of MeOH through Cartridge filter to wash the cake over 30-50 min.

38. Repeated Step 25-Step 37 twice with other two portions (1/3 each) solids of step 19.

39. Combined material of Step 37-Step 38

40. Charged Step 39 wet cake into R1.

41. Charged 9.75-9.95X of MeOH through Cartridge filter.

42. Adjusted R1 to 10-20°C under nitrogen.

43. Stirred R1 at 10-20°C for 8-12 h under nitrogen.

44. Sampled the reaction mixture separate solids and check XRPD of the solid.

45. Stirred R1 at 10-20°C for 8-12 h under nitrogen. 46. Sampled the reaction mixture separate solids and check XRPD of the solid.

47. Filtered material of R1 using centrifuge.

48. Charged 0.79-0.80X of MeOH through Cartridge filter (Ft-1) into the centrifuge and spin for 30-50 min to wash the cake inside it.

49. Charged 0.79-0.80X of MeOH again through Cartridge filter (Ft-1) into the centrifuge and spin for 30-50 min to wash the cake..

50. Charged wet cake from centrifuge of Step 49 into R1.

51. Charged 9.5-10.0X of mixture solvent (acetone/MTBE=2: 1) into R1 through Cartridge filter (Ft-1).

52. Adjusted R1 to 23-28°C under nitrogen.

53. Stirred R1 at 23-28°C for 8-12 h under nitrogen.

54. Sampled the reaction mixture separate solids and check XRPD of the solid. If the results meet the specification (XRPD matches with that of Form A), do Step 57; otherwise, do Step

55

55. Stirred R1 at 23-28°C for 8-12 h under nitrogen.

56. Sampled the reaction mixture separate solids and check XRPD of the solid.

57. Filtered material of R1 using centrifuge.

58. Charged 1.5-1.6X of mixture solvent (acetone/MTBE=2: 1) through Cartridge filter (Ft-1) into centrifuge and spin for 30-50 min to wash the cake into it.

59. Charged 1.5-1.6X of mixture solvent (acetone/MTBE=2:l) again through Cartridge filter (Ft-1) to wash the cake over 30-50 min.

60. Dried wet product under vacuum at 45-50 °C for 20-48 h under a nitrogen stream.

Example 4: in vitro studies

A. Wnt pathway inhibition

[0555] Form A, B, C, D, E, and/or F can be screened for Wnt activity. The screening assay that can be used is described as follows. Reporter cell lines are generated by stably transducing cancer cell lines (e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells) with a lentiviral construct that included a Wnt-responsive promoter driving expression of the firefly luciferase gene. [0556] SW480 colon carcinoma cells are transduced with a lentiviral vector expressing luciferase with a human Sp5 promoter consisting of a sequence of eight TCF/LEF binding sites. SW480 cells stably expressing the Sp5-Luc reporter gene and a hygromycin resistance gene are selected by treatment with 150 pg/mL of hygromycin for 7 days. These stably transduced SW480 cells are expanded in cell culture and used for all further screening activities. Form A, B, C, D, E, and/or F is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 10-point dose-response curves starting from 10 μΜ) and compound transfer is performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well white solid bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. For Sp5-Luc reporter gene assays, the cells are plated at 4,000 cells/well in 384-well plates with a DMEM medium containing 1% fetal bovine serum, and 1% Penicillin-Streptomycin and incubated for 36 to 48 hours at 37°C and 5% CO2. Following incubation, 15 μΐ of BriteLite Plus luminescence reagent (Perkin Elmer) is added to each well of the 384-well assay plates. The plates are placed on an orbital shaker for 2 min and then luminescence is quantified using the Envision (Peridn Elmer) plate reader. Readings are normalized to DMSO only treated cells, and normalized activities are utilized for ECso calculations using the dose-response log (inhibitor) vs. response -variable slope (four parameters) nonlinear regression feature available in GraphPad Prism 5.0 (or Dotmatics).

[0557] The results can show that there is a decrease in Wnt activity with an increase in the concentration of Form A, B, C, D, E, and/or F.

B. DYRK1A kinase inhibition

[0558] Form A, B, C, D, E, and/or F is screened for DYRKIA kinase activity. The screening assay is described as follows.

[0559] Form A, B, C, D, E, and/or F is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 11 -point dose-response curves from 10 μΜ to 0.00016 μΜ) and compound transfer is performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).

[0560] The DYRKIA kinase assay is run using the Ser/Thr 18 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission/fluorescein emission.

[0561] Briefly, recombinant DYRK1A kinase, ATP and Ser/Thr peptide 18 are prepared in IX Kinase buffer to final concentrations of 0.19 pg/mL, 30 μΜ, and 4 μΜ respectively. The mixture is allowed to incubate with Form A B, C, D, E, and/or F for one hour at room temperature. All reactions are performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“ 100% control”) forms of Ser/Thr 18 served as control reactions. Additionally, an 11 -point dose- response curve of Staurosporine (1 μΜ top) is mn to serve as a positive compound control.

[0562] After incubation, Development Reagent A is diluted in Development Buffer then added to the reaction and allowed to further incubate for one hour at room temperature. The plate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).

[0563] The Emission ratio (Em) is calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation is then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (F100% - F0%)))]. Dose-response curves are generated and inhibitory concentration (ICso) values are calculated using non-linear regression curve fit in the Dotmatics’ Studies

Software (Bishops Stortford, UK).

[0564] The results can show that there is a decrease in DYRK1A kinase activity with an increase in the concentration of Form A, B, C, D, E, and/or F.

C. GSK3P kinase inhibition

[0565] Form A, B, C, D, E, and/or F is screened for Θ8Κ3β kinase activity. The screening assay is described as follows.

[0566] Form A B, C, D, E, and/or F is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 11 -point dose-response curves from 10 μΜ to 0.0003 μΜ) and compound transfer is performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).

[0567] The 08Κ3β kinase assay is mn using the Ser/Thr 09 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a non-radioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as ratio of coumarin emission/fluorescein emission.

[0568] Briefly, recombinant GSK3p kinase, ATP and Ser/Thr peptide 09 are prepared in IX Kinase buffer to final concentrations of 0.04 pg/mL, 46 μΜ, and 4 μΜ respectively. The mixture is allowed to incubate with the Form A, B, C, D, E, and/or F for one hour at room temperature. All reactions are performed in duplicate. Unphosphorylated (“0% Control”) and phosphoiylated (“100% control”) forms of Ser/Thr 18 serve as control reactions.

[0569] After incubation, diluted Development Buffer is added to the reaction and allowed to further incubate for one hour at room temperature. The plate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).

[0570] The Emission ratio (Em) is calculated as a ratio of the coumarin (C) emission signal

(at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation is then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (F100% - F0%)))].

[0571] Dose-response curves are generated and inhibitory concentration (ICso) values are calculated using non-linear regression curve fit in the Dotmatics’ Studies Software (Bishops Stortford, UK).

[0572] The results showed that there is a decrease in GSK3p kinase activity with an increase in the concentration of Form A, B, C, D, E, and/or F, with an ICso of 4.5 nM.

D. CLK2 kinase inhibition

[0573] Form A, B, C, D, E, and/or F can be screened for CLK2 kinase activity. The screening assay is described as follows.

[0574] Form A, B, C, D, E, and/or F is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:3, 11 -point dose-response curves from 10 μΜ to 0.00016 μΜ) and compound transfer is performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 1536-well black-walled round bottom plates (Coming).

[0575] The CLK2 ldnase assay is run using the Ser/Thr 6 peptide Z-lyte assay kit according to manufacturer’s instructions (Life Technologies- a Division of Thermo-Fisher). This is a nonradioactive assay using fluorescence resonance energy transfer (FRET) between coumarin and fluorescein to detect kinase activity which is represented as a ratio of coumarin emission/fluorescein emission.

[0576] Briefly, recombinant CLK2 kinase, ATP and Ser/Thr peptide 6 are prepared in 1 X Kinase buffer to final concentrations of 0.43 pg/mL, 60 μΜ, and 4 μΜ respectively. The mixture is allowed to incubate with Form A, B, C, D, E, and/or F for one hour at room temperature. All reactions are performed in duplicate. Unphosphorylated (“0% Control”) and phosphorylated (“100% control”) forms of Ser/Thr 6 served as control reactions. Additionally, an 11 -point dose- response curve of Staurosporine (luM top) is run to serve as a positive compound control.

[0577] After incubation, Development Reagent A is diluted in Development Buffer then added to the reaction and allowed to further incubate for one hour at room temperature. The plate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400 Em 520 to measure the signal (EnVision Multilabel Plate Reader, PerkinElmer).

[0578] The Emission ratio (Em) is calculated as a ratio of the coumarin (C) emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm). The percent phosphorylation is then calculated using the following formula: [1 - ((Em ratio X F100%)-C100%)/ ((C0%-C100%) + (Em ratio X (F 100% - F0%)))]. Dose-response curves are generated and inhibitory concentration (ICso) values are calculated using non-linear regression curve fit in the Dotmatics’ Studies Software

(Bishops Stortford, UK). [0579] The results can show that there is a decrease in CLK2 kinase activity with an increase in the concentration of Form A, B, C, D, E, and/or F.

E. Fibrotic activity inhibition

[0580] Form A, B, C, D, E, and/or F is screened using primary human fibroblasts (derived from IFF patients) treated with TGF-βΙ to determine their ability to inhibit the fibrotic process.

[0581] Human Fibroblast Cell Culture'. Primaiy human fibroblasts derived from IFF patients (LL29 cells) [Reference 1: Xiaoqiu Liu, etal., “Fibrotic Lung Fibroblasts Show Blunted Inhibition by cAMP Due to Deficient cAMP Response Element-Binding Protein Phosphorylation”, Journal of Pharmacology and Experimental Therapeutics (2005), 315(2), 678- 687; Reference 2: Watts, K. L., et.al., “RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis”, Respiratory Research (2006), 7(1), 88] are obtained from American Type Culture Collection (ATCC) and expanded in F12 medium supplemented with 15% Fetal Bovine Serum and 1% Penicillin/Streptomycin.

[0582J Form A, B, C, D, E, and/or F is dissolved in DMSO as a 10 mM stock and used to prepare compound source plates. Serial dilution (1:2, 11 -point dose-response curves from 10 μΜ to 0.94 nM) and compound transfer is performed using the ECHO 550 (Labcyte, Sunnyvale, CA) into 384-well clear bottom assay plates (Greiner Bio-One) with appropriate DMSO backfill for a final DMSO concentration of 0.1%. LL29 cells are plated at 1,500 cells/well in 70 pL/well F12 medium supplemented with 1% Fetal Bovine Serum. TGF-βΙ (Peprotech; 20 ng/mL) is added to the plates to induce fibrosis (ref. 1 and 2 above). Wells treated with TGF-βΙ and containing DMSO are used as positive control, and cells with only DMSO are negative control. Cells are incubated at 37°C and 5% CO2 for 4 days. Following incubation for 4 days, SYTOX green nucleic acid stain (Life Technologies [Thermo Fisher Scientific]) is added to the wells at a final concentration of 1 μΜ and incubated at room temperature for 30 min. Cells are then fixed using 4% formaldehyde (Electron Microscopy Sciences), washed 3 times with PBS followed by blocking and permeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS. Cells are then stained with antibody specific to a-smooth muscle actin (aSMA; Abeam) (ref. 1 and 2 above) in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS, and incubated overnight at 4°C. Cells are then washed 3 times with PBS, followed by incubation with Alexa Flor-647 conjugated secondary antibody (Life Technologies [Thermo Fisher Scientific]) and DAPI in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) in PBS at room temperature for 1 hour. Cells are then washed 3 times with PBS and plates are sealed for imaging. aSMA staining is imaged by excitation at 630 nm and emission at 665 nm and quantified using the Compartmental Analysis program on the Celllnsight CX5 (Thermo Scientific). Dead or apoptotic cells are excluded from analysis based on positive SYTOX green staining. % of total cells positive for aSMA are counted in each well and normalized to the average of 11 wells treated with TGF-βΙ on the same plate using Dotmatics’ Studies Software. The normalized averages (fold change over untreated) of 3 replicate wells for each compound concentration are used to create dose-responses curves and ECso values are calculated using nonlinear regression curve fit in the Dotmatics’ Studies Software.

[0583] The results can show that there is a decrease in fibrotic activity with an increase in the concentration of Form A, B, C, D, E, and/or F.

Claims

WHAT IS CLAIMED IS:

1. A crystalline polymorph of 1 -(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the polymorph is Form A and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.4.

2. The polymorph of claim 1, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ at about 24.7.

3. The polymorph of any one of claims 1-2, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ at about 22.1.

4. The polymorph of any one of claims 1-3, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ at about 2.2.

5. The polymorph of claim 1, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 6.4, about 22.1, and about 24.7.

6. The polymorph of claim 1, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ occurs at about 2.2, about 6.4, about 22.1, and about 24.7.

7. The polymorph according to any one of claims 1-6, wherein the X-ray powder diffraction pattern also comprises from 1-13 of the following characteristic peaks expressed in degrees 2Θ: about 2.4, about 2.7, about 11.7, about 13.0, about 16.0, about 18.7, about 20.1, about 20.8, about 21.9, about 23.2, about 28.3, about 29.0, and about 30.2.

8. The polymorph according to any one of claims 1-6, wherein the X-ray powder diffraction pattern also comprises from 1-20 of the following characteristic peaks expressed in degrees 2Θ: about 2.4, about 2.7, about 11.7, about 12.2, about 12.8, about 13.0, about 16.0, about 16.4, about 16.6, about 17.7, about 18.7, about 20.1, about 20.8, about 21.9, about 23.2, about 24.0, about 28.3, about 28.6, about 29.0, and about 30.2.

9. The polymorph of claim 1, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 4.

10. The polymorph of any one of claims 1 -9, wherein the polymorph also has a differential scanning calorimetry pattern comprising a melting onset of about 343°C.

11. The polymorph of any one of claims 1-9, wherein the polymorph also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 5.

12. The polymorph of any one of claims 1-11, wherein the polymorph is in substantially pure form.

13. The polymorph of any one of claims 1-12, wherein the polymorph is prepared by a method consisting of:

(a) recrystallizing l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine from a solution comprising Ν,Ν-dimethylacetamide and ethanol to provide a first solid;

(c) combining the second solid with methanol to provide a third solid; and

14. The polymorph of any one of claims 1-13, wherein the polymorph is prepared by antisolvent addition of ethyl acetate to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N- dimethylmethanamine in N-methyl pyrrolidinone.

15. The polymorph of any one of claims 1-13, wherein the polymorph is prepared by agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: ethyl acetate, acetone, methyl ethyl ketone, t-butyl methyl ether, acetonitrile, tetrahydrofuran, dimethylsulfoxide, a 95:5 v/v solution of ethyl acetate:dimethylsulfoxide, and N,N-dimethylformamide.

16. A pharmaceutical composition comprising the polymorph of any one of claims 1-15, and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising the polymorph of any one of claims 1-15; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

18. A crystalline methanol solvate of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin- 2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the solvate is Form B and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.4.

19. The solvate of claim 18, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 17.6.

20. The solvate of any one of claims 18-19, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 25.6.

21. The solvate of any one of claims 18-20, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 25.8.

22. The solvate of claim 18, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 6.4, about 17.6, and about 25.6.

23. The solvate of claim 18, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occur at about 6.4, about 17.6, about 25.6, and about 25.8.

24. The polymorph according to any one of claims 18-23, wherein the X-ray powder diffraction pattern also comprises from 1-13 of the following characteristic peaks expressed in degrees 2Θ: about 7.8, about 14.3, about 14.8, about 15.6, about 18.2, about 19.0, about 19.2, about 19.8, about 20.8, about 22.1, about 22.7, about 23.7, and about 29.6.

25. The polymorph according to any one of claims 18-24, wherein the X-ray powder diffraction pattern also comprises from 1-20 of the following characteristic peaks expressed in degrees 2Θ: about 7.8, about 12.0, about 14.3, about 14.8, about 15.6, about 18.2, about 19.0, about 19.2, about 19.8, about 20.6, about 20.8, about 22.1, about 22.7, about 23.7, about 25.4, about 27.1, about 27.5, about 29.4, about 29.6, and about 29.9.

26. The solvate of claim 18, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 27.

27. The solvate of any one of claims 18-26, wherein the solvate also has a differential scanning calorimetry pattern comprising one or more melting onsets selected from the group consisting of: 130.5°C, 179.4°C, 194.4°C, 231.7°C, and269.6°C.

28. The solvate of any one of claims 18-27, wherein the solvate also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 7.

29. The solvate of any one of claims 18-28, wherein the solvate also has a thermogravimetric analysis pattern comprising a weight loss of about 7.0% at about 188°C.

30. The solvate of any one of claims 18-29, wherein the solvate also has a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 8.

31. The solvate of any one of claims 18-30, wherein the solvate is in substantially pure form.

32. The solvate of any one of claims 18-31, wherein the solvate is prepared by anti-solvent addition of methanol to a solution of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5- c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine in N-methyl pyrrolidinone.

33. The polymorph of any one of claims 18-31, wherein the solvate is prepared by agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: methanol and a 95:5 v/v solution of methanol :N- methylpyrrolidinone.

34. A pharmaceutical composition comprising the solvate of any one of claims 18-33 and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition comprising the solvate of any one of claims 18-33; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

36. A crystalline ethanol solvate of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2- yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the solvate is Form C and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.1.

37. The solvate of claim 36, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 15.5.

38. The solvate of any one of claims 36-37, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 7.8.

39. The solvate of any one of claims 36-38, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 16.9.

40. The solvate of claim 36, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 6.1, about 7.8, and about

15.5.

41. The solvate of claim 36, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 6.1, about 7.8, about

15.5, and about 16.9.

42. The polymorph according to any one of claims 36-41, wherein the X-ray powder diffraction pattern also comprises from 1-13 of the following characteristic peaks expressed in degrees 2Θ: about 2.5, about 9.4, about 12.3, about 14.2, about 14.7, about 18.4, about 20.0, about 21.1, about 22.3, about 22.7, about 25.2, about 25.9, and about 27.8.

43. The polymorph according to any one of claims 36-41, wherein the X-ray powder diffraction pattern also comprises from 1-20 of the following characteristic peaks expressed in degrees 2Θ: about 2.5, about 9.4, about 12.3, about 14.2, about 14.7, about 18.4, about 19.0, about 20.0, about 21.1, about 22.3, about 22.7, about 23.4, about 24.5, about 25.2, about 25.9, about 26.8, about 27.8, about 28.6, and about 31.1.

44. The solvate of claim 36, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 28.

45. The solvate of any one of claims 36-44, wherein the solvate also has a differential scanning calorimetry pattern comprising one or more melting onsets selected from the group consisting of: 129.5°C, 170.8°C, 194.3°C, 231.1°C, and 270.7°C.

46. The solvate of any one of claims 36-44, wherein the solvate also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 10.

47. The solvate of any one of claims 36-46, wherein the solvate also has a thermogravimetric analysis pattern comprising a weight loss of about 8.6% at about 177°C.

48. The solvate of any one of claims 36-46, wherein the solvate also has a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 11.

49. The solvate of any one of claims 36-48, wherein the solvate is in substantially pure form.

50. The solvate of any one of claims 36-49, wherein the solvate is prepared by agitating the compound of Formula I for about 1 week at about 50°C in ethanol.

51. A pharmaceutical composition comprising the solvate of any one of claims 36-50 and a pharmaceutically acceptable carrier.

52. A pharmaceutical composition comprising the solvate of any one of claims 36-50; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

53. A crystalline hydrate of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-lH- pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the hydrate is Form D and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 3.6.

54. The hydrate of claim 53, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 2.2.

55. The hydrate of any one of claims 53-54, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 5.6.

56. The hydrate of any one of claims 53-55, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 14.7.

57. The hydrate of claim 53, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 2.2, about 3.6, and about

5.6.

58. The hydrate of claim 53, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 2.2, about 3.6, about 5.6, and about 14.7.

59. The polymorph according to any one of claims 53-58, wherein the X-ray powder diffraction pattern also comprises from 1-6 of the following characteristic peaks expressed in degrees 2Θ: about 7.3, about 10.2, about 16.8, about 19.8, about 21.7, about 24.2.

60. The polymorph according to any one of claims 53-58, wherein the X-ray powder diffraction pattern also comprises from 1-9 of the following characteristic peaks expressed in degrees 2Θ: about 7.3, about 10.2, about 11.0, about 16.8, about 17.3, about 19.8, about 21.7, about 24.2, and about 27.3.

61. The hydrate of claim 53, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 29.

62. The hydrate of any one of claims 53-61, wherein the hydrate also has a differential scanning calorimetry pattern comprising a melting onset of about 125.2°C.

63. The hydrate of any one of claims 53-61, wherein the hydrate also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 13.

64. The solvate of any one of claims 53-63, wherein the solvate also has a thermogravimetric analysis pattern comprising a weight loss of about 3.9% at about 150°C.

65. The hydrate of any one of claims 53-63, wherein the hydrate also has a thermogravimetric analysis pattern that is substantially the same as that shown in FIG.

14.

66. The hydrate of any one of claims 53-65, wherein the hydrate is in substantially pure form.

67. The hydrate of any one of claims 53-66, wherein the hydrate is prepared by agitating the compound of Formula I for about 1 week at about 50°C in a solvent selected from the group consisting of: isopropyl acetate, a 1:1 v/v solution of acetone: water, and a 1:1 v/v solution of acetonitrile:water.

68. A pharmaceutical composition comprising the hydrate of any one of claims 53-67 and a pharmaceutically acceptable carrier.

69. A pharmaceutical composition comprising the hydrate of any one of claims 53-67; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

70. A crystalline tetrahydrofuran solvate of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5- c]pyridin-2-yl)-lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the solvate is Form E and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 6.5.

71. The solvate of claim 70, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 8.0.

72. The solvate of any one of claims 70-71, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 3.3.

73. The solvate of claim 70, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 6.5 and about 8.0.

74. The solvate of claim 70, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 3.3, about 6.5, and about

8.0.

75. The polymorph according to any one of claims 70-74, wherein the X-ray powder diffraction pattern also comprises from 1-7 of the following characteristic peaks expressed in degrees 2Θ: about 4.0, about 7.3, about 14.8, about 16.1, about 18.6, about 19.6, and about 20.1

76. The polymorph according to any one of claims 70-74, wherein the X-ray powder diffraction pattern also comprises from 1-10 of the following characteristic peaks expressed in degrees 2Θ: about 16.1, about 4.0, about 20.1, about 14.8, about 18.6, about 7.3, about 19.6, about 15.4, about 18.2, and about 25.6.

77. The solvate of claim 70, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 30.

78. The solvate of any one of claims 70-77, wherein the solvate also has a differential scanning calorimetry pattern comprising one or both melting onsets selected from the group consisting of: about 270.4°C and 344.6°C.

79. The solvate of any one of claims 70-77, wherein the solvate also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 16.

80. The solvate of any one of claims 70-79, wherein the solvate also has a thermogravimetric analysis pattern that is substantially the same as that shown in FIG. 17.

81. The solvate of any one of claims 70-80, wherein the solvate is in substantially pure form.

82. The solvate of any one of claims 70-81, wherein the polymorph is prepared by agitating the compound of Formula I for about 1 week at about 25°C in tetrahydrofuran.

83. A pharmaceutical composition comprising the solvate of any one of claims 70-82 and a pharmaceutically acceptable carrier.

84. A pharmaceutical composition comprising the solvate of any one of claims 70-82; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

85. A crystalline polymorph of l-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)- lH-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylmethanamine:

wherein the polymorph is Form F and has an X-ray powder diffraction pattern comprising a characteristic peak expressed in degrees 2Θ that occurs at about 8.0.

86. The polymorph of claim 85, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 2.3.

87. The polymorph of any one of claims 85-86, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 7.2.

88. The polymorph of any one of claims 85-87, wherein the X-ray powder diffraction pattern also comprises a characteristic peak expressed in degrees 2Θ that occurs at about 16.1.

89. The polymorph of claim 85, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 2.3, about 7.2, and about

8.0.

90. The polymorph of claim 85, wherein the X-ray powder diffraction pattern comprises characteristic peaks expressed in degrees 2Θ that occurs at about 2.3, about 7.2, about 8.0, and about 16.1.

91. The polymorph according to any one of claims 85-90, wherein the X-ray powder diffraction pattern also comprises from 1-10 of the following characteristic peaks expressed in degrees 2Θ: about 3.7, about 3.9, about 14.8, about 15.3, about 18.1, about 18.8, about 19.4, about 20.0, about 25.1, about 28.5.

92. The polymorph according to any one of claims 85-90, wherein the X-ray powder diffraction pattern also comprises from 1-15 of the following characteristic peaks expressed in degrees 2Θ: about 3.3, about 3.7, about 3.9, about 14.8, about 15.3, about 18.1, about 18.8, about 19.4, about 20.0, about 21.1, about 23.7, about 25.1, about 26.1, about 28.5, and about 29.9.

93. The polymorph of claim 85, wherein the X-ray powder diffraction pattern is substantially the same as that shown in FIG. 31.

94. The polymorph of any one of claims 85-93, wherein the solvate also has a differential scanning calorimetry patter comprising one or more melting onsets selected from the group consisting of: 270.4°C and 344.6°C.

95. The polymorph of any one of claims 85-93, wherein the polymorph also has a differential scanning calorimetry pattern that is substantially the same as that shown in FIG. 19.

96. The solvate of any one of claims 85-95, wherein the solvate also has a thermogravimetric analysis pattern comprising a weight loss of about 1.1% at about 180°C .

97. The polymorph of any one of claims 85-95, wherein the polymorph also has a thermogravimetric analysis pattern that is substantially the same as that shown in FIG.

20.

98. The polymorph of any one of claims 85-97, wherein the polymorph is in substantially pure form.

99. The polymorph of any one of claims 85-98, wherein the polymorph is prepared by agitating the compound of Formula I for about 1 week at about 50°C in tetrahydrofuran.

100. A pharmaceutical composition comprising the polymorph of any one of claims 85-99 and a pharmaceutically acceptable carrier.

101. A pharmaceutical composition comprising the polymorph of any one of claims 85-99; a first surfactant and a second surfactant; and optionally one or more of the following: a diluent, a binder, disintegrant, a glidant, and a lubricant.

102. A method for treating a disorder characterized by the activation of the Wnt signaling pathway, the method comprising administering to a subject in need thereof the polymorph, solvate, or hydrate of any one of claim 1-101.

103. The method of claim 102, wherein the disorder is selected from cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease, osteoarthritis and idiopathic pulmonary fibrosis.

104. The method of claim 103, wherein the disorder is idiopathic pulmonaiy fibrosis.

105. A method of making a compound of Formula I or a pharmaceutically acceptable salt thereof:

the process comprising reacting a starting material Al,

wherein:

R² is independently selected from the group consisting of H and -(C1-9 alkyl)nN(R⁹)2; each R⁹ is independently selected from the group consisting of H, -C1-9 alkyl, -(C1-3 alkyl)ncarbocyclyl and -(C1-9 alkyl)N(R¹⁶)2; each R¹⁶ is independently selected from the group consisting of H and lower alkyl;

wherein:

R⁴ is independently selected from the group consisting of -aryl(R¹³)q, -furyl(R¹⁵)q, and - thiophenyl(R¹⁵)q; each R⁸ is a substituent attached to the heterocyclyl ring and independently selected from the group consisting of H, halide, and -CM alkyl; each R¹³ is 1-2 substituents each attached to the aryl ring and independently selected from the group consisting of H, halide, -(C1-3 alkyl)nheterocyclyl(R⁸)q, -(C1-9 alkyl)nN(R⁹)2 and -(C1.9 alkyl)nNHS0₂R¹⁸; each R¹⁵ is a substituent attached to the heteroaryl ring and independently selected from the group consisting of H, lower alkyl, halide, -CF3, CN, and -C(=0)(Ci-3 alkyl); and each R¹⁸ is a lower alkyl; wherein any N-H moieties in the compound are optionally protected.

106. The method of claim 105, wherein P¹ is tetrahy dropyrany 1.

107. The method of any one of claims 105-106, wherein the process comprises: reacting A1 and A2 to form a compound of Formula (Γ)

108. The method of any one of claims 105-107, wherein the process comprises reacting a compound of Formula A3

with bis(pinacolato)diboron to form a compound of Formula A3-1

then reacting the compound of Formula A3-1 with a compound of Formula A4

109. The method of any one of claims 105-108, wherein the R⁴ aryl is phenyl.

110. The method of any one of claims 105-109 wherein the R¹³ heterocyclyl is selected from the group consisting of azetidinyl(R⁸)q, pyrrolidinyl(R⁸)q, piperidinyl(R⁸)q, piperazinyl(R⁸)q, and morpholinyl(R⁸)q.

111. The method of any one of claims 105-110, wherein R² is H.

112. The method of any one of claims 105-110, wherein R² is -(C1-9 alkyl)nN(R⁹)2.

113. The method of any one of claims 105-110, wherein R² is -CH2N(R⁹)2 or -N(R⁹)2.

114. The method of any one of claims 105-110 and 112-113, wherein R⁹ is independently selected from the group consisting of H, Me, Et, n-propyl, isopropyl, and -CH2carbocyclyl.

115. The method of any one of claims 105-108, wherein R⁴ is phenyl(R¹³)q.

116. The method of any one of claims 105-108, wherein R⁴ is -furyl(R¹⁵)q.

117. The method of any one of claims 105-108, wherein R⁴ is -thiophenyl(R¹⁵)q.

118. The method of claim 115, wherein R¹³ is one substituent attached to the phenyl ring and the substituent is a fluorine atom.

119. The method of claim 115, wherein R¹³ is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and -N(R⁹)2, wherein R⁹ is independently selected from the group consisting of H and -CH2CH2N(R¹⁶)2, and wherein R¹⁶ is independently selected from the group consisting of H, Me, and Et.

120. The method of claim 115, wherein R¹³ is two substituents each attached to the phenyl ring and the substituents are a fluorine atom and -(CH2)nNHS02R¹⁸, wherein R⁹ is independently selected from the group consisting of Me and Et.

121. The method of any one of claims 116-117, wherein R¹⁵ is one substituent attached to the thiophenyl ring and the substituents are selected from the group consisting of H, F, Me, and -C(=0)Me.

122. The method of claim 105, wherein the compound of Formula (I) has a structure selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

123. The method of claim 105, wherein the compound of Formula (I) has a structure selected from the group consisting of:

and or a pharmaceutically

acceptable salt thereof.

124. The method of claim 105, wherein the compound of Formula (I) has the following structure:

or a pharmaceutically acceptable salt thereof.