Amorphous and crystalline forms of 4-fluoro-n-methyl-n-(l-(4-(l-methyl-lh- pyrazol-5-YL)phthalazin-l-YL)piperidin-4-YL)-2-(trifluoromethyl)benzamide, and uses thereof

Abstract

Amorphous and crystalline forms of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide are described. Pharmaceutical compositions comprising the amorphous and / or crystalline forms, and the uses of such solid forms and compositions for the treatment of diseases and conditions are also described.

Description

Attorney Docket No. 2019199-016218WOAMORPHOUS AND CRYSTALLINE FORMS OF 4-FLUORO-N-METHYL-N-(l-(4-(l-METHYL-lH- PYRAZOL-5-YL)PHTHALAZIN-l-YL)PIPERIDIN-4-YL)-2-(TRIFLUOROMETHYL)BENZAMIDE, AND USES THEREOFFIELD OF THE INVENTION

[0001] Described herein are amorphous and crystalline forms of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, which is a known hedgehog pathway inhibitor. Pharmaceutical compositions comprising the amorphous and / or crystalline forms, and the uses of such solid forms and compositions for the treatment of fibrosis, particularly pulmonary fibrosis, are also described.BACKGROUND OF THE INVENTION

[0002] Interstitial lung diseases (ILDs) are a group of over 200 fibrotic disorders that cause scarring in the lungs, damaging tissues in or around the lungs' alveoli.

[0003] Idiopathic pulmonary fibrosis (IPF) and non-IPF progressive pulmonary fibrosis (PPF) are ILDs with a terminal prognosis. In the United States, the prevalence of IPF is about 150,000, with an estimated 20,000 to 40,000 individuals diagnosed annually, while the prevalence of PPF is about 186,000, with ~84,000 individuals diagnosed annually. The current standards of care (pirfenidone, nintedanib) modestly slow the decline of lung function, but do not stop or reverse it; as such IPF prognosis remains poor, with respiratory failure typically occurring within 3-7 years of diagnosis. Furthermore, pirfenidone and nintedanib have tolerability issues that limit their long-term use in most patients.

[0004] The driver of IPF is dysregulated tissue remodeling. IPF is a chronic wound undergoing the wound healing process that has become excessive and unrelenting. Wound healing processes are driven by fibroblast activation and trans differentiation of cells into myofibroblasts which deposit fibrotic extracellular matrix. The dominant pathway that governs fibroblast activation and myofibroblast accumulation is the Hedgehog (Hh) pathway through activation of Smoothened (Smo).Page 1 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0005] 4-Fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (CAS No. 1258861-20-9), also known as TALADEGIB (or LY2940680 or ENV-101), is a potent, small-molecule inhibitor of the Hedgehog (Hh) signaling pathway that causes apoptosis of myofibroblasts, thereby eliminating the driver of pulmonary fibrotic pathology.

[0006] In a recent Phase 2a study, patients with mild to moderate IPF receiving TALADEGIB experienced statistically significant improvements in lung function and lung capacity, and reversal of lung fibrosis. TALADEGIB is currently under investigation in a phase 2b trial (the WHISTLE-PF trial, see ClinicalTrials.gov ID NCT06422884), in IPF patients, evaluating a range of TALADEGIB doses, and further assessing the effects on lung capacity and lung fibrosis and the effect on patient reported outcomes.SUMMARY OF THE INVENTION

[0007] In some embodiments, the present disclosure provides the recognition that there is a need for alternate forms of TALADEGIB that present advantageous properties, such as, but not limited to solubility, bioavailability, purity, stability, shelf life and the like. Accordingly, described herein are various forms of TALADEGIB (e.g. amorphous or crystalline), compositions comprising these forms, and methods of using the forms and compositions for treating fibrotic diseases, particularly pulmonary fibrosis.

[0008] TALADEGIB, chemical name 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide, is a potent, small-molecule inhibitor of the Hedgehog (Hh) signaling pathway.TALADEGIB

[0009] Described herein are amorphous and crystalline forms of TALADEGIB.

[0010] In one aspect, described herein is amorphous TALADEGIB.Page 2 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0011] In some embodiments, a composition comprising TALADEGIB comprises at least 90% amorphous TALADEGIB, at least 91% amorphous TALADEGIB, at least 92% amorphous TALADEGIB, at least 93% amorphous TALADEGIB, at least 94% amorphous TALADEGIB, at least 95% amorphous TALADEGIB, at least 96% amorphous TALADEGIB, at least 97% amorphous TALADEGIB, at least 98% amorphous TALADEGIB or at least 99% amorphous TALADEGIB.

[0012] In some embodiments, a composition comprising TALADEGIB comprises at least 99.1% amorphous TALADEGIB, at least 99.2% amorphous TALADEGIB, at least 99.3% amorphous TALADEGIB, at least 99.4% amorphous TALADEGIB, at least 99.5% amorphous TALADEGIB, at least 99.6% amorphous TALADEGIB, at least 99.7% amorphous TALADEGIB, at least 99.8% amorphous TALADEGIB or at least 99.9% by weight amorphous TALADEGIB.

[0013] In some embodiments, a composition comprising TALADEGIB comprises from about 90% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 91% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 92% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 93% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 94% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 95% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 96% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 97% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 98% to about 99.9% amorphous TALADEGIB. In some embodiments, a composition comprising TALADEGIB comprises from about 99% to about 99.9% amorphous TALADEGIB.

[0014] In some embodiments, a composition comprising TALADEGIB comprises about 99.1% amorphous TALADEGIB, about 99.2% amorphous TALADEGIB, about 99.3% amorphous TALADEGIB, about 99.4% amorphous TALADEGIB, about 99.5% amorphous TALADEGIB, aboutPage 3 of 9113250080vlAttorney Docket No. 2019199-016218WO99.6% amorphous TALADEGIB, about 99.7% amorphous TALADEGIB, about 99.8% amorphous TALADEGIB or about 99.9% by weight amorphous TALADEGIB.

[0015] Also described herein are solid pharmaceutical compositions, comprising an effective amount of amorphous TALADEGIB as an active ingredient, and at least one excipient or carrier.

[0016] Also described herein are methods for treating or preventing fibrosis, comprising administering an effective amount of amorphous TALADEGIB.

[0017] Also described herein are methods for treating or preventing pulmonary fibrosis, comprising administering an effective amount of amorphous TALADEGIB.

[0018] Also described herein is the use of amorphous TALADEGIB in the manufacture of a medicament. In some embodiments the medicament is useful for the treatment or prevention of fibrosis. In some embodiments the medicament is useful for the treatment of fibrosis. In some embodiments the fibrosis is pulmonary fibrosis. In some embodiments the fibrosis is IPF.

[0019] Also described herein is amorphous TALADEGIB for use in treating or preventing pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis.

[0020] In another aspect, described herein are crystalline forms of TALADEGIB.

[0021] In some embodiments, the present disclosure provides a crystalline form of TALADEGIB characterized by peaks at 17.70, 21.57 and 22.46 °26 ± 0.2 °20. In some embodiments, a crystalline form of TALADEGIB further comprises at least two peaks selected from 8.90, 13.01, 13.82, 17.87, 22.27 and 27.73 °20 ± 0.2 °20. In yet further embodiments, a crystalline form of TALADEGIB characterized by an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in FIG. 1. In a related aspect described herein are crystalline forms of TALADEGIB, characterized by an endothermic point onset at about 188 °C , as determined by differential scanning calorimetry. In a related aspect described herein are crystalline forms of TALADEGIB, characterized by an endothermic point onset at 188 °C ± 2 °C, as determined by differential scanning calorimetry. In a further embodiment, a crystalline form of TALADEGIB is characterized by a differential scanning calorimetry pattern substantially the same as the differential scanning calorimetry pattern shown in FIG. 6. In yet further embodiments, a crystalline form of TALADEGIB is characterized by a melting point of aboutPage 4 of 9113250080vlAttorney Docket No. 2019199-016218WO188-189 °C. In yet further embodiments, a crystalline form of TALADEGIB is characterized by a melting point of 188-189 °C, ± 2 °C.

[0022] Also described herein, are solid pharmaceutical compositions comprising an effective amount of a crystalline form characterized by any means described above (e.g., the aforementioned x-ray diffraction patterns, differential scanning calorimetry patterns, or melting points). In some embodiments, a solid pharmaceutical composition comprises an effective amount of a crystalline form of TALADEGIB, and at least one excipient or carrier.

[0023] Also described herein are methods for treating or preventing fibrosis, comprising administering an effective amount of a crystalline form characterized by any means described above (e.g., the aforementioned diffraction patterns, the aforementioned differential scanning calorimetry patterns, or melting points). In some embodiments, a provided method comprises administering an effective amount of the crystalline form characterized by an x-ray diffraction pattern substantially similar to FIG. 1.

[0024] Also described herein are methods for treating or preventing pulmonary fibrosis, comprising administering an effective amount of the crystalline form characterized by any means described above (e.g., the aforementioned x-ray diffraction patterns, differential scanning calorimetry patterns, or melting points). In some embodiments, a provided method comprises administering an effective amount of the crystalline form characterized by an x-ray diffraction pattern substantially similar to FIG. 1.

[0025] In a further aspect are solid pharmaceutical compositions comprising an effective amount of amorphous TALADEGIB, a crystalline form of TALADEGIB, and at least one excipient or carrier. In some embodiments, a provided solid pharmaceutical composition comprises an effective amount of amorphous TALADEGIB, a crystalline form of TALADEGIB characterized by an x-ray diffraction pattern substantially similar to FIG. 1, and at least one excipient or carrier.

[0026] In a further aspect are methods for treating or preventing fibrosis, comprising administering an effective amount of a composition comprising amorphous TALADEGIB, a crystalline form of TALADEGIB, and at least one excipient or carrier. In some embodiments, a provided method comprises administering a solid pharmaceutical composition comprising anPage 5 of 9113250080vlAttorney Docket No. 2019199-016218WOeffective amount of amorphous TALADEGIB, a crystalline form of TALADEGIB characterized by an x-ray diffraction pattern substantially similar to FIG. 1, and at least one excipient or carrier.

[0027] In a further aspect are methods for treating or preventing pulmonary fibrosis, comprising administering an effective amount of a composition comprising amorphous TALADEGIB, a crystalline form of TALADEGIB, and at least one excipient or carrier.

[0028] Also described herein are uses of crystalline forms of TALADEGIB in the manufacture of a medicament. In some embodiments the medicament is useful for the treatment or prevention of fibrosis. In some embodiments the medicament is useful for the treatment of fibrosis. In some embodiments the fibrosis is pulmonary fibrosis. In some embodiments the fibrosis is IPF. In some embodiments the crystalline form of TALADEGIB is characterized by an x-ray diffraction pattern substantially similar to FIG. 1.INCORPORATION BY REFERENCE

[0029] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:FIG. 1 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB Form I.FIG. 2 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB Form I with the major peaks identified.FIG. 3 represents an illustrative Optical Photomicrograph of TALADEGIB Form I.Page 6 of 9113250080vlAttorney Docket No. 2019199-016218WOFIG. 4 represents an illustrative Single crystal X-ray ORTEP diagrams of the asymmetric unit in Form I of TALADEGIB Form I, at (a) RT; (b) 100 K; and (c) superimposed crystallographic asymmetric units at RT and 100 K.FIG. 5 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB Form I,(a) Simulated at 100K, (b) Simulated at RT, (c) Experimental at RT.FIG. 6 represents an illustrative DSC trace of TALADEGIB Form I, measured at 20 °C / min.FIG. 7 represents illustrative DSC traces of TALADEGIB Form I, measured at 2, 10 and 50°C / min. FIG. 8 represents an illustrative1H-NMR spectrum of TALADEGIB Form I.FIG. 9 represents an illustrative Solid-state13C NMR Spectrum of TALADEGIB Form I.FIG. 10 represents an illustrative Solid-state19F MAS NMR Spectrum of TALADEGIB Form I, measured at MAS rates of 15 kHz (upper trace) and 12 kHz (lower trace).FIG. 11 represents an illustrative TG-DTA thermogram of TALADEGIB Form I.FIG. 12 represents an illustrative moisture sorption isotherm of TALADEGIB Form I.FIG. 13 represents an illustrative X-ray Powder Diffraction Pattern of Amorphous TALADEGIB.FIG. 14 represents illustrative X-ray Powder Diffraction Patterns showing partial to complete conversion of amorphous TALADEGIB to an anisole solvate, by solvent drop grinding (Powder patterns of Form I and the toluene solvate are shown for reference).FIG. 15 represents superimposed illustrative X-ray Powder Diffraction Patterns of TALADEGIB crystalline forms.FIG. 16 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB toluene solvate.FIG. 17 represents an illustrative1H-NMR spectrum of TALADEGIB toluene solvate (a) and an illustrative Solid-state13C NMR Spectrum of TALADEGIB toluene solvate (b).FIG. 18 represents an illustrative TG-DTA thermogram of TALADEGIB toluene solvate.FIG. 19 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB anisole solvate.FIG. 20 represents an illustrative1H-NMR spectrum of TALADEGIB anisole solvate (a) and an illustrative solid-state13C NMR spectrum of TALADEGIB anisole solvate (b).FIG. 21 represents an illustrative TG-DTA thermogram of TALADEGIB anisole solvate.Page 7 of 9113250080vlAttorney Docket No. 2019199-016218WOFIG. 22 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB benzyl alcohol solvate I.FIG. 23 represents an illustrative1H-NMR spectrum of TALADEGIB benzyl alcohol solvate I. FIG. 24 represents an illustrative TG-DTA thermogram of TALADEGIB benzyl alcohol solvate I. FIG. 25 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB hydrate I. FIG. 26 represents an illustrative1H-NMR spectrum of TALADEGIB hydrate I (a) and an illustrative solid-state13C NMR spectrum of TALADEGIB hydrate I (b).FIG. 27 represents an illustrative TG-DTA thermogram of TALADEGIB hydrate I.FIG. 28 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB MTBE solvate. FIG. 29 represents an illustrative^-NMR spectrum of TALADEGIB MTBE solvate.FIG. 30 represents an illustrative TG-DTA thermogram of TALADEGIB MTBE solvate.FIG. 31 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB Tosylate Salts, wherein:trace i) represents pattern 1 isolated from ethyl acetate;trace ii) represents pattern 2 isolated from dichloromethane; andtrace iii) represents pattern 3 isolated from acetone.FIG. 32 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB HCI Salts, wherein:trace i) represents pattern 1 isolated from ethyl acetate;trace ii) represents pattern 2 isolated from methyl tert-butyl ether; andtrace iii) represents pattern 3 isolated from tetra hydrofuran.FIG. 33 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB HBr Salts, wherein:trace i) represents pattern 1 isolated from methyl tert-butyl ether;trace ii) represents pattern 2 isolated from ethyl acetate; andtrace iii) represents pattern 3 isolated from acetone.FIG. 34 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB Benzenesulfonate Salts, wherein theupper trace represents pattern 2 isolated from isopropanol and thePage 8 of 9113250080vlAttorney Docket No. 2019199-016218WOlower trace represents pattern 1 isolated from methyl tert-butyl ether.FIG. 35 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB HNO3 Salts, wherein theupper trace represents amorphous material isolated from methyl tert-butyl ether and the lower trace represents pattern 1 isolated from ethyl acetate.FIG. 36 represents an illustrative X-ray Powder Diffraction Pattern of TALADEGIB H2SO4 Salt. FIG. 37 represents illustrative X-ray Powder Diffraction Patterns of TALADEGIB Oxalic Acid Salts, wherein theupper trace represents pattern 1 isolated from dichloromethane and thelower trace represents pattern 1 isolated from ethyl acetate.FIG. 38 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Besylate Salt.FIG. 39 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Hydrochloride Salt.FIG. 40 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Edisylate Salt.FIG. 41 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Napadisylate Salt.FIG. 42 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Napsylate Salt.FIG. 43 represents an illustrative X-ray Powder Diffraction Pattern (upper), a1HNMR spectrum (middle) and thermograms (lower) of TALADEGIB Tosylate Salt.DETAILED DESCRIPTION OF THE INVENTION

[0031] While certain embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein are, in some circumstances, employed in practicing thePage 9 of 9113250080vlAttorney Docket No. 2019199-016218WOinvention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0032] The section headings used herein are used for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0033] The present invention relates to amorphous and crystalline forms of TALADEGIB, which is described in US Patents 8,273,742, 9,000,023, 11,628,167 and 12,090,127, and US Patent Application Publications US 20230181584, US 20230201195, US 20230201196 and US 20240342170.

[0034] The term "FORM I" refers to a crystalline form of TALADEGIB that exhibits an x-ray powder diffraction pattern substantially the same as that shown in FIG. 1, and / or a differential scanning calorimetry profile substantially the same as that shown in FIG. 6.

[0035] The present invention also relates to solid pharmaceutical compositions, comprising, as an active ingredient, an effective amount of TALADEGIB, for example, a crystalline form, e.g., FORM I, an amorphous form, or a combination thereof.

[0036] The present invention also relates to methods for treating or preventing diseases, comprising administering an effective amount of TALADEGIB, for example, a crystalline form, e.g., FORM I, an amorphous form, or a combination thereof.

[0037] The present invention also relates to uses of TALADEGIB, for example, a crystalline form, e.g., FORM I, in the manufacture of a medicament, useful for treating or preventing diseases.Crystalline Forms of Taladegib

[0038] In one embodiment, a crystalline form of TALADEGIB exhibits an x-ray powder diffraction pattern characterized by the peaks presented in Table 1A. In some embodiments, a crystalline form of TALADEGIB exhibits at least 3 peaks (±0.1 °29) listed in Table 1A.Page 10 of 9113250080vlAttorney Docket No. 2019199-016218WOTABLE 1A

[0039] In other embodiments, a crystalline form of TALADEGIB exhibits an x-ray powder diffraction pattern characterized by the peaks presented in Table IB. In some embodiments, a crystalline form of TALADEGIB exhibits at least 3 peaks (± 0.1 °20) listed in Table IB. In yet other embodiments, a crystalline form of TALADEGIB exhibits at least 4 peaks (± 0.1 °29) of Table IB, at least 5 peaks (±0.1 °26) of Table IB, at least 6 peaks (± 0.1 °20) of Table IB, at least 7 peaks (± 0.1 °20) of Table IB, at least 8 peaks (± 0.1 °20) of Table IB, at least 9 peaks (± 0.1 °20) of Table IB, at least 10 peaks (± 0.1 °20) of Table IB, at least 15 peaks (± 0.1 °20) of Table IB, or at least 20 peaks of (± 0.1 °20) of Table IB.TABLE IBPage 11 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0040] In one embodiment provided herein, a crystalline form of TALADEGIB is characterized by XRPD peaks appearing at 17.70, 21.57 and 22.46 °20 ± 0.1 °20. In further embodiments, a crystalline form of TALADEGIB is further characterized by at least one peak appearing at 13.01, 17.87, 22.27 and 27.73 °20 ± 0.1 °20. In further embodiments, a crystalline form of TALADEGIB is further characterized by at least two peaks appearing at 13.01, 17.87, 22.27 and 27.73 °20 ± 0.1 °20. In yet still further embodiments, a crystalline form of TALADEGIB exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in FIG. 1. In some embodiments, a crystalline form of TALADEGIB exhibits a DSC trace substantially the same as the DSC trace in FIG. 6 or FIG. 7. In some embodiments, a crystalline form of TALADEGIB exhibits a TG-DTA trace substantially the same as the TG-DTA trace in FIG. 6 or FIG. 7.

[0041] In some embodiments, a crystalline form of TALADEGIB is a solvate. In some embodiments, a crystal form of TALADEGIB is a toluene solvate, an anisole solvate, a benzyl alcohol solvate, or an MBTE solvate. In some embodiments, a crystalline form of TALADEGIB is a hydrate.

[0042] In one embodiment provided herein, a crystalline form of TALADEGIB is a toluene solvate and exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 16 and / or a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 18.Page 12 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0043] In one embodiment provided herein, a crystalline form of TALADEGIB is an anisole solvate and exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 19 and / or a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 21.

[0044] In one embodiment provided herein, a crystalline form of TALADEGIB is a benzyl alcohol solvate and exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 22 and / or a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 24.

[0045] In one embodiment provided herein, a crystalline form of TALADEGIB is an MBTE solvate and exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 28 and / or a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 30.

[0046] In one embodiment provided herein, a crystalline form of TALADEGIB is a hydrate and exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 25 and / or a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 1.

[0047] In some embodiments, a crystalline form of TALADEGIB is a crystalline salt form of TALADEGIB. In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with a co-former. In some embodiments, a co-former is tosylic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, oxalic acid, phosphoric acid, formic acid, acetic acid, succinic acid, fumaric acid, L-lactic acid, L-tartaric acid, methanesulfonic acid, or ethanesulfonic acid. In some embodiments, a co-former is tosylic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or oxalic acid.

[0048] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with tosylic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB tosylate salt form. In some embodiments, a crystalline TALADEGIB hydrochoride salt form is obtained by contacting TALADEGIB with hydrochloric acid and is isolated from ethyl acetate, dichloromethane, or acetone.Page 13 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0049] In some embodiments, a crystalline TALADEGIB tosylate salt form is obtained by contacting TALADEGIB with tosylic acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB tosylate salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below.Page 14 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB tosylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 31 trace i).

[0050] In some embodiments, a crystalline TALADEGIB tosylate salt form is obtained by contacting TALADEGIB with tosylic acid and is isolated from dichloromethane. In some embodiments, a crystalline TALADEGIB tosylate salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below.In one embodiment provided herein, a crystalline TALADEGIB tosylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 31 trace ii).

[0051] In some embodiments, a crystalline TALADEGIB tosylate salt form is obtained by contacting TALADEGIB with tosylic acid and is isolated from acetone. In some embodiments, a crystalline TALADEGIB tosylate salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below.Page 15 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB tosylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 31 trace iii). In one embodiment provided herein, a crystalline TALADEGIB tosylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 43, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 43, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 43.

[0052] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with hydrochloric acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB hydrochoride salt form. In some embodiments, a crystalline TALADEGIB hydrochoride salt form is obtained by contacting TALADEGIB with hydrochloric acid and is isolated from ethyl acetate, methyl tert-butyl ether, or tetrahydrofuran.

[0053] In some embodiments, a crystalline TALADEGIB hydrochoride salt form is obtained by contacting TALADEGIB with hydrochloric acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB hydrochloride salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven orPage 16 of 9113250080vlAttorney Docket No. 2019199-016218WOmore, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB hydrochloride salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 32 trace i).

[0054] In some embodiments, a crystalline TALADEGIB hydrochoride salt form is obtained by contacting TALADEGIB with hydrochloric acid and is isolated from methyl tert-butyl ether. In some embodiments, a crystalline TALADEGIB hydrochloride salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below ± 0.2 °20.Page 17 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB hydrochloride salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 32 trace ii). In one embodiment provided herein, a crystalline TALADEGIB hydrochloride salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 39, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 39, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 39.

[0055] In some embodiments, a crystalline TALADEGIB hydrochoride salt form is obtained by contacting TALADEGIB with hydrochloric acid and is isolated from tetrahydrofuran. In some embodiments, a crystalline TALADEGIB hydrochloride salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below ± 0.2 °20.Page 18 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB hydrochloride salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 32 trace iii).

[0056] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with hydrobromic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB hydrobromide salt form. In some embodiments, a crystalline TALADEGIB hydrobromide salt form is obtained by contacting TALADEGIB with hydrobromic acid and is isolated from methyl tert-butyl ether, ethyl acetate, or acetone.

[0057] In some embodiments, a crystalline TALADEGIB hydrobromide salt form is obtained by contacting TALADEGIB with hydrobromic acid and is isolated from methyl tert-butyl ether. In some embodiments, a crystalline TALADEGIB hydrobromide salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below ± 0.2 °20.Page 19 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB hydrobromide salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 33 trace i).

[0058] In some embodiments, a crystalline TALADEGIB hydrobromide salt form is obtained by contacting TALADEGIB with hydrobromic acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB hydrobromide salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, or substantially all of the locations listed in the table below ± 0.2 °20.Page 20 of 9113250080vlAttorney Docket No. 2019199-016218WOIn one embodiment provided herein, a crystalline TALADEGIB hydrobromide salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 33 trace ii).

[0059] In some embodiments, a crystalline TALADEGIB hydrobromide salt form is obtained by contacting TALADEGIB with hydrobromic acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB hydrobromide salt form is characterized by XRPD peaks at one or more, two or more, three or more, or all of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB hydrobromide salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 33 trace iii).

[0060] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with besylic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB besylate salt form. In some embodiments, a crystalline TALADEGIB besylate salt form is obtained by contacting TALADEGIB with besylic acid and is isolated from methyl tert-butyl ether, isopropyl alcohol, or ethanol.

[0061] In some embodiments, a crystalline TALADEGIB besylate salt form is obtained by contacting TALADEGIB with besylic acid and is isolated from methyl tert-butyl ether. In somePage 21 of 9113250080vlAttorney Docket No. 2019199-016218WOembodiments, a crystalline TALADEGIB besylate salt form is characterized by XRPD peaks at one or more, two or more, three or more, or all of the locations listed in the table below ± 0.2 °29.In one embodiment provided herein, a crystalline TALADEGIB besylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 34, lower trace.

[0062] In some embodiments, a crystalline TALADEGIB besylate salt form is obtained by contacting TALADEGIB with besylic acid and is isolated from isopropyl alcohol. In some embodiments, a crystalline TALADEGIB besylate salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, or all of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB besylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 34, upper trace.

[0063] In some embodiments, a crystalline TALADEGIB besylate salt form is obtained by contacting TALADEGIB with besylic acid and is isolated from ethanol. In one embodiment provided herein, a crystalline TALADEGIB besylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 38, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 38, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 38.Page 22 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0064] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with nitric acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB nitrate salt form. In some embodiments, a crystalline TALADEGIB nitrate salt form is obtained by contacting TALADEGIB with nitric acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB nitrate salt form is characterized by XRPD peaks at one or more, two or more, three or more, or all of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB besylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 35.

[0065] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with sulfuric acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB sulfate salt form. In some embodiments, a crystalline TALADEGIB sulfate salt form is obtained by contacting TALADEGIB with sulfuric acid and is isolated from dichloromethane. In some embodiments, a crystalline TALADEGIB sulfate salt form is characterized by XRPD peaks at one or both of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB sulfate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 36.

[0066] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with oxalic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB oxalate salt form. In some embodiments, a crystalline TALADEGIBPage 23 of 9113250080vlAttorney Docket No. 2019199-016218WOoxalate salt form is obtained by contacting TALADEGIB with oxalic acid and is isolated from dichloromethane or ethyl acetate.

[0067] In some embodiments, a crystalline TALADEGIB oxalate salt form is obtained by contacting TALADEGIB with oxalic acid and is isolated from dichloromethane. In some embodiments, a crystalline TALADEGIB oxalate salt form is characterized by XRPD peaks at one or more, two or more, three or more, or all of the locations listed in the table below ± 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB oxalate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 37, upper trace.

[0068] In some embodiments, a crystalline TALADEGIB oxalate salt form is obtained by contacting TALADEGIB with oxalic acid and is isolated from ethyl acetate. In some embodiments, a crystalline TALADEGIB oxalate salt form is characterized by XRPD peaks at one or more, two or more, three or more, four or more, or all of the locations listed in the table below + 0.2 °20.In one embodiment provided herein, a crystalline TALADEGIB oxalate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 37, lower trace.

[0069] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with ethanedisulfonic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB edisylate salt form. In some embodiments, a crystalline TALADEGIB edisylate salt form is obtained by contacting TALADEGIB with ethanedisulfonic acidPage 24 of 9113250080vlAttorney Docket No. 2019199-016218WOand is isolated from isopropanol. In one embodiment provided herein, a crystalline TALADEGIB edisylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 40, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 40, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 40.

[0070] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with 1,5-naphthalenedisolfonic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB napadisylate salt form. In some embodiments, a crystalline TALADEGIB napadisylate salt form is obtained by contacting TALADEGIB with 1,5-naphthalenedisolfonic acid and is isolated from ethanol. In one embodiment provided herein, a crystalline TALADEGIB napadisylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 41, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 41, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 41.

[0071] In some embodiments, a crystalline salt form of TALADEGIB is obtained by contacting TALADEGIB with naphthalene-2-sulfonic acid. In some embodiments, a crystalline salt form of TALADEGIB is a crystalline TALADEGIB napsylate salt form. In some embodiments, a crystalline TALADEGIB napsylate salt form is obtained by contacting TALADEGIB with naphthalene-2-sulfonic acid and is isolated from ethanol. In one embodiment provided herein, a crystalline TALADEGIB napsylate salt form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in Figure 42, a TG-DTA thermogram substantially the same as the TG-DTA thermogram shown in Figure 42, and / or a DSC thermogram substantially the same as the DSC thermogram shown in Figure 42.Combinations of Amorphous and Crystalline Forms

[0072] In certain embodiments, any of the TALADEGIB crystalline forms described herein optionally comprise (or are intermixed or are in combination with) a certain amount of amorphous TALADEGIB. In other embodiments, amorphous TALADEGIB optionally comprisesPage 25 of 9113250080vlAttorney Docket No. 2019199-016218WO(or is intermixed or is in combination with) a certain amount of any of the TALADEGIB crystalline forms described herein.

[0073] In certain embodiments are solid form combinations comprising one, or more than one, of the TALADEGIB crystalline forms described herein and amorphous TALADEGIB. In some embodiments are solid form combinations comprising more than one of the TALADEGIB crystalline forms described herein and amorphous TALADEGIB. In some embodiments are solid form combinations comprising one of the TALADEGIB crystalline forms described herein and amorphous TALADEGIB. In some embodiments are solid form combinations comprising TALADEGIB FORM I and amorphous TALADEGIB.

[0074] In some embodiments the combinations comprise more TALADEGIB FORM I than amorphous TALADEGIB. In other embodiments the combinations comprise less TALADEGIB FORM I than amorphous TALADEGIB.

[0075] In some embodiments, the amorphous content of an amorphous - crystal form combination comprises less than 50 wt. % of the combination, less than 25 wt. % of the combination, less than 15 wt. % of the combination, less than 10 wt. % of the combination, or less than 5 wt. % of the combination.

[0076] In other embodiments, the crystalline content of an amorphous - crystal form combination comprises less than 50 wt. % of the combination, less than 25 wt. % of the combination, less than 15 wt. % of the combination, less than 10 wt. % of the combination, or less than 5 wt. % of the combination.

[0077] I n further embodiments, a composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of amorphous TALADEGIB.Definitions

[0078] The term "subject", as used herein in reference to individuals suffering from a disorder, encompasses mammals and non-mammals. In one embodiment of the methods and compositions provided herein, the mammal is a human.Page 26 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0079] The terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound being administered that is sufficient to treat or prevent the particular disease or condition. The result is the reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0080] The terms "substantially the same as" or "substantially similar to" as used herein, refers to a powder x-ray diffraction pattern or differential scanning calorimetry pattern that is nonidentical to those depicted herein, but that falls within the limits of experimental error, when considered by one of ordinary skill in the art.Modulating Hedgehog Pathway Activity

[0081] The Hedgehog (Hh) signaling pathway plays an important role in tissue regeneration and repair. The pathway is initiated by binding the extracellular Hh ligand Sonic Hedgehog (SHH) to the transmembrane receptor Patched (PTCH). In the absence of the ligand, PTCH inhibits the activity of the G-protein-coupled receptor-like protein Smoothened (SMO). When an SHH ligand binds to PTCH, it relieves the inhibition of SMO, allowing SMO to trigger a cascade of intracellular signaling events, ultimately activating the glioma-associated oncogene homolog (GLI) family of transcription factors.

[0082] Hh pathway components are typically present at low levels in healthy adult lung tissue. Following injury, Hh signaling increases, suggesting the pathway is initially suppressed and then reactivated to support cellular regeneration. Fibroblasts transition into myofibroblasts in response to tissue trauma, initiating tissue repair, and Hh signaling is essential for this process. After normal injury repair these cells are eliminated through apoptosis or deactivated.However, during fibrosis myofibroblasts persist, secreting growth factors and cytokines that drive disease progression, with SHH signaling implicated in aberrant myofibroblast differentiation and proliferation.Page 27 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0083] In IPF lungs, the Hh pathway is dysregulated, with pathway components SHH, PTCHI, SMO, GLI1, and GLI2 upregulated as compared with normal lungs. IPF is characterized by increased SHH expression, leading to sustained activation of Hh signaling by SHH. Inhibiting the Hh pathway greatly decreases myofibroblast differentiation and ECM protein levels. These findings highlight aberrant Hh signaling as a critical factor in the pathophysiology of IPF.

[0084] Described herein are methods of modulating hedgehog pathway activity by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway.

[0085] The term "modulate" refers to either wholly or partially inhibiting or wholly or partially activating hedgehog pathway activity.

[0086] In some embodiments, the component of the hedgehog pathway is Sonic Hedgehog (SHH), smoothened (SMO), protein patched homolog 1 (PTCHI), GLI1, GLI2, GLI3, or any combination thereof.

[0087] In some embodiments are provided methods of inhibiting hedgehog pathway activity by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to inhibit the activity of the hedgehog pathway.

[0088] In some embodiments are provided methods of inhibiting hedgehog pathway activity in a solution by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said solution.

[0089] In some embodiments are provided methods of inhibiting hedgehog pathway activity in a cell by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said cell.

[0090] In some embodiments are provided methods of inhibiting hedgehog pathway activity in a tissue by contacting a component of the hedgehog pathway with an amount of an amorphousPage 28 of 9113250080vlAttorney Docket No. 2019199-016218WOor crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said tissue.

[0091] In some embodiments are provided methods of inhibiting hedgehog pathway activity in blood by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in blood.

[0092] In some embodiments are provided methods of inhibiting hedgehog pathway activity in plasma by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in plasma.

[0093] In some embodiments are provided methods of inhibiting hedgehog pathway activity in an animal by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said animal.

[0094] In some embodiments are provided methods of inhibiting hedgehog pathway activity in a mammal by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said mammal.

[0095] In some embodiments are provided methods of inhibiting hedgehog pathway activity in a human by contacting a component of the hedgehog pathway with an amount of an amorphous or crystalline form of TALADEGIB, or a combination thereof, as described herein, sufficient to modulate the activity of the hedgehog pathway in said human.Pharmaceutical Compositions

[0096] Described herein are pharmaceutical compositions comprising an effective amount of TALADEGIB. In some embodiments, a pharmaceutical composition comprises an effective amount of TALADEGIB, and at least one pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition comprises an amorphous and / or a crystalline form of TALADEGIB, as described herein.Page 29 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0097] In some embodiments, a pharmaceutical composition comprises an effective amount of an amorphous form of TALADEGIB, and at least one pharmaceutically acceptable carrier.

[0098] In some embodiments, a pharmaceutical composition comprises an effective amount of a crystalline form of TALADEGIB, as described herein, and at least one pharmaceutically acceptable carrier.

[0099] In some embodiments, a pharmaceutical composition comprises an effective amount of FORM I, as described herein, and at least one pharmaceutically acceptable carrier.

[0100] In some embodiments, a pharmaceutical composition comprises an effective amount of a combination of amorphous and FORM I, as described herein, and at least one pharmaceutically acceptable carrier.

[0101] In some embodiments the pharmaceutical compositions are useful for the treatment of disorders. In some embodiments the pharmaceutical compositions are useful for the treatment of disorders in a mammal. In some embodiments the pharmaceutical compositions are useful for the treatment of disorders in a human.

[0102] In some embodiments the pharmaceutical compositions are useful for the treatment or prophylaxis of fibrosis. In some embodiments the pharmaceutical compositions are useful for the treatment or prophylaxis of pulmonary fibrosis. In some embodiments the pharmaceutical compositions are useful for the treatment or prophylaxis of idiopathic pulmonary fibrosis (IPF) or non-IPF progressive pulmonary fibrosis (PPF).Modes of Administration, Formulations and Dosage Forms

[0103] Described herein are pharmaceutical compositions comprising an amorphous and / or crystalline forms of TALADEGIB, as described herein.

[0104] The compound, solid forms and compositions described herein are administered either alone, or in combination with, pharmaceutically acceptable carriers, excipients, or diluents in a pharmaceutical composition, according to standard pharmaceutical practice.

[0105] Administration is achieved by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema),Page 30 of 9113250080vlAttorney Docket No. 2019199-016218WOparenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route depends upon, for example, the condition and disorder of the recipient. Those of skill in the art will be familiar with administration techniques that can be employed with the compounds, solid forms, compositions and methods described herein.

[0106] By way of example only, the compounds, solid forms and compositions described herein are, in some embodiments, administered locally to the area in need of treatment, by for example, inhalation, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant, said implant made for example, out of a porous, non-porous, or gelatinous material, including membranes.

[0107] The pharmaceutical compositions described herein are, for example, in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[0108] The pharmaceutical composition is, in some embodiments, in unit dosage forms suitable for single administration of precise dosages. Pharmaceutical compositions include a compound or solid form as described herein as an active ingredient, and a conventional pharmaceutical carrier or excipient. In some embodiments these compositions include other or additional medicinal or pharmaceutical agents, carriers, adjuvants, etc. Pharmaceutical compositions are conveniently presented in unit dosage form. In some embodiments, they are prepared with a specific amount of active compound by any of the methods well known or apparent to those skilled in the pharmaceutical arts.Doses

[0109] The amount of pharmaceutical compositions administered will firstly be dependent on the mammal being treated. In the instances where pharmaceutical compositions arePage 31 of 9113250080vlAttorney Docket No. 2019199-016218WOadministered to a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, gender, diet, weight, general health and response of the individual patient, the severity of the patient's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, time of administration, route of administration, the disposition of the composition, rate of excretion, drug combination, and the discretion of the prescribing physician. Also, the route of administration may vary depending on the condition and its severity.

[0110] The pharmaceutical composition is, in some embodiments, in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Determination of the proper dosage for a particular situation is within the skill of the art. For convenience, in some embodiments, the total daily dosage is divided and administered in portions during the day if desired. The amount and frequency of administration will be regulated according to the judgment of the attending clinician physician considering such factors as described above. Thus, the amount of pharmaceutical composition to be administered is variable depending upon the circumstances.

[0111] Administration occurs in an amount of between about 0.001 mg / kg of body weight to about 100 mg / kg of body weight per day (administered in single or multiple doses), or at least about 0.1 mg / kg of body weight per day. A particular therapeutic dosage includes, in some embodiments, from about 0.01 mg to about 7000 mg of compound, or, from about 0.05 mg to about 2500 mg. The quantity of active compound in a unit dose is, in some embodiments, varied or adjusted from about 0.1 mg to 1000 mg, from about 1 mg to 500 mg, or 10 mg to 400 mg, or 25 mg to 200 mg according to the particular application. In some instances, the particular therapeutic dosage is about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg or about 400 mg. In some instances, dosage levels below the lower limit of the aforesaid range are more than adequate, while in other cases still larger doses arePage 32 of 9113250080vlAttorney Docket No. 2019199-016218WOemployed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[0112] In combinational applications in which the compound is not the sole therapy, it is possible to administer lesser amounts of compound and still have therapeutic or prophylactic effect.Combination Therapies

[0113] The compounds and solid forms described herein may be administered as a sole therapy or in combination with another therapy or therapies. By way of example only, if one of the side effects experienced by a patient upon receiving a compound or solid form as described herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the compound. Or, by way of example only, the therapeutic effectiveness of a compound or solid form as described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering a compound or solid form as described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0114] In the instances where the compounds or solid forms as described herein are administered with other therapeutic agents, they need not be administered in the same pharmaceutical composition as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound or solid form as described herein may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according toPage 33 of 9113250080vlAttorney Docket No. 2019199-016218WOestablished protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0115] The compounds, solid forms and compositions described herein, and where appropriate other therapeutic agent may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) sequentially or separately, depending upon the nature of the disease, the condition of the patient, and the actual choice of other therapeutic agent to be administered. For combinational applications and uses, the compounds, solid forms and compositions described herein and the therapeutic agent need not be administered simultaneously or essentially simultaneously. Thus, the compounds, solid forms and compositions as described herein may be administered first followed by the administration of the therapeutic agent; or the therapeutic agent may be administered first followed by the administration of the compounds, solid forms and compositions as described herein. This alternate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the therapeutic agent may be administered first, and then the treatment continued with the administration of the compounds, solid forms and compositions as described herein followed, where determined advantageous, by the administration of the therapeutic agent, and so on until the treatment protocol is complete. Thus, in accordance with experience and knowledge, the practicing physician can modify each administration protocol for treatment according to the individual patient's needs, as the treatment proceeds. The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

[0116] Specific, non-limiting examples of possible combination therapies include use of the compounds, solid forms and compositions described herein with one or more antifibrotics (e.g., pirfenidone, nintedanib, vismodegib, nerandomilast and the like), anti-inflammatories (e.g.Page 34 of 9113250080vlAttorney Docket No. 2019199-016218WOsteroids, glucocorticoids, azathioprine and the like), immune suppressants (e.g. cyclophosphamide, mycophenolate mofetil, azathioprine and the like), anti-tussives (e.g., dextromethorphan, guaifenesin, cough drops, hydrocodone, benzonatate and the like), acid reflux treatments, (e.g., proton pump inhibitors, H2-Blockers and the like), or therapies such as oxygen therapy. This list should not be construed to be closed, but should instead serve as an illustrative example common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration, including but not limited to oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.DiseasesDescribed herein are methods of treating a disease or disorder in an individual suffering from the disease or disorder, comprising administering to said individual an effective amount of amorphous TALADEGIB or of a crystalline form of TALADEGIB, or a combination thereof.

[0117] Further described herein are methods of treating a disease or disorder in an individual suffering from the disease or disorder, comprising administering to said individual a pharmaceutical composition comprising an effective amount of amorphous TALADEGIB, or of a crystalline form of TALADEGIB, or a combination thereof, and at least one excipient or carrier.

[0118] In some embodiments, amorphous TALADEGIB is administered. In some embodiments, a crystalline form of TALADEGIB is administered. In some embodiments, a combination of amorphous TALADEGIB and a crystalline form of TALADEGIB is administered. In some embodiments, the crystalline form is FORM I.

[0119] Also described herein are methods of preventing a disease or disorder in an individual suffering from the disease or disorder, comprising administering to said individual an effective amount of amorphous TALADEGIB or of a crystalline form of TALADEGIB, or a combination thereof.

[0120] Further described herein are methods of preventing a disease or disorder in an individual suffering from the disease or disorder, comprising administering to said individual a pharmaceutical composition comprising an effective amount of amorphous TALADEGIB, or of a crystalline form of TALADEGIB, or a combination thereof, and at least one excipient or carrier.Page 35 of 9113250080vlAttorney Docket No. 2019199-016218WOIn some embodiments, amorphous TALADEGIB is administered. In some embodiments, a crystalline form of TALADEGIB is administered. In some embodiments, a combination of amorphous TALADEGIB and a crystalline form of TALADEGIB is administered. In some embodiments, the crystalline form is FORM I.

[0121] Also described herein is the use of amorphous TALADEGIB, or a crystalline form of TALADEGIB, or a combination thereof, in the manufacture of a medicament for treating or preventing a disease or disorder.

[0122] In some embodiments, amorphous TALADEGIB is used. In some embodiments, a crystalline form of TALADEGIB is used. In some embodiments, a combination of amorphous TALADEGIB and a crystalline form of TALADEGIB is used. In some embodiments, the crystalline form is FORM I.

[0123] In some embodiments, the disease or disorder is fibrosis. In some embodiments, the disease or disorder is pulmonary fibrosis. In some embodiments, the disease or disorder is Idiopathic pulmonary fibrosis (IPF) or non-IPF progressive pulmonary fibrosis (PPF) are ILDs.Kits

[0124] The compounds, solid forms, compositions and methods described herein provide kits for the treatment of diseases and disorders, such as the ones described herein. These kits comprise a compound, solid form, compounds, solid forms or compositions described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits, in some embodiments, also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein are provided, marketed and / or promoted to health providers, including physicians, nurses,Page 36 of 9113250080vlAttorney Docket No. 2019199-016218WOpharmacists, formulary officials, and the like. Kits are also, in some embodiments, marketed directly to the consumer.

[0125] In some embodiments, the compounds, solid forms and pharmaceutical compositions described herein are utilized for diagnostics and as research reagents. For example, in some embodiments, the compounds, solid forms and pharmaceutical compositions, either alone or in combination with other compounds, are used as tools in differential and / or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues. As one non-limiting example, expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses are performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.

[0126] Besides being useful for human treatment, the compounds, solid forms and pharmaceutical compositions described herein are also useful for veterinary treatment of animals.

[0127] Among other things, the present disclosure provides the following Embodiments:1. A method for treating or preventing fibrosis, comprising administering an effective amount of a crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide:characterized by XRPD peaks at 17.70, 21.57 and 22.46 °29 ± 0.1 °20.Page 37 of 9113250080vlAttorney Docket No. 2019199-016218WO2. The method according to Embodiment 1, wherein the crystalline form is further characterized by at least one further XRPD peak at 13.01, 17.87, 22.27 or 27.73 °20 ± 0.1 °20.3. The method according to Embodiment 1, wherein the crystalline form exhibits an x-ray powder diffraction pattern substantially the same as the x-ray powder diffraction pattern shown in FIG. 1.4. The method according to any one of Embodiments 1-3, for treating fibrosis.5. The method according to any one of Embodiments 1-4, wherein the fibrosis is pulmonary fibrosis.6. The method according to Embodiment 5, wherein pulmonary fibrosis is Idiopathic Pulmonary Fibrosis (IPF) or non-IPF Progressive Pulmonary Fibrosis (PPF).7. A method for treating or preventing fibrosis, comprising administering an effective amount of a composition comprising an amorphous form of 4-fluoro-N-methyl-N-(l-(4- (l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide:and a crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.8. The method according to Embodiment 7, for treating fibrosis.9. The method according to Embodiment 7 or 8, wherein the fibrosis is pulmonary fibrosis.Page 38 of 9113250080vlAttorney Docket No. 2019199-016218WO10. The method according to Embodiment 9, wherein pulmonary fibrosis is Idiopathic Pulmonary Fibrosis (IPF) or non-IPF Progressive Pulmonary Fibrosis (PPF).11. The method according to any one of Embodiments 7-10, wherein the crystalline form is characterized by one or more XRPD peaks at 17.70, 21.57 or 22.46 °20 ± 0.2 °20.12. The method according to Embodiment 11, wherein the crystalline form is characterized by two or more XRPD peaks at 17.70, 21.57 or 22.46 °20 ± 0.2 °20.13. The method according to Embodiment 11, wherein the crystalline form is characterized by XRPD peaks at 17.70, 21.57 or 22.46 °20 ± 0.2 °20.14. The method according to any one of Embodiments 7-13, wherein the composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of the amorphous form of 4-fluoro-N-methyl-N-(l-(4- (l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.15. A crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l- yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide:characterized by one or more XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °26.16. The crystalline form according to Embodiment 15, wherein the crystalline form isPage 39 of 9113250080vlAttorney Docket No. 2019199-016218WOcharacterized by two or more XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °26.17. The crystalline form according to Embodiment 15 wherein the crystalline form is characterized by three or more XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °20.18. The crystalline form according to Embodiment 15, wherein the crystalline form is characterized by XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °20.19. A composition comprising the crystalline form according to any one of Embodiments 15- 18.20. The composition according to Embodiment 19, wherein the composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of the crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH- pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoro methyl) benzamide.21. The composition according to Embodiment 19, wherein the composition is a pharmaceutically acceptable composition further comprising one or more pharmaceutically acceptable excipients.22. The composition according to Embodiment 21, wherein the composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of an amorphous form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl- lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.Page 40 of 9113250080vlAttorney Docket No. 2019199-016218WO23. A method for treating or preventing fibrosis, comprising administering an effective amount of the composition of Embodiment 21 or 22.24. The method of Embodiment 23, for treating fibrosis.25. The method of Embodiment 23 or 24, wherein the fibrosis is pulmonary fibrosis.26. The method of Embodiment 25, wherein pulmonary fibrosis is Idiopathic Pulmonary Fibrosis (IPF) or non-IPF Progressive Pulmonary Fibrosis (PPF).27. The crystalline form or composition according to any one of the preceding embodiments for use in the method of treating according to any one of the preceding embodiments.28. The crystalline form or composition according to any one of the preceding embodiments for use in the manufacture of a medicament for use in the method of treating according to any one of the preceding embodiments.EXAMPLES

[0128] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.INTRODUCTION

[0129] TALADEGIB was prepared according to previously described methods, see for example, US patent 8,273,742, Column 11, Example 11. In brief, N-methyl-l-(4-lmethyl-lH-pyrazol-5-yl)phthalazine-l-yl)piperidin-4-amine and 4-fluoro-2-(trifluoromethyl) benzoly chloride were coupled in the presence of base. Purification of the resulting product by flash silica gelPage 41 of 9113250080vlAttorney Docket No. 2019199-016218WOchromatography (hexane / ethyl acetate / 2M NH3 in MeOH 20 / 5 / 1) provides the free base as a yellow foam.

[0130] Amorphous TALADEGIB was prepared by rapid evaporation, under vacuum, of a methanol solution.

[0131] A first, non-solvated, crystalline form, designated FORM I, was readily identified by crystallization from ethanol and water.

[0132] Described herein are studies to:- characterize TALADEGIB crystalline FORM I;- comprehensively screen for and subsequently characterize solid-state forms of TALADEGIB; - understand TALADEGIB crystallization behavior.

[0133] A variety of crystallization techniques and conditions were employed to screen for TALADEGIB solid crystalline forms. While most conditions yielded FORM I (the thermodynamically most stable form), seven additional crystalline forms were identified and characterized: five solvates - toluene, anisole, benzyl alcohol (x2), and methyl t-butyl ether (MTBE), a variable hydrate and a new form characterized by XRPD pattern B. The following abbreviations may be used:Page 42 of 9113250080vlAttorney Docket No. 2019199-016218WOCHARACTERIZATION OF FORM I EXAMPLE 1: FORM I X-RAY POWDER DIFFRACTION (XRPD)

[0134] X-ray powder diffraction (XRPD) patterns were collected on a Bruker D8 Advance X-ray powder diffractometer, equipped with a CuKa source (X=l.54056 A) and a Linxeye detector, and operating at 40 kV and 40 mA, with a 0.2 mm divergence slit (samples were scanned from 4-30° in 0.02°2 steps at a rate of 0.2 seconds per step). Experimental data was processed using DiffracPIus EVA software (Version 14.0).

[0135] X-ray capillary analysis was performed using a Bruker D8 Advance diffractometer, equipped with a General Area Diffraction Detection System (GADDS, v. 4.1.20). An incident beam of CuK radiation was produced using a fine-focus tube (40 kV, 40 mA), cross-coupled powder Gobel mirrors and a 0.5 mm double pinhole collimator. Samples were packed into standard (special) glass thin-walled capillary tubes (Charles Supper Co.) and sealed using vinyl plastic putty (Critoseal®, McCormick Scientific) prior to mounting on the goniometer. A video camera and laser were used to position the area of interest to intersect the incident beam in transmission geometry. Diffraction patterns were collected using a Hi-Star area detector located at 20 or 30 cm from the sample and processed using GADDS. The signal intensity in the GADDS image was integrated using a step size of 0.04° 20 to produce a diffraction pattern as a function of 29. Experimental data were processed using DiffracPIus EVA software (Version 14.0).

[0136] FIGURE 1 shows the FORM I XRPD pattern.

[0137] FIGURE 2 shows the FORM I XRPD pattern with major peaks identified.

[0138] Table 2 shows the FORM I XRPD peak list, sorted by relative intensity.Table 2: FORM I XRPD Peak List (sorted by relative intensity)Page 43 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 2: FORM I OPTICAL PHOTOMICROGRAPH

[0139] An optical photomicrograph of FORM I was collected using an Olympus BX51TF polarizing light microscope, equipped with Olympus 10X, 20X and 50X LMPIan Fl objectives, a 100X oil immersion objective, a PaxCAM2 digital camera, and interfaced with a PC. Samples were imaged in their mother liquors or in the dry state between glass slides. In some instances, oil (Non-drying Immersion Oil for Microscopy Type A, Cargille Laboratories, Inc.) was used. Images were processed using PAX-it software (Versions 6.3 or 7.4). FIGURE 3 shows the FORM I Optical Photomicrograph.EXAMPLE 3: SINGLE CRYSTAL X-RAY of FORM IPage 44 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0140] Single crystal X-ray diffraction data were collected using a Bruker-Nonius Kappa geometry diffractometer equipped with either a CuKa(X = 1.54178A) or MoKa(X = 0.71073A) radiation source and a SMART 6000CCD area detector. Cell refinement and data reduction were accomplished using the SAINT software program (SAINT version 6.2, Bruker AXS Inc.). Structures were solved by direct methods using Siemens SHELXTL-PLUS (Sheldrick, G.M. SHELXTL V5.1). Non-hydrogen atoms were refined anisotropically. All other hydrogen atoms, which were included in the structure factor calculations, were placed in idealized positions (dc-H = 0.95A) and independently refined. The single crystal X-ray structure of FORM I was solved at 100K and room temperature.

[0141] FORM I crystallizes in the centrosymmetric monoclinic space group, P2- c, with one molecule in the crystallographic asymmetric unit (Z' = 1).

[0142] FIGURE 4 shows ORTEP diagrams of the molecule identified in the asymmetric unit, at (a) RT; (b) 100 K; and (c) superimposed crystallographic asymmetric units at both temperatures.

[0143] Table 3 shows the crystal data and structure refinement of FORM I.Table 3: Crystal Data and Structure Refinement of FORM I< < < << < < < < <Page 45 of 9113250080vlAttorney Docket No. 2019199-016218WO< < < < < <>Using the atomic coordinates & unit cell parameters, the powder patterns of FORM I were calculated at (a) 100K and (b) room temperature and (c) compared to the corresponding experimental room temperature diffraction pattern, as shown in FIGURE 5.EXAMPLE 4: FORM I DIFFERENTIAL SCANNING CALORIMETRY (DSC)

[0144] Differential scanning calorimetry (DSC) was conducted using a TA Q1000 DSC. Samples were equilibrated at 25°C in hermetically-sealed aluminum pans, then heated to ~200°C at 2, 5, 20 or 50 °C / min with a nitrogen purge (50mL / min). The temperature and heat flow were calibrated against indium melting.

[0145] FIGURE 6 shows the TALADEGIB FORM I DSC trace measured at 20°C / min. A single endothermic transition was observed at 189.0°C, corresponding to the melting point.The heat of fusion was ~100 J / g.

[0146] FIGURE 7 shows TALADEGIB FORM I DSC traces measured at 50°C / min (upper trace), 10°C / min (middle trace) and 2°C / min (lower trace). Single endothermic transitions were observed at 189.6°C, 188.7°Cand 188.0°C, respectively, corresponding to the melting point.

[0147] The heat of fusion was ~100 J / g.EXAMPLE 5: FORM I NMRPage 46 of 9113250080vlAttorney Docket No. 2019199-016218WOSolution-state1H NMR

[0148] Solution-state1H NMR spectra were collected on a 400 MHz Varian Unity INOVA spectrometer operating at1H and13C frequencies of 399.770 and 100.531 MHz, respectively, using a 5 mm Varian 400ATB PFG probe.FIGURE 8 shows theXH-NMR spectrum of TALADEGIB FORM I, collected in DMSO-d6at 25°C.Solid-state13C NMR

[0149] Cross polarization / magic angle spinning (CP / MAS) NMR (solid-state NMR) spectra were obtained on a Bruker Avance III 400 wide-bore NMR spectrometer operating at1H and13C frequencies of 400.131 and 100.623 MHz, respectively, and using a Bruker 4 mm triple resonance probe.13C chemical shifts were externally referenced (± 0.05 ppm) to the proton-decoupled13C peak of SiMe4 via the high-field resonance of adamantane (8 = 29.5 ppm).FIGURE 9 shows the solid-state13C NMR spectrum of TALADEGIB FORM I, collected at 297K. Solid-state19F Magic Angle Spinning NMR

[0150] 19F Magic angle spinning (MAS) NMR spectra were obtained using a Bruker Avance II 400 MHz NMR spectrometer operating at a fluorine frequency of 376.459 MHz and equipped with a Bruker 4 mm triple resonance probe.3H decoupling was employed using TPPM15 (55.0 Watts). Chemical shifts were externally referenced to polytetrafluoroethylene (6 = -122.7 ppm).FIGURE 10 shows the solid-state19F NMR spectra of TALADEGIB FORM I, collected at 25 °C, and measured at magic angle spinning (MAS) speeds of 15 kHz (upper trace) and 12 kHz (lower trace). It should be noted, peaks that shift as a function of the sample spin rate are designated as spinning side bands, while peaks that do not shift are the isotropic19F resonances (denoted by arrows in the figure). Predicted and observed19F chemical shifts were as follows:Predicted ObservedC-F -61 ppm -60.2 ppmCF3 -110 ppm 3 peaks between -100 and -120 ppmEXAMPLE 6: DIFFERENTIAL THERMAL (DT) / TH ERMOGRAVI METRIC (TG) ANALYSES

[0151] Differential thermal / thermogravimetric analyses were carried out on a TA simultaneous DSC-TGA model Q600. Samples were heated in aluminum pans from ambient temperature to 160-300 °C at a 10 °C / min heating rate with a nitrogen purge (lOOmL / min). The temperaturePage 47 of 9113250080vlAttorney Docket No. 2019199-016218WOwas calibrated with Indium. Weight calibration was performed with manufacturer supplied standards and verified against sodium tartrate dihydrate desolvation.

[0152] FIGURE 11 shows the TALADEGIB FORM I TG-DTA thermogram which presents a single endothermic event at ~188°C, corresponding to the melting point. TGA showed the total volatile content was negligible, confirming the material to be non-solvated.EXAMPLE 7: FORM I MOISTURE SORPTION ANALYSIS

[0153] Moisture sorption analysis was performed at 25°C using a VTI flow moisture balance (Model SGA-100 or Model CX). The following experimental conditions were used: sample size ~20 mg, 5-95% RH adsorption / desorption range, 5% RH step interval. The minimum equilibration criterion was <0.01% weight gain in 15 minutes for a maximum time of 120 minutes.

[0154] FIGURE 12 shows the TALADEGIB FORM I moisture sorption isotherm. A small weight gain was observed by moisture sorption up to 55% RH, followed by a sudden decrease in weight from 55-70% RH.EXAMPLE 8: AMORPHOUS FORM XRPD

[0155] The XRPD of amorphous material was obtained according to the procedures described above. The pattern, showing no sharp peaks, is shown in FIGURE 13.EXAMPLE 9: CONVERSION of FORM I to AMORPHOUS

[0156] FORM I was dissolved in either methanol or THF at room temperature, syringe filtered (0.25 pm filter) into a round bottom flask and the solvent was then rapidly evaporated to dryness under vacuum. The resultant material was analyzed by XRPD and the results presented in Table 4, which shows that fast evaporation of methanol on a small scale yields amorphous material; however, a slightly larger scale yields a mixture of FORM I and amorphous material. Fast evaporation of THF (in which TALADEGIB has higher solubility) yields the amorphous form with trace amounts of FORM I.Table 4: Preparation of Amorphous TALADEGIBPage 48 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 10: CRYSTALLIZATION of the AMORPHOUS FORM

[0157] Amorphous TALADEGIB was seeded with crystalline solvate forms under varying humidity and temperature conditions. The results are presented in Table 5, and show that seeding at room temperature / high humidity or elevated temperature / lower humidity, results in crystallization of amorphous TALADEGIB to FORM I. In all other instances, crystallization was not observed and amorphous material was isolated.Table 5: Solvate Seeding of Amorphous FormSCREENING for NEW CRYSTALLINE FORMSSOLUTION BASED CRYSTALLIZATION

[0158] Solution based crystallization techniques were implemented to identify crystalline forms of TALADEGIB. Amorphous material was prepared by rotary evaporation from methanol or THF. Solvents were purchased from typical suppliers and used as received. Solvents used forPage 49 of 9113250080vlAttorney Docket No. 2019199-016218WOcrystallization screening were reagent grade (99+% purity). Solvents used for preparing mobile phases were HPLC grade. Solvent abbreviations include the following:Abbr NameEXAMPLE 11: SLURRY- SOLUBILITY SCREEN

[0159] Solubility (mg / mL) was measured at 25°C and / or 50°C, in solvents and aqueous-organic solvent mixtures. Suspensions were sampled after 2 and 24 hours and residue analysis performed. The results are presented in Table 6 and show that all conditions (with one exception - DMSO at 25°C), resulted in FORM I. Equilibration in DMSO at 25°C yielded amorphous material (A*) with two sharp diffraction peaks (~8.9 and 17.720), neither of which correspond to FORM I; at 50°C FORM I was isolated.Table 6: Slurry-Solubility Screen performed at 25°C (2hr & 24hr) and 50°C (24hr)Page 50 of 9113250080vlAttorney Docket No. 2019199-016218WO> > > >> > >EXAMPLE 12: LABILE SOLVATE SLURRY SCREEN

[0160] A screen for labile solvates (solvates that are stable only in suspensions) was performed.

[0161] Slurries of FORM I in various solvents / solvent systems (see Table 7) were prepared and allowed to stand at room temperature for ~ 11 days. The slurries were then filtered and the isolated solids, both from the wet cakes and after drying, were analyzed by XRPD. In all instances only FORM I was observed, indicating no solvate formation had occurred.Table 7: Labile Slurry ScreenPage 51 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 13: CRYSTALLIZATION FROM MTBE

[0162] Amorphous TALADEGIB was dissolved in MTBE and stirred at 60°C for 1 hour; during which time the MTBE solvate crystallized. The slurry was cooled to room temperature then stirred overnight. The solid product was filtered under vacuum and air dried to provide an MTBE solvate form.EXAMPLE 14: EVAPORATIVE CRYSTALLIZATION

[0163] An evaporative crystallization screen was performed, under slow (room temp and 5°C) and fast (50°C) evaporation conditions. TALADEGIB (~25mg) was dispensed into 24 (4 mL) vials and then solvents (0.1-4mL) were added. The resulting suspensions / solutions were filtered through 0.45 pm syringe filters into clean vials. The vials were covered with either parafilm or aluminum foil rendered with a pinhole or loosely capped, then placed in a fume hood or refrigerator, allowing the solvents to slowly evaporate at room temperature or 5°C. Filtered solutions were also evaporated at 50°C uncovered. Residues were analyzed after evaporation to dryness. The results are presented in Table 8 and show that most (~70%) conditions resulted in formation of FORM I. Conditions designed to capture metastable, disordered forms (high temperature, fast evaporation) from the more volatile organic solvents yielded amorphous material.

[0164] One new XRPD pattern - a toluene solvate - crystallized concomitantly with FORM I from toluene-organic solvent mixtures. The toluene solvate crystallizes upon scraping the glassy material produced by solvent evaporation with a spatula, (rather than occurring spontaneously upon solvent evaporation). In some instances, (*) solids initially observed as a glass, crystallized on scraping with a spatula.Table 8: Evaporative CrystallizationPage 52 of 9113250080vlAttorney Docket No. 2019199-016218WOPage 53 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 15: COOLING CRYSTALLIZATION

[0165] A cooling crystallization screen was conducted from pure and mixed solvent systems, under linear or natural cooling conditions.

[0166] TALADEGIB (~0.8 mg) was dispensed into vials and solvents (0.5-1.6 mL) were added. The vials were transferred to an Avantium Crystall6 parallel crystallizer, equipped with heating / cooling, magnetic stirring and turbidity sensors. The suspensions were stirred at 700 or 1000 rpm and heated to 60°C at l°C / min, equilibrated for 15 minutes, then cooled to 5°C at 0.25°C / min. The heat / cool cycle was performed twice. Alternatively, TALADEGIB was weighedPage 54 of 9113250080vlAttorney Docket No. 2019199-016218WOinto round bottom flasks and solvents were added. The solutions were generally heated to ~5°C above the temperature at which dissolution was visually complete. The heat source was then removed and the solutions allowed to cooled naturally. Any resulting solids were isolated by vacuum filtration or decantation. When cooling failed to induce precipitation, the resulting solutions were stored in the refrigerator for ~12 days. If crystallization was not observed following low temperature storage, the solutions were warmed to room temperature and allowed to slowly evaporate. The results are presented in Table 9 and show that all conditions yielded FORM I exclusively. [Note, in some solvents, dissolution was incomplete (*)].Table 9: Cooling Crystallization ExperimentsPage 55 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 16: ANTISOLVENT ADDITION CRYSTALLIZATION

[0167] An antisolvent addition crystallization screen was performed.

[0168] TALADEGIB (40 ± 2 mg) was dispensed into 45 (4 mL) vials and solvents (1-4 mL) were added. For standard antisolvent addition experiments (AA), antisolvent was added dropwise until either persistent clouding was observed or the maximum volume of the vial was reached. Reverse antisolvent addition experiments (RAA) involved filtering the solutions into vials containing antisolvent. Standard antisolvent addition experiments (AA) were conducted at room temperature only; reverse antisolvent addition experiments (RAA) were conducted at 5°C, ~25°C (room temperature) and 50°C. Solid products were isolated by vacuum filtration andPage 56 of 9113250080vlAttorney Docket No. 2019199-016218WOair-dried. The results are presented in Table 10, which shows that in all instances where solids were isolated, only FORM I was isolated.Table 10: Antisolvent Addition Crystallization Experiments>Page 57 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 17: VAPOR DIFFUSION CRYSTALLIZATION

[0169] A vapor diffusion screen was performed.

[0170] Antisolvents vapors were diffused into either solutions (method LL: liquid-liquid diffusion), or onto solid amorphous material (method LS: liquid-solid diffusion), to induce crystallization.

[0171] Amorphous TALADEGIB (~20 mg) was dispensed into 4 mL vials, solvents (0.2-4 mL) added and the resulting solutions stirred and filtered to remove any undissolved particulates. Antisolvent (1-2 mL) was added to a 20 mL jar. The open vial was placed in the jar which was then capped. Liquid-solid vapor diffusion experiments were performed by diffusing solvent vapors onto freshly prepared solid amorphous TALADEGIB. All experiments were conducted at room temperature. The solid products were recovered by either decantation of the mother liquor or vacuum filtration, then air-dried. The results are presented in Table 11, which shows that in all instances only FORM I was isolated.Table 11: Vapor Diffusion CrystallizationPage 58 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 18: CRYSTALLIZATION FROM HIGHLY SUPERSATURATED SOLUTIONS

[0172] Amorphous material was rapidly dissolved in acetone or toluene at various concentrations, at room temperature. The results are presented in Table 12, which shows regardless of time, uniquely crystal FORM I was isolated from acetone, and uniquely the toluene solvate was isolated from toluene.Table 12: Crystallization as a Function of Supersaturation< < < < < < < < < < <c / s = concentration / solubility with respect to crystalline FORM IEXAMPLE 19: SUBLIMATIONPage 59 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0173] Sublimation of amorphous material was attempted in search of high temperature crystalline forms. After heating at 110°C for 7 days, the amorphous material transformed to FORM I, with partial degradation. No sublimation was observed.EXAMPLE 20: THERMAL ANNEALING

[0174] Crystallization from the amorphous state was studied by isothermal annealing at various temperatures. The results are presented in Table 13, and show that thermal annealing resulted in no form change from the starting amorphous material. Annealing of amorphous material at 130°C resulted in conversion to FORM I.Table 13: Thermal AnnealingEXAMPLE 21: MOISTURE ANNEALING

[0175] Crystallization from the amorphous state was studied by isothermal annealing at various temperatures under two high humidity conditions (75% and 100% RH). The results are presented in Table 14, and show the amorphous form crystallized to FORM I at both higher temperatures and higher relative humidity conditions.Table 14: Thermal Annealing, under various humidity conditionsPage 60 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 22: SLURRY ANNEALING

[0176] Crystallization from slurries of amorphous material under a range of conditions, was studied. The results are presented in Table 15, and show that with one exception (*), all of the slurry experiments yielded FORM I. Slurrying in water at 90°C for 2 hours produced FORM I, along with two additional sharp diffraction peaks (~7.8 and 19.7°20). On cooling to room temperature, the two new peaks disappeared and the isolated solid was pure FORM I.Table 15: Slurry Annealing<<<EXAMPLE 23: WET GRINDING of FORM I

[0177] Crystallization from wet grinding of crystalline FORM I, at room temperature, was studied.

[0178] TALADEGIB FORM I (20-50 mg) was placed in a 2 mL stainless steel Retsch MM200 grinding mill (GM). Two stainless steel balls and ~4-5 drops of solvent were added and the jar closed with a stainless steel cap. The jar was shaken in 5 or 10 minute increments for 5-30 minutes, at a power setting of 30 Hz. Alternatively, a few drops of solvent were added to solid material and the wetted solids were gently ground using a pestle and mortar (P&M). Recovered solids were air dried at room temperature. The results are presented in Table 16, and show that grinding of FORM I yielded only FORM I. Even after extended grinding (~30 minutes), FORM I remained unchanged.Page 61 of 9113250080vlAttorney Docket No. 2019199-016218WOTable 16: Wet Grinding of FORM I&EXAMPLE 24: WET GRINDING of AMORPHOUS MATERIAL

[0179] Crystallization from wet grinding of amorphous material, at room temperature, was studied. The above procedures were employed starting with amorphous material and the results are presented in Table 17, which shows that wet grinding yielded:a benzyl alcohol solvate form (designated benzyl alcohol solvate I),an anisole solvate form,the toluene solvate form, anda new form characterized byXRPD Pattern B.Table 17: Wet Grinding of amorphous material&& &&& &EXAMPLE 25: FORMATION / TRANSFORMATION OF TOLUENE AND ANISOLE SOLVATES

[0180] The formation and transformation of the toluene and anisole solvates were studied as a function of grinding time. The resulting XRPD patterns are shown in FIGURE 14, and correspond to:a) XRPD pattern of toluene solvate (shown for reference)b) XRPD pattern of FORM I (shown for reference)c) XRPD pattern of anisole solvate produced after extended (30 minutes) grindingPage 62 of 9113250080vlAttorney Docket No. 2019199-016218WOd) XRPD pattern of anisole solvate produced after 5 minutes of mechanical grindinge) XRPD pattern of anisole solvate produced after 10 minutes of manual grindingf) XRPD pattern of starting, amorphous materialThese results show:Solvent drop grinding of amorphous material with toluene produces the toluene solvate.Solvent drop grinding of amorphous material with anisole produces the anisole solvate.On extended grinding (>30 minutes), the anisole solvate begins conversion to FORM I.EXAMPLE 26: THERMAL ANNEALING of the TOLUENE SOLVATE

[0181] Crystallization of the toluene solvate was studied by thermal annealing under varying conditions of humidity, temperature and time. The results are presented in Table 18, and show: At lower temperatures, the toluene solvate partially transforms to hydrate I.At higher temperatures, the toluene solvate transforms to a mixture of hydrate I, FORM I and toluene solvate.Table 18: Thermal and Moisture Annealing of the Toluene SolvatePage 63 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 27: THERMAL ANNEALING of the ANISOLE SOLVATE

[0182] Thermal annealing of the anisole solvate at 120°C resulted in complete conversion to FORM I within 2 hours.

[0183] Thermal annealing of the anisole solvate at room temperature, over 5 days, under increasing humidity conditions (0%, 58% and 98% relative humidity) showed some transformation to FORM I at higher moisture levels, see Table 19.Table 19: Annealing of anisole solvate under increasing moisture levelsEXAMPLE 28: THERMAL ANNEALING of BENZYL ALCOHOL SOLVATE I

[0184] Thermal annealing of the benzyl alcohol solvate I at 120°C resulted in complete conversion to FORM I within 2 hours.

[0185] Thermal annealing of the benzyl alcohol solvate I, at room temperature, over5 days, under increasing moisture levels (0, 58% and 98% relative humidity), resulted in no change in crystalline form, see Table 20.Table 20: Annealing of benzyl alcohol solvate I under increasing moisture levelsEXAMPLE 29: TOLUENE, ANISOLE AND BENZYL ALCOHOL SOLVATE I SLURRY ANNEALING

[0186] Slurry experiments with suspensions of the toluene solvate, anisole solvate and benzyl alcohol solvate I in various organic solvents resulted in conversion to FORM I, as shown in Table 21.Table 21: Solvate Slurry AnnealingPage 64 of 9113250080vlAttorney Docket No. 2019199-016218WO< > < ><PREPARATION OF TALADEGIB CRYSTALLINE FORMS

[0187] Solid form screening identified seven crystal forms:anhydrous FORM Itoluene solvateanisole solvatebenzyl alcohol (I) solvateMTBE solvatevariable hydrate Ian unconfirmed form characterized by XRPD pattern B.In order to fully characterize them, large scale preparation of the newly identified forms was undertaken.EXAMPLE 30: PREPARATION OF CRYSTALLINE FORMS

[0188] The hydrate I, toluene, anisole, benzyl alcohol I, and MTBE solvate forms were prepared as described below.Hydrate I

[0189] Hydrate I was prepared as a physical mixture with the toluene solvate by extended grinding of amorphous TALADEGIB (~50 mg) with a few drops of toluene on a RetschMM200 grinding mill at 30 Hz power for 30 minutes. The ground solids were dried overnight in a fume hood, under ambient conditions, to remove residual solvent.Page 65 of 9113250080vlAttorney Docket No. 2019199-016218WOToluene solvate

[0190] The toluene solvate was prepared by solvent drop grinding of amorphous TALADEGIB (~200mg) with toluene (0.5 mL) for 10-15 minutes using a mortar and pestle. The damp solids were air dried at room temperature to remove residual solvent.Anisole solvate

[0191] The anisole solvate was prepared by dissolving the toluene solvate in anisole at 100°C, and the solution further heated to 120°C for 3 hours. The heat source was then removed and the solution allowed to cool to R room temperature T. The anisole solvate crystallized at approximately 43°C. The suspension was stirred overnight at room temperature, filtered under vacuum and the solid product air dried.Benzyl alcohol solvate I

[0192] The benzyl alcohol solvate I was prepared by solvent drop grinding of amorphous TALADEGIB (153mg) with a few drops of benzyl alcohol for 10-15 minutes using a mortar and pestle. The sample was air dried at room temperature.MTBE solvate

[0193] Amorphous TALADEGIB (~100 mg) was dissolved in MTBE then stirred at 60°C for 1 hour; during which time the MTBE solvate crystallized. The slurry was cooled to room temperature then stirred overnight. The solid product was filtered under vacuum and air dried.

[0194] The toluene, anisole, and benzyl alcohol (I), MTBE, solvates were prepared using a variety of methods, including slow crystallization (SC), slow evaporation (SE), Grinding, cooling crystallization (CC), and cooling crystallization with seeding (for the toluene solvate *), as presented in Table 22.Table 22: Preparation of New Crystalline Solvate Forms<Page 66 of 9113250080vlAttorney Docket No. 2019199-016218WO<<< <<<<CHARACTERIZATION OF TALADEGIB SOLVATE CRYSTALLINE FORMS EXAMPLE 31: SINGLE CRYSTAL X-RAY OF BENZYL ALCOHOL SOLVATES I & II Table 23: Crystal Data and Structure Refinement of Benzyl Alcohol Solvates s I & II< < < << < < << < < <Page 67 of 9113250080vlAttorney Docket No. 2019199-016218WO>EXAMPLE 32: XRPD PATTERNS

[0195] XRPD patterns were obtained as described above.FIGURE 15 shows the superimposed XRPD patterns for the MTBE, Benzyl alcohol I, Benzyl alcohol II, Anisole, Hydrate I and Toluene solvates and FORM I.EXAMPLE 33: CRYSTAL FORM CHARACTERIZATION

[0196] XRPD, NMR (Solution3H NMR and Solid-state13C NMR), and TG-DTA characterization of the various crystal forms was performed AS DESCRIBED ABOVE, and the results presented in Figures 16-30.FIGURE 16 shows the toluene solvate XRPD pattern.FIGURE 17 shows the toluene solvate (a) solution1H NMR and (b) solid-state13C NMR spectrum FIGURE 18 shows the toluene solvate TG-DTA thermogramFIGURE 19 shows the anisole solvate XRPD patternFIGURE 20 shows the anisole solvate (a) solutionXH NMR and (b) solid-state13C NMR spectrum FIGURE 21 shows the anisole solvate TG-DTA thermogramFIGURE 22 shows the benzyl alcohol solvate I XRPD patternFIGURE 23 shows the benzyl alcohol solvate I solution3H NMR spectrum. (The resonance at ~5.2 ppm (arrow) is due to an impurity in benzyl alcohol)FIGURE 24 shows the benzyl alcohol solvate I TG-DTA thermogramFIGURE 25 shows the hydrate I XRPD patternFIGURE 26 shows the hydrate I (a) solution3H NMR and (b) solid-state13C NMR spectrum FIGURE 27 shows the hydrate I TG-DTA thermogramFIGURE 28 shows the MTBE solvate XRPD patternPage 68 of 9113250080vlAttorney Docket No. 2019199-016218WOFIGURE 29 shows the MTBE solvate solution1H NMR spectrumFIGURE 30 shows the MTBE solvate TG-DTA thermogramTALADEGIB SALT AND CO-CRYSTAL SCREENSEXAMPLE 34: Preparation and Evaluation of TALADEGIB salts TALADEGIB was mixed with 18 different acids (Table 24) to evaluate crystal salt formation.

[0197] A stock solution (approx. 27.3mg / mL, 0.05M) of TALADEGIB (450mg, 0.88mmol) in methanol (16.5mL) was prepared and 100 pL transferred to each well of a 96-well plate. A solution of test acid in methanol (0.1M, 58uL, l.leq) was added to each well and the plate placed in a fume hood under ambient conditions and evaporated to dryness (~1 day). One of eight test solvents (200 pL) was then added, and the plate covered with a film perforated with pinholes and placed in a fume hood under ambient conditions for slow solvent evaporation (~3 days). After evaporation to dryness, any observed solids were analyzed by polarized light microscopy (PLM) and XRPD. The observations and analyses of the materials produced are summarized in table 25.Table 24: Test Acids><Page 69 of 9113250080vlAttorney Docket No. 2019199-016218WO""of crystallinity and displayed irregular crystalline shapes.

[0199] Methanesulfonic Acid, Ethanesulfonic Acid, Maleic Acid and Citric Acid generated no solid material. Non-glassy solids isolated from Formic Acid, Acetic Acid, Succinic Acid, Fumaric Acid, L-Lactic Acid and L-Tartaric Acid were starting material. Non-glassy solids isolated from Phosphoric Acid were amorphous. Tosylic Acid, HCI, HBr, Nitric Acid, Sulfuric Acid and Oxalic Acid and generated crystalline material, displaying new XRPD patterns, indicating the formation of new crystalline states.Table 25: Results of TALADEGIB salt screenPage 70 of 9113250080vlAttorney Docket No. 2019199-016218WOS: solid; G: glassy; AM: amorphous; SM: starting material; P: pattern; * Insufficient material ACN: Acetonitrile; DCM = Dichloromethane; EA = Ethyl acetate; IPA = Isopropyl alcohol;MTBE = Methyl t-butyl ether; THF = Tetra hydrofuran

[0200] p-TsOH - Three XRPD patterns were observed (figure 31), all displaying irregular shaped crystals: Pattern 1 was observed for a sample obtained from ethyl acetate, Pattern 2 was observed for a sample obtained from dichloromethane and Pattern 3 was observed for a sample obtained from acetone. The major XRPD peaks for each form are listed in table 26.Table 26: XRPD Peak Listing for TALADEGIB Tosylate SaltsPage 71 of 9113250080vlAttorney Docket No. 2019199-016218WO16.72 26% 5.300 19.99 15% 4.439 17.37 8% 5.101 20.30 8% 4.370 18.63 27% 4.759 21.50 10% 4.130 19.07 44% 4.649 22.02 9% 4.033 20.46 31% 4.338 23.39 9% 3.800 20.69 12% 4.289 26.70 9% 3.3364 21.22 100% 4.185 27.41 7% 3.2517 22.56 20% 3.93922.78 28% 3.90122.93 13% 3.87523.43 14% 3.79424.30 18% 3.66026.01 8% 3.42327.07 15% 3.29128.05 9% 3.17928.87 12% 3.09029.22 6% 3.05430.70 6% 2.91033.05 7% 2.70833.72 6% 2.65635.30 7% 2.540

[0201] HCI - Three XRPD patterns were observed (figure 32), all displaying irregular shaped crystals: Pattern 1 was obtained from ethyl acetate, Pattern 2 was obtained from MTBE, and Pattern 3 was obtained from THF. The major XRPD peaks for each form are listed in table 27.Table 27: XRPD Peak Listing for TALADEGIB HCI SaltsPage 72 of 9113250080vlAttorney Docket No. 2019199-016218WO23.05 8% 3.855 23.31 19% 3.813 23.60 10% 3.767 24.37 14% 3.649 24.73 12% 3.597 25.46 22% 3.496 25.75 10% 3.457 26.08 14% 3.415 28.11 9% 3.172 29.57 100% 3.019 34.63 9% 2.589 36.30 8% 2.473 39.81 8% 2.263

[0202] HBr - Three XRPD patterns were observed (figure 33), all displaying irregular shaped crystals: Pattern 1 was observed for a sample obtained from MTBE, Pattern 2 was observed for a sample obtained from ethyl acetate, and Pattern 3 was observed for a sample obtained from acetone. The major XRPD peaks for each pattern are listed in table 28.Page 73 of 9113250080vlAttorney Docket No. 2019199-016218WOTable 28: XRPD Peak Listing for TALADEGIB HBr Salts

[0203] Benzenesulfonic Acid - Two XRPD patterns were observed (figure 34): Pattern 1 was observed for a sample obtained from MTBE and Pattern 2 was observed for a sample obtained from isopropanol. The major XRPD peaks for each pattern are listed in table 29.Table 29: XRPD Peak Listing forTALADEGIB Besylate SaltsPage 74 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0204] HNO3- One XRPD pattern was observed (figure 35) for a sample obtained from ethyl acetate, displaying plate shapes crystals. The major XRPD peaks are listed in table 30.Table 30: XRPD Peak Listing for TALADEGIB Nitrate SaltAngle Relative d Value(°20) Intensity (A)4.51 100% 19.57919.11 17% 9.700813.72 15% 6.448623.02 23% 3.8597

[0205] H2SO4- One XRPD pattern was observed (figure 36) for a sample obtained from dichloromethane, with low crystallinity. The major XRPD peaks are listed in table 31.Table 31: XRPD Peak Listing for TALADEGIB Sulfate SaltAngle Relative d Value(°26) _ Intensity _ (A)18.40 _ 100% _ 4.81820.97 52% 4.232

[0206] Oxalic Acid - One XRPD pattern was obtained (see figure 37) for a sample obtained from dichloromethane and ethyl acetate; both samples displayed low crystallinity, with irregular shaped crystals. The major XRPD peaks are listed in table 32.Table 32: XRPD Peak Listing for TALADEGIB Oxalate Salt

[0207] NMR analysis of the crystalline salts from HCI, HBr, sulfuric acid, p-TsOH, BsOH and nitric acid was performed in DMSO-d6. The signals at 6.60 ppm (pyrazole proton) and 7.8-8.5 ppm (phthalazine proton) of the free base TALADEGIB starting material were significantly shifted,Page 75 of 9113250080vlAttorney Docket No. 2019199-016218WOindicating these materials are salts. NMR analysis of the samples generated from oxalic acid and phosphoric acid did not present any discernable chemical shifts.EXAMPLE 35: TALADEGIB Co-crystal Screen (first)

[0208] A first TALADEGIB cocrystal screen was performed using the following 41 co-formers, known to be pharmaceutically acceptable and / or GRAS (Generally Recognized As Safe).Ascorbyl palmitate Hydroxyethyl morpholine ProlineAspartame Hydroxyethyl pyrrolidine Propyl gallate Benzathine Imidazole SarcosineCaffeine Inositol SorbitolCapric acid Isonicotinamide Stearic acidCholic acid Lactose SucraloseChrysin Lauric acid Tromethamine Diethanolamine Leucine Tryptophan Ethanolamine Lysine TyrosineErythritol Maltol ValineGenistein Meglumine VanillinGlucose Methionine XanthineGlycine Nicotinamide XyloseHistidine Nicotinic acid

[0209] In brief, equimolar amounts of co-former and TALADEGIB were mixed in a variety of solvents, under varying conditions (milling, saturated slurry and / or co-melt). Any isolated solids were analyzed by XRPD, NMR, TGA and / or DSC, as described below. No new crystalline material was observed.X-ray Powder Diffraction (XRPD)

[0210] A Rigaku SmartLab X-Ray Diffractometer was configured in Bragg-Brentano reflection geometry equipped with a beam stop and knife edge to reduce incident beam and air scatter. Data collection parameters were as follows:Parameter Value Parameter Value Geometry: Bragg-Brentano Receiving Slit 1 (mm): 18Tube Anode: Cu Receiving Slit 2 (mm): Open, 20.1 Tube Type: Long Fine Focus Start Angle 2i? (°): 2Tube Voltage (kV): 40 End Angle 2i (°): 40Tube Current (mA): 44 and 50 Step Size (°): 0.02Page 76 of 9113250080vlAttorney Docket No. 2019199-016218WODetector: HyPix-3000 Scan Speed (o / min): 6 Monochromator: Ni foil Cu / C Filter Spinning (rpm): 11Incident Slit (°): 1 / 3 Sample Holder: Low-background SiPowder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder.1H Nuclear Magnetic Resonance Spectroscopy (NMR)

[0211] The 1H NMR spectra were acquired on a Bruker Neo 400 MHz spectrometer (observed 400.15 MHz) using TopSpin 4.1.4 GxP software. Samples were prepared by dissolving material in DMSO-c / 6. Solutions were placed into individual 5-mm NMR tubes for subsequent spectral acquisition. Chemical shifts are reported in ppm (5) relative to the solvent peak. The probe was set to keep the sample at a constant 298K.Thermogravimetric Analysis (TGA)

[0212] The TG analyses were carried out using a TA Instruments Q5500 Discovery Series instrument. The instrument balance was calibrated using class M weights and the temperature calibration was performed using alumel. The nitrogen purge was ~10 mL per minute at the balance and ~25 mL per minute at the furnace. Each sample was placed into a pre-tared platinum pan and heated from approximately 25°C to 300°C at a rate of 10°C per minute.Differential Scanning Calorimetry (DSC)

[0213] The DSC analyses were carried out using a TA Instruments Q2000 Discovery Series instrument. The DSC cell was kept under a nitrogen purge of ~50 mL per minute during each analysis. Each sample was placed in a standard, crimped aluminum pan and heated from approximately -30°C to 300°C at a rate of 10°C per minute.I Preparation of Co-Crystals via Milling

[0214] TALADEGIB Form I (approx. 20 mg) was loaded into a PEEK grinding cup with an internal volume of ~2mL. Co-former (1 eq) and indicated solvent (10pL) were added. A stainless-steelPage 77 of 9113250080vlAttorney Docket No. 2019199-016218WOball was added, and the grinding cup placed on a Retsch mill and milled at 25 Hz for 30 minutes. The results are shown in table 33.Table 33: Results of Cocrystal Screen after Milling at 25Hz for 30 minutesPage 78 of 9113250080vlAttorney Docket No. 2019199-016218WOForm I = TALADEGIB free base Form I; CF = co-formerNC = Non-Crystalline material observedII Preparation of Co-Crystals via Saturated Slurry (SS)

[0215] TALADEGIB Form I and co-former were added to a solution until solids persisted. The suspension was stirred at ambient temperature for several days. The suspension was centrifuged, the mother liquor was decanted, and any remaining solids were analyzed by XRPD.

[0216] If unique peaks (not attributable to either starting material) were present in the XRPD pattern, TALADEGIB was combined with the co-former (1 eq) in a vial equipped with a stir bar. A solution pre-saturated with both components was then added and the suspension stirred at ambient temperature for several days. The suspension was centrifuged, the mother liquor was decanted, and the remaining solids were analyzed by XRPD. The results are shown in table 34.Table 34: Results of Cocrystal Screen via Saturated SlurryPage 79 of 9113250080vlAttorney Docket No. 2019199-016218WOIII Preparation of Co-Crystals via Co-melt

[0217] TALADEGIB Form I was combined with co-former on a glass slide. The slide was placed on a hotstage and the mixture heated until all solids melted. Once melting was complete, the liquid was mixed with a spatula to ensure homogeneity. The slide was removed from the hotstage and cooled to ambient temperature. The results are shown in table 35.Table 35: Results of Cocrystal Screen via Co MeltingEXAMPLE 36: TALADEGIB Co-crystal / Salt Screen (second)Page 80 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0218] A second TALADEGIB cocrystal / salt screen was performed using additional co-formers / acids, according to the methods described in example 35. The results are summarized in Table 36.Table 36. Results of Expanded Cocrystal / Salt Screen>> >>>>Page 81 of 9113250080vlAttorney Docket No. 2019199-016218WO> >>>Form I = TALADEGIB free base Form I; CF = co-former

[0219] Slurrying conditions generated new crystalline material isolated from six acids, (described in greater detail below, examples 37 - 42):Benzenesulfonic acid (Besylic acid, BSA)Ethane-l,2-disulfonic acid (Edisylic acid, EDSA)Hydrochloric acid (HCI)Naphthalene-l,5-disulfonic acid (Napadisylate, NDSA)Naphthalene-2-sulfonic acid (Napsylate, NSA)Toluenesulfonic acid (Tosylic acid, TSA)EXAMPLE 37: TALADEGIB BesylatePage 82 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0220] A solution of benzenesulfonic acid (11.3 mg, 1 eq) in ethanol (0.5mL) was added to TALADEGIB (34.3 mg), to afford a clear solution. The solution was placed in a refrigerator and stirred at sub-ambient temperature for approximately 5 days, during which time solids formed. The resulting suspension was centrifuged, the mother liquor removed by decanting, and the remaining solids isolated and analyzed.

[0221] XRPD shows the material is crystalline and is likely hydrated.

[0222] 1HNMR is consistent with the chemical structures of TALADEGIB and benzenesulfonic acid in a 1:1 stoichiometry. TALADEGIB peak shifts, from 2.8 & 3.3 ppm to 3.3 & 3.5 respectively, are indicative of salt formation. The peaks around 4 ppm are also slightly shifted downfield. Trace solvent contaminants (0.1 moles diethyl ether) were observed,The TG thermogram shows overlapping weight losses from ambient to 80°C (2.9%) and from 80°C to 132°C (1.0%), consistent with a hydrated material.

[0223] The total loss is likely due to water, equivalent to about 1.5 mole water per mole of the 1:1 salt.

[0224] The DSC thermogram shows a broad endotherm at 77°C, concurrent with the weight loss, and is likely a dehydration event. This is followed by two additional endotherms at 150°C (likely a solid-state transition upon heating) and 171°C likely due to melting.

[0225] Figure 38 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Besylate salt.EXAMPLE 38: TALADEGIB HydrochloridePage 83 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0226] Concentrated hydrochloric acid (7.6 pL, 1 eq) was added to a suspension of TALADEGIB (45.1 mg,) in methyl tert-butyl ether (ImL). The resultant mixture was stirred at ambient temperature for approximately 5 days. It was then centrifuged, the mother liquor removed by decanting, and the remaining solids isolated and analyzed.

[0227] By XRPD, the material is crystalline containing trace TALADEGIB Form I.

[0228] 1HNMR is consistent with the chemical structure of TALADEGIB, and the same peak shifts as observed for the Besylate salt were present.

[0229] The TG thermogram shows a very small (0.2%) weight loss starting at 139°C, equivalent to a negligible amount of water or MTBE, consistent with anhydrous material.

[0230] The DSC thermogram shows an endotherm at 215°C likely due to melting, with a shoulder present at 186°C possibly due to the melt of TALADEGIB Form I.

[0231] Figure 39 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Hydrochloride salt.EXAMPLE 39: TALADEGIB Edisylate

[0232] A solution of ethane-l,2-disulfonic acid dihydrate (21.7 mg, 1 eq) in / so-propanol (0.5mL) was added to TALADEGIB (46.9 mg). Additional solvent (0.5 mL) was added, and the resulting suspension heated for two hours at approximately 50°C, resulting in complete dissolution. The solution was cooled to ambient temperature and then placed in a refrigerator and stirred at sub-ambient temperature for approximately 5 days, during which time solids formed. The resulting suspension was centrifuged, the mother liquor removed by decanting, and the remaining solids isolated and analyzed.

[0233] Edisylate 1 is likely a mixed IPA solvate / hydrate.

[0234] XRPD shows the material to be crystalline with a significant amorphous component.Page 84 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0235] 1HNMR is consistent with the chemical structures of TALADEGIB and ethane-1,2-disulfonic acid and shows the presence of 0.9 moles / so-propanol. The TALADEGIB : acid stoichiometry is 3:2 or possibly 2:1 with a slight excess of acid.

[0236] The TG thermogram shows significant weight loss (9.1%) from ambient through 149°C.

[0237] The DSC thermogram does not show a clear melt event, though the minor endotherm at 148°C, is likely due to melting. The broad endotherm at 115°C is concurrent with the weight loss observed in the TG thermogram, likely due to dehydration / desolvation.

[0238] Figure 40 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Edisylate salt.EXAMPLE 40: TALADEGIB Napadisylate

[0239] A solution of naphthalene-l,5-disulfonic acid tetrahydrate (31.5 mg, 1 eq) in ethanol (0.5mL) was added to TALADEGIB (43.1 mg), to produce a clear solution. The solution was placed in a refrigerator and stirred at sub-ambient temperature for approximately 5 days, during which time solids formed. The resulting suspension was then centrifuged, the mother liquor removed by decanting, and the remaining solids isolated and analyzed.

[0240] The obtained TALADEGIB napadysilate salt is likely hydrated.

[0241] XRPD shows the material to be crystalline, with some disorder and amorphous content.

[0242] 1HNMR is consistent with the chemical structures of TALADEGIB and naphthalene-1,5-disulfonic acid in a 2:1 stoichiometry. Trace amounts (0.05 moles) of ethanol were present. Similar peak shifts as seen for other salts were observed.

[0243] The TG thermogram shows a 1.3% weight loss, mostly occurring below 100°C, attributed to water loss, equivalent to one mole of water per mole of salt.Page 85 of 9113250080vlAttorney Docket No. 2019199-016218WO

[0244] The DSC thermogram does not show a clear melt endotherm. The endotherm at 78°C is due to dehydration / desolvation as it is broad and occurs concurrently with the weight loss in the TG thermogram.

[0245] Figure 41 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Napadisylate salt.EXAMPLE 41: TALADEGIB Napsylate>

[0246] A solution of naphthalene-2-sulfonic acid monohydrate (24.4 mg, 1 eq) in / so-propanol (0.5mL) was added to TALADEGIB (46.7 mg). Additional solvent (0.5 mL) was added, and the suspension was heated at 50°Cfortwo hours, resulting in complete dissolution. The solution was cooled to ambient temperature and then placed in a refrigerator and stirred at subambient temperature for approximately 5 days, during which time solids formed. The resulting suspension was centrifuged, the mother liquor removed by decanting, and the remaining solids isolated.

[0247] XRPD shows the material to be crystalline and likely hydrated.

[0248] ^NMR is consistent with the chemical structures of TALADEGIB and naphthalene-2-sulfonic acid in a 1:1 stoichiometry. Trace amounts (0.02 moles) of / so-propanol were observed. Similar peak shifts as seen for other salts were observed.

[0249] The TG thermogram shows a 2.3% weight loss below 125°C, attributed to water loss, equivalent to one mole of water per mole of salt.The DSC thermogram shows a broad endotherm at 124°C attributable to a dehydration event. Melting occurred at 158°C.

[0250] Figure 42 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Napsylate salt.Page 86 of 9113250080vlAttorney Docket No. 2019199-016218WOEXAMPLE 42: TALADEGIB Tosylate

[0251] A solution of toluenesulfonic acid (20.9 mg, 1 eq) in acetone (0.5mL) was added to TALADEGIB (38.4mg,), resulting in the formation of a thick solid plug. Additional solvent was added, and the thick suspension stirred at ambient temperature for approximately 5 days. The suspension was centrifuged, the mother liquor removed by decanting, and the remaining solids isolated.

[0252] XRPD shows the material to be crystalline, with some disordered and amorphous material.

[0253] 1HNMR is consistent with the chemical structures of TALADEGIB and toluenesulfonic acid in a 1:1 stoichiometry. A small amount (0.2 moles) of acetone was observed. Similar peak shifts as seen for other salts were observed.

[0254] The TG thermogram shows a 2.8% weight loss from ambient to 155°C, equivalent to either 0.2 moles of acetone (as observed in the1HNMR) and 0.5 moles of water per mole of salt; or one mole of water per mole of salt. Thus, Tosylate is likely hydrated.

[0255] The DSC thermogram shows broad endotherms at 82°C and 138°C, concurrent with weight loss likely due to dehydration / desolvation. There is another endotherm at 162°C, followed by an exotherm at 174°C and subsequent endotherm at 195°C, indicative of a meltrecrystallization-melt event, with a final melt at 195°C.

[0256] Figure 43 shows the XRPD (top),1HNMR spectrum (middle) and thermograms (bottom) of the TALADEGIB Tosylate salt.Page 87 of 9113250080vl

Claims

Attorney Docket No. 2019199-016218WOCLAIMSWhat is claimed is:

1. A method for treating or preventing fibrosis, comprising administering an effective amount of a composition comprising an amorphous form of 4-fluoro-N-methyl-N-(l-(4- (l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide:and a crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.

2. The method according to claim 1, for treating fibrosis.

3. The method according to claim 1, wherein the fibrosis is pulmonary fibrosis.

4. The method according to claim 3, wherein the pulmonary fibrosis is Idiopathic Pulmonary Fibrosis (IPF) or non-IPF Progressive Pulmonary Fibrosis (PPF).

5. The method according to claim 1, wherein the crystalline form is characterized by one or more XRPD peaks at 17.70, 21.57 or 22.46 °20 + 0.2 °20.

6. The method according to claim 5, wherein the crystalline form is characterized by two or more XRPD peaks at 17.70, 21.57 or 22.46 °20 ± 0.2 °20.

7. The method according to claim 5, wherein the crystalline form is characterized by XRPD peaks at 17.70, 21.57 or 22.46 °20 ± 0.2 °20.Page 88 of 9113250080vlAttorney Docket No. 2019199-016218WO8. The method according to claim 1, wherein the composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of the amorphous form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.

9. A method for treating or preventing fibrosis, comprising administering an effective amount of a composition, wherein the composition comprises a crystalline form of 4- fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2- (trifluoromethyl)benzamide:characterized by one or more XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °29.

10. The method according to claim 9, wherein the crystalline form of 4-fluoro-N-methyl-N- (l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2- (trifluoromethyl)benzamide is characterized by two or more XRPD peaks at 17.70, 21.57 and 22.46 °20 + 0.2 °20.

11. The method according to claim 9, wherein the crystalline form of 4-fluoro-N-methyl-N- (l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2- (trifluoromethyl)benzamide is characterized by three or more XRPD peaks at 17.70, 21.57 and 22.46 °20 ± 0.2 °20.

12. The method according to claim 9, wherein the crystalline form of 4-fluoro-N-methyl-N- (l-(4-(l-methyl-lH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4-yl)-2-Page 89 of 9113250080vlAttorney Docket No. 2019199-016218WO(trifluoromethyl)benzamide is characterized by XRPD peaks at 17.70, 21.57 and 22.46 °20 ± O.2 °20.

13. The method according to claim 9, wherein the composition comprises at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8% or at least 99.9% by weight of the crystalline form of 4-fluoro-N-methyl-N-(l-(4-(l-methyl-lH-pyrazol-5- yl)phthalazin-l-yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide.

14. The method of claim 9, for treating fibrosis.

15. The method of claim 9, wherein the fibrosis is pulmonary fibrosis.

16. The method of claim 15, wherein pulmonary fibrosis is Idiopathic Pulmonary Fibrosis (IPF) or non-IPF Progressive Pulmonary Fibrosis (PPF).Page 90 of 9113250080vl

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