Polymorphs and solid forms of a tetrahydroisoquinolinpyrazoloquinolin compound, and pharmaceutical compositions thereof

Abstract

The present invention relates to amorphous and crystalline forms of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline, available both as a free base and as pharmaceutically acceptable salts, for the treatment of cancer and other diseases associated with the FMS-like tyrosine kinase 3 (FLT3) gene. The disclosure also includes processes for preparation these polymorphic forms.

Description

Lomond.24.0001.W POLYMORPHS AND SOLID FORMS OF A TETRAHYDROISOQUINOLIN- PYRAZOLOQUINOLIN COMPOUND, AND PHARMACEUTICAL COMPOSITIONS THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Patent Application Serial No. 63 / 706,035 filed October 11, 2024, entitled “Polymorphs and solid forms of a tetrahydroisoquinolin-pyrazoloquinolin compound, and pharmaceutical compositions thereof” the disclosure of which are incorporated by reference in its entirety for all purposes. FIELD OF INVENTION

[0002] The present invention relates to amorphous and crystalline forms of 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline, available both as a free base and as pharmaceutically acceptable salts, for the treatment of cancer and other diseases associated with the FMS-like tyrosine kinase 3 (FLT3) gene. The disclosure also includes processes for preparation these polymorphic forms. BACKGROUND

[0003] Acute myeloid leukemia (AML) is a cancer affecting the myeloid line of blood cells. It is marked by the rapid proliferation of abnormal cells, which accumulate in the bone marrow and bloodstream, disrupting normal blood cell production. As an acute leukemia, AML progresses quickly and can be fatal within weeks or months if left untreated.

[0004] AML is a highly heterogeneous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is FLT3. Activating mutations in FLT3, especially the FLT3-internal tandem duplication (FLT3-ITD), are linked to reduced progression-free and overall survival. Recognizing the significance of FLT3-ITD and the FLT3 pathway in the prognosis of AML patients has spurred efforts to develop therapeutic FLT3 inhibitors. Although these inhibitors have demonstrated promising antileukemic activity, their effectiveness as single agents has been limited, suggesting the need for combination with cytotoxic chemotherapies.

[0005] In 2015, AML affected approximately one million people and caused 147,000 deaths worldwide. It most commonly occurs in older adults and affects males more often than females. The five-year survival rate is about 35% for individuals under 60 years old and 10% for those over 60. Older adults with poor health who are unable to undergo intensive chemotherapy typically have a survival span of five to ten months. AML accounts for roughly 1.1% of all cancer cases and 1.9% of cancer deaths in the United States. 1. ASBLomond.24.0001.W

[0006] In some patients with AML, the leukemia cells have a mutation in the FLT3 gene, which helps produce a protein (also called FLT3) that promotes cell growth. Drugs targeting the FLT3 protein can help treat these leukemias. The most advanced example of such drugs is Gilteritinib. Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations.

[0007] Multiple crystal forms of a drug substance can exhibit differences in bioavailability, shelf life, and physical-chemical properties such as melting point, crystal morphology, intrinsic dissolution rates, solubility, and stability, as well as behavior during processing. X-ray powder diffraction (XRPD) is a powerful tool for identifying different crystal phases by their unique diffraction patterns. Other useful techniques include solid-state Nuclear Magnetic Resonance (NMR) spectroscopy, RAMAN spectroscopy, and Differential Scanning Calorimetry (DSC).

[0008] The pharmaceutical industry frequently encounters multiple polymorphs of the same crystalline chemical entity. Polymorphism is defined as the ability of a drug substance, or Active Pharmaceutical Ingredient (API), to exist in two or more crystalline phases with different arrangements and / or conformations of the molecules in the crystal lattices, resulting in distinct physicochemical properties. The ability to reliably manufacture the selected polymorphic form is a crucial factor in determining the success of the drug product.

[0009] Regulatory agencies worldwide require a reasonable effort to identify the polymorphs of a drug substance and monitor for polymorph interconversions. Due to the often-unpredictable behavior of polymorphs and their differing physicochemical properties, it is essential to demonstrate consistency in manufacturing across batches of the same product. A thorough understanding of the polymorph landscape and the nature of the polymorphs will contribute to manufacturing consistency.

[0010] Determining crystal structure at the atomic level and analyzing intermolecular interactions provide critical information for establishing absolute configuration (enantiomers), phase identification, quality control, and process development and optimization. X-ray diffraction is widely recognized as a reliable tool for analyzing the crystal structure of pharmaceutical solids and identifying crystal forms.

[0011] The availability of a single crystal of the drug substance is preferred due to the speed and accuracy of structure determination. However, it is not always possible to obtain a crystal of suitable size for data collection. In such cases, synchrotron X-ray powder diffraction is a useful technique. The crystal structure can be solved from X-ray powder diffraction data obtained through measurements at ambient conditions and / or at variable temperature or humidity.

[0012] There is a need to develop new polymorphic forms of drug substances and methods for preparing them. 2. ASBLomond.24.0001.W SUMMARY

[0013] A first aspect of the invention relates to crystalline polymorph or amorphous forms of a FLT3 kinase inhibitor, referred to herein as the Formula (I) compound and having the structure: , or a pharmaceutically thereof.

[0014] Another a compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form A that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.5, 6.9, 7.1, 10.2, 10.6, 10.9, 12.9, 13.8, 14.2, 14.9, 16.4, 17.6, 18.1, 18.6, 19.3, 19.4, 20.1, 20.5, 21.3, 22.0, 22.6, 23.1, 23.3, 23.8, 24.2, 24.9, 25.5, 25.7, 26.6, 27.3, 27.7, 28.6, 29.7, 30.1, 30.4, 30.8, 31.8, 32.3, 32.6, 33.3, 34.2, 35.7, 36.4, 36.6, 37.1, 37.9, 39.0 and 39.7.

[0015] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form B that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.3, 7.5, 8.8, 11.4, 13.4, 14.8, 15.1, 16.6, 16.6, 17.5, 17.6, 17.9, 18.0, 18.9, 19.4, 19.9, 21.1, 21.4, 22.5, 23.5, 24.0, 24.7, 24.9, 26.3, 26.8, 27.5, 28.3, 28.7, 30.2, 31.9, 32.3, 32.9, 34.3, 35.6, 36.5 and 38.3.

[0016] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form C that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 7.6, 9.8, 10.4, 13.8, 15.1, 17.6, 18.5, 19.3, 20.2, 20.9, 21.8, 22.2, 22.8, 23.8, 24.5, 25.1, 25.6, 26.1, 26.7, 27.9, 29.4, 29.8, 30.6, 31.5, 32.3, 32.8, 33.8, 37.3, and 38.1.

[0017] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form D that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.1, 6.6, 8.5, 9.4, 10.6, 12.2, 12.5, 13.5, 13.9, 14.2, 14.7, 15.3, 3. ASBLomond.24.0001.W 16.0, 16.4, 18.0, 19.4, 20.7, 21.0, 21.8, 22.2, 22.9, 24.0, 24.4, 25.2, 25.6, 26.2, 26.8, 28.1, 28.6, 30.7, 31.9, and 32.2.

[0018] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form E that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.4, 7.6, 8.9, 9.7, 10.2, 13.7, 15.2, 17.7, 18.1, 18.8, 19.3, 20.1, 20.9, 22.1, 22.4, 23.0, 23.4, 23.9, 24.4, 25.6, 26.0, 27.5, 28.5, 30.6, 32.1, 35.7 and 38.0.

[0019] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form F that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.2, 8.1, 9.7, 10.6, 11.7, 12.6, 15.0, 16.3, 17.5, 18.5, 19.7, 20.9, 21.3, 22.0, 22.8, 23.7, 24.2, 24.7, 25.4, 25.7, 26.4, 28.3, 28.6, 31.2, 32.4, and 35.4.

[0020] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.18, 6.38, 7.23, 9.26, 9.67, 11.19, 11.68, 12.88, 13.83, 14.52, 15.13, 16.20, 16.87, 17.11, 17.81, 18.72, 19.41, 20.29, 20.85, 21.80, 23.16, 23.49, 23.94, 24.31, 25.34, 26.50, 26.96, 27.37, 28.50, 29.76, 30.60, and 31.73.

[0021] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline (di)phosphate, selected from: a Form 1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.95, 9.26, 10.59, 11.94, 12.55, 14.84, 17.36, 17.95, 18.09, 18.61, 19.08, 20.02, 20.53, 21.56, 22.58, 23.05, 23.57, 23.96, 24.72, 25.27, 25.62, 26.39, 27.76, 28.90, 30.20, 31.45, 31.92, 33.64, 36.38, and 41.77; a Form 3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.61, 5.95, 8.92, 9.21, 9.99, 10.71, 11.13, 12.13, 12.66, 13.69, 15.09, 15.57, 16.77, 17.42, 17.94, 18.77, 19.22, 19.73, 20.42, 21.09, 21.41, 22.23, 22.82, 23.38, 23.69, 23.98, 24.94, 25.82, 26.40, 27.23, 27.90, 29.31, 30.16, 31.46, 32.26, 34.41, 35.94, 36.34, 36.98, 37.79, 38.06, and 40.11; a Form 4 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.93, 8.17, 8.71, 9.22, 11.88, 12.14, 12.51, 14.45, 14.89, 16.99, 17.49, 17.86, 18.43, 18.67, 19.36, 19.68, 20.32, 20.49, 21.17, 22.01, 22.21, 22.48, 23.08, 23.75, 24.79, 25.13, 25.76, 26.19, 26.53, 27.57, 29.15, 29.98, 30.34, 31.12, 33.53, 34.37, 36.19, 38.48, 39.28, 40.28, 42.47, and 48.77; 4. ASBLomond.24.0001.W a Form 5 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.22, 8.04, 9.19, 9.74, 10.57, 12.17, 14.43, 13.36, 13.97, 15.39, 15.79, 16.95, 18.28, 18.79, 19.12, 19.50, 20.02, 20.78, 21.29, 21.84, 24.02, 24.45, 24.64, 25.10, 25.67, 26.43, 26.98, 27.79, 30.85, 31.38, 32.62, and 33.18; a Form 6 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.37, 6.26, 7.62, 8.74, 9.28, 10.76, 12.54, 13.28, 15.31, 16.27, 17.54, 17.99, 18.51, 18.78, 19.02, 19.37, 19.82, 20.27, 20.55, 21.03, 21.28, 21.63, 22.63, 23.05, 23.91, 24.49, 25.42, 25.73, 26.21, 26.73, 27.13, 27.82, 28.44, 28.70, 29.09, 29.44, 29.84, 30.01, 31.12, 31.84, 32.54, 34.04, 34.43, 34.80, 35.65, 36.12, 36.57, 36.97, 37.49, 37.81, 38.54, 39.24, 39.95, 40.25, 40.70, 41.42, 42.75, 43.30, 44.89, 45.57, 46.47, 47.44, 47.88 and 49.46; a Form 7 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.48, 7.08, 12.90, 15.10, 16.54, 18.44, 19.46, 20.03, 21.28, 21.77, 22.22, 23.18, 25.05, 25.46, 26.42, 27.32, 29.26, 30.74, 32.60, 42.94 and 44.21.

[0022] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate, selected from: a Form D1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.2, 9.7, 12.9, 16.4, 18.6, 19.7, 21.0, 21.8, 22.7, 23.7, 24.3, 24.8, and 25.4; a Form D2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 5.2, 8.2, 9.7, 10.4, 12.6, 15.6, 16.5, 17.6, 18.3, 19.2, 19.7, 20.5, 21.8, 22.6, 23.1, 23.6, 24.4, 24.9, 26.1, 26.4, 27.4, and 30.2; a Form D3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.8, 8.1, 9.6, 10.3, 15.6, 16.4, 17.6, 18.1, 19.1, 19.6, 20.4, 22.5, 23.0, 23.5, 24.3, 24.8, 26.0, 26.3, and 27.3.

[0023] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate, selected from: a Form E1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.12, 13.33, 15.24, 16.28, 17.51,17.95, 19.17, 20.27, 21.11, 21.86, 22.30, 23.40, 24.01, 25.41, 25.98, 27.09, and 28.22; a Form E2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.85, 5.54, 6.77, 12.69, 13.16, 5. ASBLomond.24.0001.W 14.56, 15.17, 15.97, 19.21, 20.36, 20.77, 21.86, 22.13, 22.61, 25.51, 25.84, 26.20, 26.47, 26.80, 28.23, 37.93, and 44.40; a Form E3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 4.84, 6.75, 7.44, 8.10, 8.31, 9.99, 10.33, 12.94, 14.67, 15.25, 15.88, 16.29, 17.23, 17.63, 17.92, 18.33,18.80, 19.52, 20.08, 20.65, 21.27, 22.19, 22.43, 22.91, 23.44, 23.71, 24.30, 24.61, 25.12, 25.64, 26.09, 26.46, 26.78, 28.56, 28.86, 29.76, 30.78, 31.25, 31.88, 33.00, 34.39, 35.00, 36.46, 37.62, 38.45, 39.19, and 39.88; a Form E4 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.71, 7.69, 9.08, 11.25, 12.57, 14.04, 15.47, 16.43, 17.29, 18.54, 19.36, 20.73, 21.25, 22.74, 23.28, 24.58, 26.11, and 28.35; a Form E5 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.67, 5.29, 7.06, 7.73, 8.79, 9.11, 10.62, 11.13, 12.36, 13.83, 15.48, 16.53, 17.17, 18.02, 18.49, 18.82, 19.43, 19.69, 20.11, 20.80, 21.33, 22.04, 22.79, 23.20, 24.08, 24.62, 25.08, 26.22, 26.93, 27.61, 28.05, 28.92, 29.36, and 30.39; a Form E6 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 2.49, 4.55, 6.23, 6.69, 7.17, 7.95, 9.11, 10.40, 11.25, 12.50, 13.24, 13.69, 15.20, 15.71, 17.41, 17.85, 18.16, 18.79, 19.26, 19.51, 20.56, 21.63, 22.18, 22.49, 23.10, 23.91, 24.89, 25.41, 25.60, 26.23, 26.62, 27.70, 28.19, 31.42, and 31.89.

[0024] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate, selected from: a Form F1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.64, 9.17, 11.19, 12.26, 14.94, 15.40, 18.09, 19.99, 21.13, 22.48, 23.37, 25.72, 26.26, and 29.02.

[0025] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate, selected from: a Form G1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.74, 12.75, 13.60, 14.29, 15.24, 20.39, 25.86, and 26.30; a Form G2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 7.88, 9.04, 10.94, 12.17, 6. ASBLomond.24.0001.W 13.60, 15.26, 17.52, 18.20, 18.86, 20.33, 21.22, 22.39, 23.73, 24.64, 25.84, 26.41, 27.63, and 28.86.

[0026] Another aspect of the invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate, selected from: a Form H1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.15, 4.50, 5.55, 6.22, 9.02, 9.86, 13.81, 14.17, 15.63, 17.04, 17.80, 18.73, 19.46, 20.63, 22.95, 24.60, 25.66, 25.92, and 26.96.

[0027] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of the compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, or cocrystal thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0028] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form A that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.5, 6.9, 7.1, 10.2, 10.6, 10.9, 12.9, 13.8, 14.2, 14.9, 16.4, 17.6, 18.1, 18.6, 19.3, 19.4, 20.1, 20.5, 21.3, 22.0, 22.6, 23.1, 23.3, 23.8, 24.2, 24.9, 25.5, 25.7, 26.6, 27.3, 27.7, 28.6, 29.7, 30.1, 30.4, 30.8, 31.8, 32.3, 32.6, 33.3, 34.2, 35.7, 36.4, 36.6, 37.1, 37.9, 39.0 and 39.7 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0029] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form B that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.3, 7.5, 8.8, 11.4, 13.4, 14.8, 15.1, 16.6, 16.6, 17.5, 17.6, 17.9, 18.0, 18.9, 19.4, 19.9, 21.1, 21.4, 22.5, 23.5, 24.0, 24.7, 24.9, 26.3, 26.8, 27.5, 28.3, 28.7, 30.2, 31.9, 32.3, 32.9, 34.3, 35.6, 36.5, and 38.3 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0030] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form C that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 7.6, 9.8, 10.4, 13.8, 15.1, 17.6, 18.5, 19.3, 20.2, 20.9, 21.8, 22.2, 22.8, 23.8, 24.5, 25.1, 25.6, 26.1, 26.7, 27.9, 29.4, 29.8, 30.6, 31.5, 32.3, 32.8, 33.8, 37.3, and 38.1 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. 7. ASBLomond.24.0001.W

[0031] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form D that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.1, 6.6, 8.5, 9.4, 10.6, 12.2, 12.5, 13.5, 13.9, 14.2, 14.7, 15.3, 16.0, 16.4, 18.0, 19.4, 20.7, 21.0, 21.8, 22.2, 22.9, 24.0, 24.4, 25.2, 25.6, 26.2, 26.8, 28.1, 28.6, 30.7, 31.9, and 32.2 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0032] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form E that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.4, 7.6, 8.9, 9.7, 10.2, 13.7, 15.2, 17.7, 18.1, 18.8, 19.3, 20.1, 20.9, 22.1, 22.4, 23.0, 23.4, 23.9, 24.4, 25.6, 26.0, 27.5, 28.5, 30.6, 32.1, 35.7 and 38.0 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0033] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline in Form F that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.2, 8.1, 9.7, 10.6, 11.7, 12.6, 15.0, 16.3, 17.5, 18.5, 19.7, 20.9, 21.3, 22.0, 22.8, 23.7, 24.2, 24.7, 25.4, 25.7, 26.4, 28.3, 28.6, 31.2, 32.4, and 35.4 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0034] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph form of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline dihydrochloride that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.18, 6.38, 7.23, 9.26, 9.67, 11.19, 11.68, 12.88, 13.83, 14.52, 15.13, 16.20, 16.87, 17.11, 17.81, 18.72, 19.41, 20.29, 20.85, 21.80, 23.16, 23.49, 23.94, 24.31, 25.34, 26.50, 26.96, 27.37, 28.50, 29.76, 30.60, and 31.73 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0035] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.95, 9.26, 10.59, 11.94, 12.55, 14.84, 17.36, 17.95, 18.09, 18.61, 19.08, 20.02, 20.53, 21.56, 22.58, 23.05, 23.57, 23.96, 8. ASBLomond.24.0001.W 24.72, 25.27, 25.62, 26.39, 27.76, 28.90, 30.20, 31.45, 31.92, 33.64, 36.38, and 41.77; and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0036] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.61, 5.95, 8.92, 9.21, 9.99, 10.71, 11.13, 12.13, 12.66, 13.69, 15.09, 15.57, 16.77, 17.42, 17.94, 18.77, 19.22, 19.73, 20.42, 21.09, 21.41, 22.23, 22.82, 23.38, 23.69, 23.98, 24.94, 25.82, 26.40, 27.23, 27.90, 29.31, 30.16, 31.46, 32.26, 34.41, 35.94, 36.34, 36.98, 37.79, 38.06, and 40.11; and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0037] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 4 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.93, 8.17, 8.71, 9.22, 11.88, 12.14, 12.51, 14.45, 14.89, 16.99, 17.49, 17.86, 18.43, 18.67, 19.36, 19.68, 20.32, 20.49, 21.17, 22.01, 22.21, 22.48, 23.08, 23.75, 24.79, 25.13, 25.76, 26.19, 26.53, 27.57, 29.15, 29.98, 30.34, 31.12, 33.53, 34.37, 36.19, 38.48, 39.28, 40.28, 42.47, and 48.77; and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0038] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 5 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.22, 8.04, 9.19, 9.74, 10.57, 12.17, 14.43, 13.36, 13.97, 15.39, 15.79, 16.95, 18.28, 18.79, 19.12, 19.50, 20.02, 20.78, 21.29, 21.84, 24.02, 24.45, 24.64, 25.10, 25.67, 26.43, 26.98, 27.79, 30.85, 31.38, 32.62, and 33.18; and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0039] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 6 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.37, 6.26, 7.62, 8.74, 9.28, 10.76, 12.54, 13.28, 15.31, 16.27, 17.54, 17.99, 18.51, 18.78, 19.02, 19.37, 19.82, 20.27, 20.55, 21.03, 21.28, 21.63, 22.63, 23.05, 23.91, 24.49, 25.42, 25.73, 26.21, 26.73, 27.13, 27.82, 9. ASBLomond.24.0001.W 28.44, 28.70, 29.09, 29.44, 29.84, 30.01, 31.12, 31.84, 32.54, 34.04, 34.43, 34.80, 35.65, 36.12, 36.57, 36.97, 37.49, 37.81, 38.54, 39.24, 39.95, 40.25, 40.70, 41.42, 42.75, 43.30, 44.89, 45.57, 46.47, 47.44, 47.88 and 49.46; and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0040] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form 7 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.48, 7.08, 12.90, 15.10, 16.54, 18.44, 19.46, 20.03, 21.28, 21.77, 22.22, 23.18, 25.05, 25.46, 26.42, 27.32, 29.26, 30.74, 32.60, 42.94 and 44.21 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0041] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form D1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline tartrate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.2, 9.7, 12.9, 16.4, 18.6, 19.7, 21.0, 21.8, 22.7, 23.7, 24.3, 24.8, and 25.4 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0042] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form D2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline tartrate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 5.2, 8.2, 9.7, 10.4, 12.6, 15.6, 16.5, 17.6, 18.3, 19.2, 19.7, 20.5, 21.8, 22.6, 23.1, 23.6, 24.4, 24.9, 26.1, 26.4, 27.4, and 30.2 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0043] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form D3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline tartrate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.8, 8.1, 9.6, 10.3, 15.6, 16.4, 17.6, 18.1, 19.1, 19.6, 20.4, 22.5, 23.0, 23.5, 24.3, 24.8, 26.0, 26.3, and 27.3 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0044] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.12, 13.33, 15.24, 16.28, 10. ASBLomond.24.0001.W 17.51,17.95, 19.17, 20.27, 21.11, 21.86, 22.30, 23.40, 24.01, 25.41, 25.98, 27.09, and 28.22 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0045] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.85, 5.54, 6.77, 12.69, 13.16, 14.56, 15.17, 15.97, 19.21, 20.36, 20.77, 21.86, 22.13, 22.61, 25.51, 25.84, 26.20, 26.47, 26.80, 28.23, 37.93, and 44.40 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0046] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 4.84, 6.75, 7.44, 8.10, 8.31, 9.99, 10.33, 12.94, 14.67, 15.25, 15.88, 16.29, 17.23, 17.63, 17.92, 18.33,18.80, 19.52, 20.08, 20.65, 21.27, 22.19, 22.43, 22.91, 23.44, 23.71, 24.30, 24.61, 25.12, 25.64, 26.09, 26.46, 26.78, 28.56, 28.86, 29.76, 30.78, 31.25, 31.88, 33.00, 34.39, 35.00, 36.46, 37.62, 38.45, 39.19, and 39.88 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0047] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E4 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.71, 7.69, 9.08, 11.25, 12.57, 14.04, 15.47, 16.43, 17.29, 18.54, 19.36, 20.73, 21.25, 22.74, 23.28, 24.58, 26.11, and 28.35 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0048] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E5 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.67, 5.29, 7.06, 7.73, 8.79, 9.11, 10.62, 11.13, 12.36, 13.83, 15.48, 16.53, 17.17, 18.02, 18.49, 18.82, 19.43, 19.69, 20.11, 20.80, 21.33, 22.04, 22.79, 23.20, 24.08, 24.62, 25.08, 26.22, 26.93, 27.61, 28.05, 28.92, 29.36, and 30.39 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. 11. ASBLomond.24.0001.W

[0049] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form E6 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 2.49, 4.55, 6.23, 6.69, 7.17, 7.95, 9.11, 10.40, 11.25, 12.50, 13.24, 13.69, 15.20, 15.71, 17.41, 17.85, 18.16, 18.79, 19.26, 19.51, 20.56, 21.63, 22.18, 22.49, 23.10, 23.91, 24.89, 25.41, 25.60, 26.23, 26.62, 27.70, 28.19, 31.42, and 31.89 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0050] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form F1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline fumarate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.64, 9.17, 11.19, 12.26, 14.94, 15.40, 18.09, 19.99, 21.13, 22.48, 23.37, 25.72, 26.26, and 29.02 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0051] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form G1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline citrate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.74, 12.75, 13.60, 14.29, 15.24, 20.39, 25.86, and 26.30 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0052] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form G2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline citrate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 7.88, 9.04, 10.94, 12.17, 13.60, 15.26, 17.52, 18.20, 18.86, 20.33, 21.22, 22.39, 23.73, 24.64, 25.84, 26.41, 27.63, and 28.86 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0053] Another aspect of the invention is directed to pharmaceutical compositions comprising a polymorph Form H1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline sulfate that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.15, 4.50, 5.55, 6.22, 9.02, 9.86, 13.81, 14.17, 15.63, 17.04, 17.80, 18.73, 19.46, 20.63, 22.95, 24.60, 25.66, 25.92, and 26.96 and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. 12. ASBLomond.24.0001.W

[0054] Another aspect of the invention relates to a process for preparing a crystalline polymorph or amorphous form of the compound of Formula (I) or solvates, tautomers, or pharmaceutically acceptable salts or cocrystals thereof.

[0055] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline in Form A that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.5, 6.9, 7.1, 10.2, 10.6, 10.9, 12.9, 13.8, 14.2, 14.9, 16.4, 17.6, 18.1, 18.6, 19.3, 19.4, 20.1, 20.5, 21.3, 22.0, 22.6, 23.1, 23.3, 23.8, 24.2, 24.9, 25.5, 25.7, 26.6, 27.3, 27.7, 28.6, 29.7, 30.1, 30.4, 30.8, 31.8, 32.3, 32.6, 33.3, 34.2, 35.7, 36.4, 36.6, 37.1, 37.9, 39.0 and 39.7.

[0056] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline in Form B that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.3, 7.5, 8.8, 11.4, 13.4, 14.8, 15.1, 16.6, 16.6, 17.5, 17.6, 17.9, 18.0, 18.9, 19.4, 19.9, 21.1, 21.4, 22.5, 23.5, 24.0, 24.7, 24.9, 26.3, 26.8, 27.5, 28.3, 28.7, 30.2, 31.9, 32.3, 32.9, 34.3, 35.6, 36.5, and 38.3.

[0057] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline in Form C that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 7.6, 9.8, 10.4, 13.8, 15.1, 17.6, 18.5, 19.3, 20.2, 20.9, 21.8, 22.2, 22.8, 23.8, 24.5, 25.1, 25.6, 26.1, 26.7, 27.9, 29.4, 29.8, 30.6, 31.5, 32.3, 32.8, 33.8, 37.3, and 38.1.

[0058] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline in Form D that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.1, 6.6, 8.5, 9.4, 10.6, 12.2, 12.5, 13.5, 13.9, 14.2, 14.7, 15.3, 16.0, 16.4, 18.0, 19.4, 20.7, 21.0, 21.8, 22.2, 22.9, 24.0, 24.4, 25.2, 25.6, 26.2, 26.8, 28.1, 28.6, 30.7, 31.9, and 32.2.

[0059] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline in Form E that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.4, 7.6, 8.9, 9.7, 10.2, 13.7, 15.2, 17.7, 18.1, 18.8, 19.3, 20.1, 20.9, 22.1, 22.4, 23.0, 23.4, 23.9, 24.4, 25.6, 26.0, 27.5, 28.5, 30.6, 32.1, 35.7 and 38.0.

[0060] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- 13. ASBLomond.24.0001.W c]quinoline in Form F that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.2, 8.1, 9.7, 10.6, 11.7, 12.6, 15.0, 16.3, 17.5, 18.5, 19.7, 20.9, 21.3, 22.0, 22.8, 23.7, 24.2, 24.7, 25.4, 25.7, 26.4, 28.3, 28.6, 31.2, 32.4, and 35.4.

[0061] Another aspect of the invention relates to a process for preparing a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline dihydrochloride that exhibit an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.18, 6.38, 7.23, 9.26, 9.67, 11.19, 11.68, 12.88, 13.83, 14.52, 15.13, 16.20, 16.87, 17.11, 17.81, 18.72, 19.41, 20.29, 20.85, 21.80, 23.16, 23.49, 23.94, 24.31, 25.34, 26.50, 26.96, 27.37, 28.50, 29.76, 30.60, and 31.73.

[0062] Another aspect of the invention relates to a process for preparing a polymorph Form 1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.95, 9.26, 10.59, 11.94, 12.55, 14.84, 17.36, 17.95, 18.09, 18.61, 19.08, 20.02, 20.53, 21.56, 22.58, 23.05, 23.57, 23.96, 24.72, 25.27, 25.62, 26.39, 27.76, 28.90, 30.20, 31.45, 31.92, 33.64, 36.38, and 41.77.

[0063] Another aspect of the invention relates to a process for preparing a polymorph Form 3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.61, 5.95, 8.92, 9.21, 9.99, 10.71, 11.13, 12.13, 12.66, 13.69, 15.09, 15.57, 16.77, 17.42, 17.94, 18.77, 19.22, 19.73, 20.42, 21.09, 21.41, 22.23, 22.82, 23.38, 23.69, 23.98, 24.94, 25.82, 26.40, 27.23, 27.90, 29.31, 30.16, 31.46, 32.26, 34.41, 35.94, 36.34, 36.98, 37.79, 38.06, and 40.11.

[0064] Another aspect of the invention relates to a process for preparing a polymorph Form 4 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.93, 8.17, 8.71, 9.22, 11.88, 12.14, 12.51, 14.45, 14.89, 16.99, 17.49, 17.86, 18.43, 18.67, 19.36, 19.68, 20.32, 20.49, 21.17, 22.01, 22.21, 22.48, 23.08, 23.75, 24.79, 25.13, 25.76, 26.19, 26.53, 27.57, 29.15, 29.98, 30.34, 31.12, 33.53, 34.37, 36.19, 38.48, 39.28, 40.28, 42.47, and 48.77.

[0065] Another aspect of the invention relates to a process for preparing a polymorph Form 5 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.22, 8.04, 9.19, 9.74, 10.57, 12.17, 14.43, 13.36, 13.97, 15.39, 15.79, 16.95, 18.28, 18.79, 19.12, 19.50, 20.02, 20.78, 21.29, 21.84, 24.02, 24.45, 24.64, 25.10, 25.67, 26.43, 26.98, 27.79, 30.85, 31.38, 32.62, and 33.18. 14. ASBLomond.24.0001.W

[0066] Another aspect of the invention relates to a process for preparing a polymorph Form 6 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.37, 6.26, 7.62, 8.74, 9.28, 10.76, 12.54, 13.28, 15.31, 16.27, 17.54, 17.99, 18.51, 18.78, 19.02, 19.37, 19.82, 20.27, 20.55, 21.03, 21.28, 21.63, 22.63, 23.05, 23.91, 24.49, 25.42, 25.73, 26.21, 26.73, 27.13, 27.82, 28.44, 28.70, 29.09, 29.44, 29.84, 30.01, 31.12, 31.84, 32.54, 34.04, 34.43, 34.80, 35.65, 36.12, 36.57, 36.97, 37.49, 37.81, 38.54, 39.24, 39.95, 40.25, 40.70, 41.42, 42.75, 43.30, 44.89, 45.57, 46.47, 47.44, 47.88 and 49.46.

[0067] Another aspect of the invention relates to a process for preparing a polymorph Form 7 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline phosphate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.48, 7.08, 12.90, 15.10, 16.54, 18.44, 19.46, 20.03, 21.28, 21.77, 22.22, 23.18, 25.05, 25.46, 26.42, 27.32, 29.26, 30.74, 32.60, 42.94 and 44.21.

[0068] Another aspect of the invention relates to a process for preparing a polymorph Form D1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline tartrate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.2, 9.7, 12.9, 16.4, 18.6, 19.7, 21.0, 21.8, 22.7, 23.7, 24.3, 24.8, and 25.4.

[0069] Another aspect of the invention relates to a process for preparing a polymorph Form D2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline tartrate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 5.2, 8.2, 9.7, 10.4, 12.6, 15.6, 16.5, 17.6, 18.3, 19.2, 19.7, 20.5, 21.8, 22.6, 23.1, 23.6, 24.4, 24.9, 26.1, 26.4, 27.4, and 30.2.

[0070] Another aspect of the invention relates to a process for preparing a polymorph Form D3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline tartrate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.8, 8.1, 9.6, 10.3, 15.6, 16.4, 17.6, 18.1, 19.1, 19.6, 20.4, 22.5, 23.0, 23.5, 24.3, 24.8, 26.0, 26.3, and 27.3.

[0071] Another aspect of the invention relates to a process for preparing a polymorph Form E1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.12, 13.33, 15.24, 16.28, 17.51,17.95, 19.17, 20.27, 21.11, 21.86, 22.30, 23.40, 24.01, 25.41, 25.98, 27.09, and 28.22.

[0072] Another aspect of the invention relates to a process for preparing a polymorph Form E2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- 15. ASBLomond.24.0001.W c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.85, 5.54, 6.77, 12.69, 13.16, 14.56, 15.17, 15.97, 19.21, 20.36, 20.77, 21.86, 22.13, 22.61, 25.51, 25.84, 26.20, 26.47, 26.80, 28.23, 37.93, and 44.40.

[0073] Another aspect of the invention relates to a process for preparing a polymorph Form E3 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 4.84, 6.75, 7.44, 8.10, 8.31, 9.99, 10.33, 12.94, 14.67, 15.25, 15.88, 16.29, 17.23, 17.63, 17.92, 18.33,18.80, 19.52, 20.08, 20.65, 21.27, 22.19, 22.43, 22.91, 23.44, 23.71, 24.30, 24.61, 25.12, 25.64, 26.09, 26.46, 26.78, 28.56, 28.86, 29.76, 30.78, 31.25, 31.88, 33.00, 34.39, 35.00, 36.46, 37.62, 38.45, 39.19, and 39.88.

[0074] Another aspect of the invention relates to a process for preparing a polymorph Form E4 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.71, 7.69, 9.08, 11.25, 12.57, 14.04, 15.47, 16.43, 17.29, 18.54, 19.36, 20.73, 21.25, 22.74, 23.28, 24.58, 26.11, and 28.35.

[0075] Another aspect of the invention relates to a process for preparing a polymorph Form E5 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.67, 5.29, 7.06, 7.73, 8.79, 9.11, 10.62, 11.13, 12.36, 13.83, 15.48, 16.53, 17.17, 18.02, 18.49, 18.82, 19.43, 19.69, 20.11, 20.80, 21.33, 22.04, 22.79, 23.20, 24.08, 24.62, 25.08, 26.22, 26.93, 27.61, 28.05, 28.92, 29.36, and 30.39.

[0076] Another aspect of the invention relates to a process for preparing a polymorph Form E6 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline maleate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 2.49, 4.55, 6.23, 6.69, 7.17, 7.95, 9.11, 10.40, 11.25, 12.50, 13.24, 13.69, 15.20, 15.71, 17.41, 17.85, 18.16, 18.79, 19.26, 19.51, 20.56, 21.63, 22.18, 22.49, 23.10, 23.91, 24.89, 25.41, 25.60, 26.23, 26.62, 27.70, 28.19, 31.42, and 31.89.

[0077] Another aspect of the invention relates to a process for preparing a polymorph Form F1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline fumarate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.64, 9.17, 11.19, 12.26, 14.94, 15.40, 18.09, 19.99, 21.13, 22.48, 23.37, 25.72, 26.26, and 29.02.

[0078] Another aspect of the invention relates to a process for preparing a polymorph Form G1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- 16. ASBLomond.24.0001.W c]quinoline citrate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.74, 12.75, 13.60, 14.29, 15.24, 20.39, 25.86, and 26.30.

[0079] Another aspect of the invention relates to a process for preparing a polymorph Form G2 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline citrate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 7.88, 9.04, 10.94, 12.17, 13.60, 15.26, 17.52, 18.20, 18.86, 20.33, 21.22, 22.39, 23.73, 24.64, 25.84, 26.41, 27.63, and 28.86.

[0080] Another aspect of the invention relates to a process for preparing a polymorph Form H1 of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3- c]quinoline sulfate that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.15, 4.50, 5.55, 6.22, 9.02, 9.86, 13.81, 14.17, 15.63, 17.04, 17.80, 18.73, 19.46, 20.63, 22.95, 24.60, 25.66, 25.92, and 26.96.

[0081] In one aspect, the crystalline polymorphs provided herein is milled. In another aspect, the crystalline, anhydrate polymorphs provided herein is milled.

[0082] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0083] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride.

[0084] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0085] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate.

[0086] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate.

[0087] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate.

[0088] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate.

[0089] Another aspect of the invention relates to an amorphous 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate.

[0090] In one aspect, provided is a process for preparing the amorphous compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride, comprising heating a crystalline form of the compound until dissolution followed 17. ASBLomond.24.0001.W by cooling to form the amorphous compound. In one aspect the cooling is by fast cooling, such as in a dry-ice or liquid nitrogen bath.

[0091] In one aspect, provided is a process for preparing the amorphous compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, comprising heating a crystalline form of the compound until dissolution followed by cooling to form the amorphous compound. In one aspect the cooling is by fast cooling, such as in a dry-ice or liquid nitrogen bath.

[0092] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof.

[0093] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of amorphous or crystallin 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical composition thereof.

[0094] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form A or pharmaceutical composition thereof.

[0095] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form B or pharmaceutical composition thereof.

[0096] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form C or pharmaceutical composition thereof.

[0097] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- 18. ASBLomond.24.0001.W yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form D or pharmaceutical composition thereof.

[0098] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form E or pharmaceutical composition thereof.

[0099] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the polymorphic Form F or pharmaceutical composition thereof.

[0100] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of amorphous or crystalline 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline (di)hydrochloride, polymorph, cocrystal, or pharmaceutical composition thereof.

[0101] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline (di)hydrochloride or pharmaceutical composition thereof.

[0102] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of amorphous or crystalline 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline (di)phosphate, polymorph, cocrystal, or pharmaceutical composition thereof.

[0103] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline (di)phosphate or pharmaceutical composition thereof.

[0104] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- 19. ASBLomond.24.0001.W yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof.

[0105] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof.

[0106] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof.

[0107] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof.

[0108] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof.

[0109] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof.

[0110] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the polymorphic Form D1 or pharmaceutical composition thereof.

[0111] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- 20. ASBLomond.24.0001.W yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the polymorphic Form D2 or pharmaceutical composition thereof.

[0112] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the polymorphic Form D3 or pharmaceutical composition thereof.

[0113] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E1 or pharmaceutical composition thereof.

[0114] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E2 or pharmaceutical composition thereof.

[0115] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E3 or pharmaceutical composition thereof.

[0116] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E4 or pharmaceutical composition thereof.

[0117] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E5 or pharmaceutical composition thereof.

[0118] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- 21. ASBLomond.24.0001.W yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the polymorphic Form E6 or pharmaceutical composition thereof.

[0119] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate in the polymorphic Form F1 or pharmaceutical composition thereof.

[0120] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the polymorphic Form G1 or pharmaceutical composition thereof.

[0121] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the polymorphic Form G2 or pharmaceutical composition thereof.

[0122] Another aspect of the invention is directed to a method of inhibiting FMS-like tyrosine kinase 3 (FLT3). The method involves administering to a patient in need thereof an effective amount of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7- yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate in the polymorphic Form H1 or pharmaceutical composition thereof.

[0123] Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0124] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0125] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3). 22. ASBLomond.24.0001.W

[0126] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form A or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0127] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form B or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0128] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form C or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0129] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form D or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0130] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form E or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0131] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form F or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0132] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0133] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0134] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, 23. ASBLomond.24.0001.W cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0135] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0136] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0137] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0138] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0139] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0140] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0141] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0142] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the Form D1, or Form D2, or Form D3, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3). 24. ASBLomond.24.0001.W

[0143] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the Form E1, or Form E2, or Form E3, or Form E4, or Form E5, or Form E6, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0144] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate in the Form F1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0145] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the Form G1, Form G2, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0146] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate in the Form H1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0147] Another aspect of the present invention relates to use of compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0148] Another aspect of the present invention relates to use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0149] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0150] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form A, Form B, Form C, Form D, Form E, Form F, or mixture thereof, or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3). 25. ASBLomond.24.0001.W

[0151] Another aspect of the present invention relates to use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0152] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0153] Another aspect of the present invention relates to use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, cocrystal, or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0154] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0155] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0156] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0157] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0158] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0159] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline 26. ASBLomond.24.0001.W phosphate in the polymorphic Form 6 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0160] Another aspect of the present invention relates to use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof, in the treatment of diseases and disorders associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3).

[0161] Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0162] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0163] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0164] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form A, Form B, Form C, Form D, Form E, Form F, or mixture thereof, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0165] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0166] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0167] Another aspect of the present invention relates to 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, cocrystal, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 27. ASBLomond.24.0001.W

[0168] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0169] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0170] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0171] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0172] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0173] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0174] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0175] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the Form D1, or Form D2, or Form D3, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0176] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline 28. ASBLomond.24.0001.W maleate in the Form E1, or Form E2, or Form E3, or Form E4, or Form E5, or Form E6, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0177] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate in the Form F1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0178] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the Form G1, Form G2, or mixture thereof or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0179] Another aspect of the present invention relates to a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate in the Form H1 or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0180] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof.

[0181] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical composition thereof.

[0182] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0183] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in 29. ASBLomond.24.0001.W the Form A, Form B, Form C, Form D, Form E, Form F, or mixture thereof, or pharmaceutical compositions thereof.

[0184] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride, polymorph, cocrystal, or pharmaceutical composition thereof.

[0185] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0186] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0187] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof.

[0188] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof.

[0189] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof.

[0190] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- 30. ASBLomond.24.0001.W dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof.

[0191] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof.

[0192] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof.

[0193] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof.

[0194] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the Form D1, or Form D2, or Form D3, or mixture thereof or pharmaceutical composition thereof.

[0195] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the Form E1, or Form E2, or Form E3, or Form E4, or Form E5, or Form E6, or mixture thereof, or pharmaceutical composition thereof.

[0196] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate in the Form F1 or pharmaceutical composition thereof. 31. ASBLomond.24.0001.W

[0197] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the Form G1, Form G2, or mixture thereof or pharmaceutical composition thereof.

[0198] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate in the Form H1 or pharmaceutical composition thereof.

[0199] Another aspect of the present invention relates to the use of compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0200] Another aspect of the present invention relates to the use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0201] Another aspect of the present invention relates to the use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0202] Another aspect of the present invention relates to the use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form A, Form B, Form C, Form D, Form E, Form F, or mixture thereof, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0203] Another aspect of the present invention relates to the use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0204] Another aspect of the present invention relates to the use of a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0205] Another aspect of the present invention relates to the use of 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, 32. ASBLomond.24.0001.W cocrystal, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0206] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0207] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0208] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0209] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0210] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0211] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0212] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0213] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline tartrate in the Form D1, or Form D2, or Form D3, or mixture thereof, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein. 33. ASBLomond.24.0001.W

[0214] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline maleate in the Form E1, or Form E2, or Form E3, or Form E4, or Form E5, or Form E6, or mixture thereof, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0215] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline fumarate in the Form F1 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0216] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline citrate in the Form G1, Form G2, or mixture thereof, or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0217] Another aspect of the present invention relates to the use of compounds of a crystalline compound, 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline sulfate in the Form H1 or pharmaceutical composition thereof, in the treatment of a disease or disorder disclosed herein.

[0218] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, polymorph, cocrystal, or pharmaceutical composition thereof.

[0219] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical composition thereof.

[0220] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0221] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- 34. ASBLomond.24.0001.W dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in the Form A, Form B, Form C, Form D, Form E, Form F, or mixture thereof, or pharmaceutical compositions thereof.

[0222] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical composition thereof.

[0223] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline hydrochloride, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0224] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate, polymorph, cocrystal, or pharmaceutical compositions thereof.

[0225] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate or pharmaceutical composition thereof.

[0226] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 1 or pharmaceutical composition thereof.

[0227] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 3 or pharmaceutical composition thereof.

[0228] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient 35. ASBLomond.24.0001.W suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 4 or pharmaceutical composition thereof.

[0229] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 5 or pharmaceutical composition thereof.

[0230] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 6 or pharmaceutical composition thereof.

[0231] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate in the polymorphic Form 7 or pharmaceutical composition thereof.

[0232] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline tartrate in the Form D1, or Form D2, or Form D3, or mixture thereof, or pharmaceutical composition thereof.

[0233] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline maleate in the Form E1, or Form E2, or Form E3, or Form E4, or Form E5, or Form E6, or mixture thereof, or pharmaceutical composition thereof.

[0234] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline fumarate in the Form F1 or pharmaceutical composition thereof. 36. ASBLomond.24.0001.W

[0235] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline citrate in the Form G1, Form G2, or pharmaceutical composition thereof.

[0236] The present invention further provides methods of treating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3), comprising administering to a patient suffering from at least one of said diseases or disorders a crystalline compound, 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline sulfate in the Form H1 or pharmaceutical composition thereof.

[0237] The present invention provides inhibitors of FMS-like tyrosine kinase 3 (FLT3) that are therapeutic agents in the treatment of diseases and disorders.

[0238] The present invention further provides methods of treating a disease, disorder, or condition selected from cancer, acute myeloid leukemia (AML), cytogenetically normal acute myeloid leukemia (CN-AML).

[0239] In some aspects, the present disclosure provides a polymorph obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in Experimental Part).

[0240] In some aspects, the present disclosure provides a method of preparing polymorphs of the present disclosure.

[0241] In some aspects, the present disclosure provides a method of preparing polymorphs of the present disclosure, comprising one or more steps described herein.

[0242] In some specific non-limiting aspects, the present disclosure provides methods of preparing polymorphs of the present disclosure, described in the examples.

[0243] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. 37. ASBLomond.24.0001.W

[0244] Other features and advantages of the disclosure will be apparent from the following detailed description, drawings and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0245] Figure 1 shows comparison of the PXRD patterns of Form 1, Form 3, Form 4, Form 5, Form 6 and Form 7 of the phosphate salt of a crystalline compound 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0246] Figure 2 shows the inter-conversion relationships between polymorph forms 1, 3, 4, 5, 6 and 7 of a crystalline compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)- 2,3-dihydropyrazolo[4,3-c]quinoline phosphate in a schematic diagram. The given pathways are to be considered as examples because there might exist other methods to produce a distinct form.

[0247] Figure 3 shows the PXRD pattern of crystalline compound 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride.

[0248] Figure 4 shows the TG-FTIR thermogram of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride.

[0249] Figure 5 shows DVS for a crystalline compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride salt with a double humidity cycle with a scan rate of 5% r.h. per hour at 25°C.

[0250] Figure 6 shows DVS isotherm of a crystalline compound 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline dihydrochloride salt.

[0251] Figure 7 shows PXRD pattern of Form 1 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0252] Figure 8 shows1H-NMR spectrum of Form 1 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0253] Figure 9 shows Raman spectrum of Form 1 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0254] Figure 10 shows DVS isotherm of a crystalline compound 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate salt in the Form 1, the change of water content and relative humidity as a function of time. 38. ASBLomond.24.0001.W

[0255] Figure 11 shows DVS isotherm of a crystalline compound 3-(3,4-dimethoxyphenyl)-1- (1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate salt in the Form 1, the change of water content as a function of relative humidity.

[0256] Figure 12 shows PXRD pattern of Form 3 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0257] Figure 13 shows Raman spectrum of Form 3 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0258] Figure 14 shows TG-FTIR thermogram of Form 3 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0259] Figure 15 shows PXRD pattern of Form 4 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0260] Figure 16 shows TG-FTIR thermogram of Form 4 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0261] Figure 17 shows DVS isotherm of Form 4 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate: the change of water content and relative humidity as a function of time.

[0262] Figure 18 shows DVS isotherm of Form 4 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate: the change of water content as a function of relative humidity.

[0263] Figure 19 shows Raman spectrum of Form 4 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0264] Figure 20 shows PXRD pattern of Form 5 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0265] Figure 21 shows Raman spectrum of Form 5 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate. 39. ASBLomond.24.0001.W

[0266] Figure 22 shows TG-FTIR thermogram of Form 5 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0267] Figure 23 shows PXRD pattern of Form 6 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0268] Figure 24 shows TG-FTIR thermogram of Form 6 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0269] Figure 25 shows DVS isotherm of Form 6 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate: the change of water content and relative humidity as a function of time.

[0270] Figure 26 shows DVS isotherm of t of Form 6 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate: the change of water content as a function of relative humidity.

[0271] Figure 27 shows Raman spectrum of Form 6 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0272] Figure 28 shows PXRD pattern of Form 7 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0273] Figure 29 shows TG-FTIR thermogram of Form 7 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0274] Figure 30 shows Raman spectrum of Form 7 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0275] Figure 31 shows PXRD patterns of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form A; Form C; mesomorphic form; and amorphous form.

[0276] Figure 32 shows PXRD pattern of Form E of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0277] Figure 33 shows Raman spectrum of Form E of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline. 40. ASBLomond.24.0001.W

[0278] Figure 34 shows TG-FTIR thermogram of Form E of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0279] Figure 35 shows PXRD pattern of Form F of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0280] Figure 36 shows PXRD patterns of 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form F; Form E; Form A; and Form C.

[0281] Figure 37 shows TG-FTIR thermogram of Form F of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0282] Figure 38 shows PXRD pattern of Form A of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0283] Figure 39 shows TG-FTIR thermogram of Form A of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0284] Figure 40 shows DSC thermogram of a crystalline compound 3-(3,4-dimethoxyphenyl)- 1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form A.

[0285] Figure 41 shows TG-FTIR thermogram of Form 1 of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline phosphate.

[0286] Figure 42 shows PXRD patterns of two samples of compound 5.

[0287] Figure 43 shows PXRD pattern of Form B of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0288] Figure 44 shows PXRD pattern of Form D of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline.

[0289] Figure 45 shows DSC / TGA Thermogram Overlay of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form B.

[0290] Figure 46 shows DSC / TGA Thermogram Overlay of a crystalline compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline in Form C.

[0291] Figure 47 shows DSC / TGA Thermogram Overlay of amorphous compound 3-(3,4- dimethoxyphenyl)-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-2,3-dihydropyrazolo[4,3-c]quinoline. DETAILED DESCRIPTION 41. ASBLomond.24.0001.W

[0292] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3) by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0293] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions

[0294] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and are consistent with.

[0295] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0296] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0297] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0298] As used herein, the term "about" or “approximately” when used in reference to X-ray powder diffraction pattern peak positions refers to the inherent variability of the peaks depending on, for example, the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material and the like, depending on the instrumentation used. In this case the measure variability of the instrument was about plus / minus ± 0.3 degrees 2-theta (θ). A person skilled in the art, having the benefit of this disclosure, would understand the use of "about" or “approximately” in this context unless specified otherwise (e.g. ± 0.05 degrees 2-theta). The term "about" or “approximately” in reference to other defined parameters, e.g., water content, Cmax, tmax, AUC, intrinsic dissolution rates, temperature, and time, indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. A person skilled 42. ASBLomond.24.0001.W in the art, having the benefit of this disclosure, would understand the variability of a parameter as connoted by the use of the word about or approximately.

[0299] "Polymorph", as used herein, refers to the occurrence of different crystalline forms of a compound differing in packing or conformation / configuration but with the same chemical composition. Crystalline forms have different arrangements and / or conformations of the molecule in the crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate. Hydrates / solvates may exist as polymorphs for compounds with the same solvent content but different lattice packing or conformation. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, morphology, density, flowability, compactibility and / or X-ray diffraction peaks. The solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to characterize and investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffractometry and by other methods such as, infrared or Raman or solid-state NMR spectrometry.

[0300] The acronym "PXRD" means powder X-ray diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component with a display of the X- ray diffraction pattern. The X-ray diffraction pattern may be made using CuKαl radiation. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. Materials with similar unit cells will give X-ray diffraction patterns that are similar in position as measured in °2θ (theta). Solvates which exhibit this property are called isostructural or isomorphous solvates. The intensity of the reflections varies according to the electron density causing diffraction as well as sample, sample preparation, and instrument parameters. Analysis of PXRD data is based upon the general appearance of the measured powder pattern(s) with respect to the known response of the X-ray diffraction system used to collect the data. For diffraction peaks that may be present in the powder pattern, their positions, shapes, widths, and relative intensity distributions can be used to characterize the type of solid state order in the powder sample. The position, shape, and intensity of any broad diffuse scatter (halos) on top of the instrumental background can be used to characterize the level and type of solid state disorder. The combined interpretation of the solid state order and disorder present in a powder sample provides a qualitative measure of the macro-structure of the sample. 43. ASBLomond.24.0001.W

[0301] The term “cocrystal” refers to a crystalline molecular complex composed of two or more different molecular compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. The cocrystal consists of a hydrogen-bonded complex with a “pharmaceutically acceptable” coformer. Coformers include, but are not limited to, acetylsalicylic acid, trans-acontic acid, adipic acid, L-ascorbic acid, benzoic acid, citric acid, fructose, fumaric acid, gallic acid, glucose, glutaric acid, hippuric acid, 4-hydroxybenzoic acid, maleic acid, malonic acid, mannitol, nicotinamide, nicotinic acid, phenylalanine, riboflavin, salicylic acid, succinic acid, and vanillic acid.

[0302] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate)) salts. Other salts include acid salts such as coformers described above. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0303] The term “hydrochloride” as disclosed herein refers to monohydrochloride, dihydrochloride, trihydrochloride, and tetrahydrochloride.

[0304] The term “phosphate” as disclosed herein refers to monophosphate, diphosphate, triphosphate, and tetraphosphate.

[0305] The term “sulfate” as disclosed herein refers to monosulfate, disulfate, trisulfate, and tetrasulfate.

[0306] The term “tartrate” as disclosed herein refers to monotartrate, ditartrate, tritartrate, and tetratartrate.

[0307] The term “maleate” as disclosed herein refers to monomaleate, dimaleate, trimaleate, and tetramaleate.

[0308] The term “fumarate” as disclosed herein refers to monofumarate, difumarate, trifumarate, and tetrafumarate. 44. ASBLomond.24.0001.W

[0309] The term “citrate” as disclosed herein refers to monocitrate, dicitrate, tricitrate, and tetracitrate.

[0310] The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. For example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, methanesulfonic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0311] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0312] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, cyclohexanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Other solvents that may form solvates include the Class 2 and 3 groups from “Q3C - Tables and List Guidance for Industry:” (June 2017) US Dept. HHS, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). The Class 2 group of solvents that may form solvates are: Acetonitrile, Chlorobenzene, Chloroform, Cyclohexane, Cumene, 1,2-Dichloroethene, Dichloromethane, 1,2-Dimethoxyethane, N,N-Dimethylacetamide, N,N-Dimethylformamide, 1,4- Dioxane, 2-Ethoxyethanol, Ethyleneglycol, Formamide, Hexane, Methanol, 2-Methoxyethanol, Methylbutyl ketone, Methylcyclohexane, Methylisobutylketone, N-Methylpyrrolidone, Nitromethane, Pyridine, Sulfolane, Tetrahydrofuran (THF), Tetralin, Toluene, Trichloroethene, and Xylene. The Class 3 group of solvents that may also form solvates are: Acetic acid, Heptane, Acetone, Isobutyl acetate, Anisole, Isopropyl acetate, 1-Butanol, Methyl acetate, 2-Butanol, 3- Methyl-1-butanol, Butyl acetate, Methylethyl ketone, fertButylmethyl ether, 2-Methyl-1- propanol, Dimethyl sulfoxide, Pentane, Ethanol, 1-Pentanol, Ethyl acetate, 1-Propanol, Ethyl ether, 2-Propanol, Ethyl formate, Propyl acetate, Formic acid, and Triethylamine.

[0313] The term "hydrate" refers to the complex where the solvent molecule is water.

[0314] The term “stereoisomer” refers to compounds that have the same molecular formula and sequence of bonded atoms (constitution) but differ in the three-dimensional orientations of their atoms in space. 45. ASBLomond.24.0001.W

[0315] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with2H and14C). Deuterated (i.e.,2H or D) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0316] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0317] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0318] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0319] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0320] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0321] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0322] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula I (and / or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An 46. ASBLomond.24.0001.W effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized. Compounds of the Present Disclosure

[0323] The present disclosure includes polymorphs and amorphous forms of Formula (I) compound, (CAS Registry Number 2923221-56-9), having the structure: , and named7-yl)-2,3- dihydropyrazolo[4,3-c]quinoline (PCT / US2022 / 045555; US18 / 701,223; TW2023 / 17567, each of which are incorporated by reference). As used herein, the Formula (I) compound includes tautomers, solvates, hydrates, pharmaceutically acceptable salts and cocrystals thereof.

[0324] The compound of Formula (I) is the API (Active Pharmaceutical Ingredient) in formulations for use in the treatment of diseases, disorders and conditions associated with disfunction of FMS-like tyrosine kinase 3 (FLT3), such as cancer, acute myeloid leukemia (AML), cytogenetically normal acute myeloid leukemia (CN-AML) and others.

[0325] In some embodiments, the compound of Formula (I) is a free base of Formula (I-A): 47. ASBLomond.24.0001.W , solvate, hydrate,

[0326] In some salt of Formula (I- B): , solvate, hydrate, selected from 1 to 4.

[0327] In some embodiments the hydrochloride salt of the present disclosure is monohydrochloride.

[0328] In some embodiments the hydrochloride salt of the present disclosure is dihydrochloride.

[0329] In some embodiments, A is 0.5.

[0330] In some embodiments, A is 1.0.

[0331] In some embodiments, A is 1.5.

[0332] In some embodiments, A is 2.0.

[0333] In some embodiments, A is 2.5.

[0334] In some embodiments, A is 3.0.

[0335] In some embodiments, A is 3.5.

[0336] In some embodiments, A is 4.0.

[0337] In some embodiments, the compound of Formula (I) is a dihydrochloride salt of Formula (I-B-1): 48. ASBLomond.24.0001.W , solvate, hydrate,

[0338] In somesalt of Formula (I-C): , solvate, hydrate, selected from 1 to 4.

[0339] In some embodiments the phosphate salt of the present disclosure is monophosphate.

[0340] In some embodiments the phosphate salt of the present disclosure is diphosphate.

[0341] In some embodiments the phosphate salt of the present disclosure is triphosphate.

[0342] In some embodiments the phosphate salt of the present disclosure is tetraphosphate.

[0343] In some embodiments, A is 0.5.

[0344] In some embodiments, A is 1.0.

[0345] In some embodiments, A is 1.5.

[0346] In some embodiments, A is 2.0.

[0347] In some embodiments, A is 2.5.

[0348] In some embodiments, A is 3.0.

[0349] In some embodiments, A is 3.5.

[0350] In some embodiments, A is 4.0.

[0351] In some embodiments, the compound of Formula (I) is a phosphate salt of Formula (I-C- 1): 49. ASBLomond.24.0001.W 1), wherein A is a 0 to 10.

[0352] In somesalt monohydrate of Formula (I-C-1-a): a).

[0353] In somesalt dihydrate of Formula (I-C-1-b): b).

[0354] In someof Formula (I-D): , solvate, hydrate,from 1 to 4. 50. ASBLomond.24.0001.W

[0355] In some embodiments the tartrate salt of the present disclosure is monotartrate.

[0356] In some embodiments the tartrate salt of the present disclosure is ditartrate.

[0357] In some embodiments the tartrate salt of the present disclosure is tritartrate.

[0358] In some embodiments the tartrate salt of the present disclosure is tetratartrate.

[0359] In some embodiments, A is 0.5.

[0360] In some embodiments, A is 1.0.

[0361] In some embodiments, A is 1.5.

[0362] In some embodiments, A is 2.0.

[0363] In some embodiments, A is 2.5.

[0364] In some embodiments, A is 3.0.

[0365] In some embodiments, A is 3.5.

[0366] In some embodiments, A is 4.0.

[0367] In some embodiments, the compound of Formula (I) is a maleate salt of Formula (I-E): , solvate, hydrate,from 1 to 4.

[0368] In some embodiments the maleate salt of the present disclosure is monomaleate.

[0369] In some embodiments the maleate salt of the present disclosure is dimaleate.

[0370] In some embodiments the maleate salt of the present disclosure is trimaleate.

[0371] In some embodiments the maleate salt of the present disclosure is tetramaleate.

[0372] In some embodiments, A is 0.5.

[0373] In some embodiments, A is 1.0.

[0374] In some embodiments, A is 1.5.

[0375] In some embodiments, A is 2.0.

[0376] In some embodiments, A is 2.5.

[0377] In some embodiments, A is 3.0.

[0378] In some embodiments, A is 3.5.

[0379] In some embodiments, A is 4.0.

[0380] In some embodiments, the compound of Formula (I) is a maleate salt of Formula (I-E-1): 51. ASBLomond.24.0001.W 1), of Formula (I-E-2):2), of Formula (I-F):F), solvate, hydrate,from 1 to 4.

[0383] In some embodiments the fumarate salt of the present disclosure is monofumarate.

[0384] In some embodiments the fumarate salt of the present disclosure is difumarate.

[0385] In some embodiments the fumarate salt of the present disclosure is trifumarate.

[0386] In some embodiments the fumarate salt of the present disclosure is tetrafumarate.

[0387] In some embodiments, A is 0.5.

[0388] In some embodiments, A is 1.0.

[0389] In some embodiments, A is 1.5.

[0390] In some embodiments, A is 2.0.

[0391] In some embodiments, A is 2.5. 52. ASBLomond.24.0001.W

[0392] In some embodiments, A is 3.0.

[0393] In some embodiments, A is 3.5.

[0394] In some embodiments, A is 4.0.

[0395] In some embodiments, the compound of Formula (I) is a fumarate salt of Formula (I-F-1): , solvate, hydrate,

[0396] In some a salt of Formula (I-F-2): 2), solvate, hydrate,

[0397] In some embodiments, the compound of Formula (I) is a citrate salt of Formula (I-G): , solvate,from 1 to 4.

[0398] In some embodiments the citrate salt of the present disclosure is monocitrate.

[0399] In some embodiments the citrate salt of the present disclosure is dicitrate.

[0400] In some embodiments the citrate salt of the present disclosure is tricitrate.

[0401] In some embodiments the citrate salt of the present disclosure is tetracitrate. 53. ASBLomond.24.0001.W

[0402] In some embodiments, A is 0.5.

[0403] In some embodiments, A is 1.0.

[0404] In some embodiments, A is 1.5.

[0405] In some embodiments, A is 2.0.

[0406] In some embodiments, A is 2.5.

[0407] In some embodiments, A is 3.0.

[0408] In some embodiments, A is 3.5.

[0409] In some embodiments, A is 4.0.

[0410] In some embodiments, the compound of Formula (I) is a sulfate salt of Formula (I-H): , solvate, hydrate, selected from 1 to 4.

[0411] In some embodiments the sulfate salt of the present disclosure is monosulfate.

[0412] In some embodiments the sulfate salt of the present disclosure is disulfate.

[0413] In some embodiments, A is 0.5.

[0414] In some embodiments, A is 1.0.

[0415] In some embodiments, A is 1.5.

[0416] In some embodiments, A is 2.0. Crystallization and screening the compound of Formula (I)

[0417] Initial polymorph screening experiments were performed using a variety of crystallization or solid transition methods, including: anti-solvent addition, reverse anti-solvent addition, slow evaporation, slow cooling, slurry at room temperature, slurry at 50°C, solid vapor diffusion, liquid vapor diffusion, and polymer induced crystallization. Crystallization and screening the compound of Formula (I-A)

[0418] The first crystalline sample of I-A was obtained after extraction of the precipitated free base from an aqueous suspension using dichloromethane (DCM). This sample was designated a form C. Later on, the DCM extraction step was considered as unnecessary and direct filtration of the solid free base from aqueous suspensions after precipitation with NaOH was performed. Washing of the filter cake with water was efficient enough to remove the NaCl in the system. However, this led to an amorphous phase in the first step. Continued suspension equilibration of 54. ASBLomond.24.0001.W the amorphous form in water led to semicrystalline or mesomorphous phase with broad and weak intensity reflections.

[0419] In the Table 1 presents list of free base samples prepared from free base (I-A), dihydrochloride salt (I-B) and phosphate salt (I-C).

[0420] Table 1: Crystalline compound of Formula (I-A) preparation. Starting Sample Solid Form Preparation Characterization compound ,55. ASBLomond.24.0001.W Starting Sample Solid Form Preparation Characterization compound

[0421] The amorphous freebase (I-A) DSC / TGA thermogram overlay is shown in Figure 47. The DSC shows a broad endotherm with onset ~40°C, an endotherm with onset ~99°C, an exotherm with onset ~131°C, and a sharp endotherm with onset ~212°C.

[0422] Figure 31 shows the four different diffraction patterns for the samples I-A-a, I-A-b, I-A-c and I-A-d.

[0423] Description of the PXRD pattern for the compound of Formula (I-A) in the Form A is provided in Table 2.

[0424] Table 2. Description of the PXRD pattern of Form A of the compound of Formula (I-A). Angle 2θ d value, Å Intensity* Relative intensity, %56. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 10.2152 8.652436 m 28.81ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 31.8087 2.810976 w 10.35

[0425] The PXRD pattern of the Form B of the compound of Formula (I-A) is depicted in Figure 43 and shows that the sample is crystalline in nature.

[0426] Description of the PXRD pattern for the compound of Formula (I-A) in the Form B is provided in Table 3.

[0427] Table 3. Description of the PXRD pattern of Form B of the compound of Formula (I-A). Angle 2θ Intensity Relative intensity, % ASBLomond.24.0001.W Angle 2θ Intensity Relative intensity, % 19.4 39.3 9.4

[0428] The Pattern B DSC / TGA thermogram overlay is shown in the Figure 45. The DSC shows a broad endotherm with peak ~53°C, a broad endotherm with onset ~82°C, and a sharp endotherm with onset ~205°C. The TGA shows ~4.96% weight loss from 30°C to ~71°C and ~10.79% weight loss from ~71°C to 150°C.

[0429] Description of the PXRD pattern for the compound of Formula (I-A) in the Form C is provided in Table 4.

[0430] Table 4. Description of the PXRD pattern of Form C of the compound of Formula (I-A). Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 7.5592 11.685535 vs 81.93

[0431] In the Table 5 presented solubility data for the Form C of the compound of Formula (I- A). 60. ASBLomond.24.0001.W

[0432] Table 5. Solubility of a crystalline compound 3-(3,4-dimethoxyphenyl)-1-(1,2,3,4- tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-c]quinoline in the Form C. # Solvent Solubility, mg / mL 1 Acetic acid* S>112

[0433] The Pattern C DSC / TGA thermogram overlay is shown in the Figure 46. The DSC shows a broad endotherm with peak ~46°C, a broad exotherm with onset ~190°C, and a sharp endotherm with onset ~214°C. The TGA shows ~4.58% weight loss from 30°C to 150°C.

[0434] The PXRD pattern of the Form D of the compound of Formula (I-A) is depicted in Figure 44 and shows that the sample is crystalline in nature.

[0435] Description of the PXRD pattern for the compound of Formula (I-A) in the Form D is provided in Table 6.

[0436] Table 6. Description of the PXRD pattern of Form D of the compound of Formula (I-A). Angle 2θ Intensity Relative intensity, %. ASBLomond.24.0001.W Angle 2θ Intensity Relative intensity, % 6.6 21.6 12.362. ASBLomond.24.0001.W

[0437] A sample I-A-e-1 with a new Raman spectrum and a new PXRD pattern was obtained from suspension equilibration experiment of compound (I-A) in methanol at room temperature. Another sample I-A-e-2 with essentially the same PXRD pattern was obtained from a slurry in methanol at 50°C. The sample I-A-e-1 was examined by TG-FTIR and it was found 6.1% of water but no methanol was detected although the sample was just allowed to dry under ambient conditions. Therefore, the Form E is a hydrated, the water content is close to the theoretical water content for a sesquihydrate.

[0438] The PXRD pattern of the Form E of the compound of Formula (I-A) is depicted in Figure 32 and shows that the sample is crystalline in nature.

[0439] Description of the PXRD pattern for the compound of Formula (I-A) in the Form E is provided in Table 7.

[0440] Table 7. Description of the PXRD pattern of Form E of the compound of Formula (I-A). Angle 2θ d value, Å Intensity* Relative intensity, % 4425 19953104 4906. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 27.5499 3.235066 w 11.9

[0441] The Raman Spectrum of the Form E of the compound of Formula (I-A) is depicted in Figure 33.

[0442] Thermoanalytical characterization of the Form E of the compound of Formula (I-A) is depicted in Figure 34.

[0443] A sample with a new PXRD pattern was obtained from a suspension equilibration experiment with compound of Formula (I-A) in ethanol at 50°C. The sample I-A-g-1 was tested by HPLC and TG-FTIR. HPLC revealed the purity was essentially the same as the starting material sample, and TG-FTIR showed a water content of 3.5%, but no ethanol was detected. To conclude, this form, which is designated as Form F, appears to be reproducible, and could by another monohydrate, even though the water seems to be less strongly bound than in Form A.

[0444] The PXRD pattern of the Form F of the compound of Formula (I-A) is depicted in Figure 35 and shows that the sample is crystalline in nature.

[0445] Description of the PXRD pattern for the compound of Formula (I-A) in the Form F is provided in Table 8.

[0446] Table 8. Description of the PXRD pattern of Form F of the compound of Formula (I-A). Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 19.7147 4.499522 s 36.49

[0447] The PXRD patterns of the Form A, Form C, Form E, and Form F are depicted in Figure 36.

[0448] The TG-FTIR thermogram for the Form F is depicted in Figure 37 and shows a mass loss of 3.5% which is essentially attributable to water.

[0449] Experiments for the production of free base were conducted from both the phosphate salt and the hydrochloride salt as the starting materials. The solubility properties of the dihydrochloride are different from the properties of the phosphate. The phosphate salt is insoluble is typical process solvents such as ketones, alcohols, esters, or mixtures thereof, and while the aqueous solubility is good for pharmaceutical application is it still fairly low for an efficient recrystallization process. In the test experiments the phosphate salt was not entirely dissolved. As a consequence, the reaction was heterogeneous and more difficult to control. In addition, filtration times were longer and the crystallinity of the solid products lower than in the experiments with the dihydrochloride salt. Therefore, the dihydrochloride salt was used as the starting material to produce the desired amount of free base in a well-defined crystalline form that can easily be reproduced. 65. ASBLomond.24.0001.W

[0450] The PXRD pattern of the sample I-A-d-1 shows that the material is highly crystalline in nature and the PXRD pattern corresponds to Form A. The PXRD pattern of Form A of free base is presented in Figure 38.

[0451] The TG-FTIR thermogram is depicted in Figure 39 and shows that the sample exhibits a mass loss of 4.1% which is essentially attributable to water. This value is close to the expected water content for a monohydrate which is 4.0%.

[0452] The DSC thermogram is presented in Figure 40 and shows a first endothermic signal with a maximum at 94°C. Since the test was carried out in a sample pan with a pinhole, this signal is likely due to loss of the hydrate water. A first melting peak is observed at 204°C which followed by a small exothermic event and a third endotherm. This is typical for a polymorphic phase transformation into a high-temperature stable form. Crystallization and screening the compound of Formula (I-B)

[0453] The PXRD pattern of sample of the compound of Formula (I-B) is depicted in Figure 3. Polarized microscopy shows that roughly 50% of the material is birefringent. The observed PXRD reflections likely correspond to the birefringent part of the sample, while the sample contains an amorphous fraction, possibly 50% or more, which is not well detectable by transmission PXRD.

[0454] TG-FTIR was carried out for sample I-B and reveals a water content of approx.9% before the decomposition starts at about 240°C. The TG-FTIR thermogram is presented in Figure 4.

[0455] DVS was carried out for dihydrochloride salt sample I-B using a double humidity cycle with a scan rate of 5% r.h. per hour at 25°C. The thick trace in Figure 5 shows the applied measurement program, and the thin curve shows the estimated water content. The sample contains approx. 8.6% of water at 50% r.h. at the start of the experiment. At 0% r.h., the sample lost approximately 4% of water to reach a minimum water content of about 5%. At 95% r.h., the water content increases to approx. 30%. This sample is classified as very hygroscopic. There is an obvious difference between both cycles which is noted from Figure 5, where both hysteresis cycles are not superposable. The water content at the end of the measurement was more than 10% larger than at the start of the measurement.

[0456] Description of the PXRD pattern for the compound of Formula (I-B) is provided in Table 9.

[0457] Table 9. Description of the PXRD pattern for the compound of Formula (I-B). Angle 2θ d value, Å Intensity* Relative intensity, %66. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 9.26 9.54 vs 84Compound 5

[0458] The chemical structure of the compound 5 is presented below: 67. ASBLomond.24.0001.W .

[0459] The -1H-pyrazolo[4,3-c] - -

[0460] Compound 5 samples were investigated by PXRD and approximate solubility tests because compound 5 was used for transformation into a phosphate salt by debocylation with phosphoric acid. A few potentially useful solvents for the debocylation process or recrystallization of compound 5 were discussed and qualitative solubilities were estimated during the ongoing experimental work. The results are presented in Table 10 and confirm that 2-MeTHF is a good solvent for debocylation.

[0461] Table 10. Approximate solubility data for compound 5. Solvent T, °C Solubility, mg / mL woPXRD patterns as depicted in Figure 42 shows that the two patterns are likely corresponding to two different crystalline forms. No further investigations were undertaken because the main goal was to obtain some reference data to monitor debocylation experiments. Crystallization and screening the compound of Formula (I-C)

[0463] Essentially three different pathways to produce and investigate new phosphate salt (I-C) forms were explored: a) salt formation with the free base as the starting material, b) debocylation of compound 5 with phosphoric acid, and c) crystallization experiments starting with phosphate salt, i.e., experiments that are typically performed in studies of the polymorphism landscape of a given compound. 68. ASBLomond.24.0001.W

[0464] Surprisingly, each method led to different phosphate salt phases. This is very unusual and we believe that this fact is a good argument to obtain a granted patent for several of the most important forms.

[0465] Phosphate (I-C) exists in various crystalline phases that are now referred to as Form 1 to Form 7.

[0466] Form 1 was characterized by basic physicochemical methods and is likely a diphosphate hydrate (Formula I-C-F1) with an aqueous solubility of 9 mg / mL in pure water at a resultant pH of about 2.5: .

[0467] Form 1 is kinetically very stableand would be suitable for a drug product.

[0468] Form 1 is a channel hydrate that is typically containing about 4.5% of water which would, in principle, correspond to a sesquihydrate. However, it seems that the water content can vary between 0% (after prolonged exposure to 0% r.h.), and about 7.5% at 95% r.h. PXRD of a Form 1 sample under variable r.h. is useful to monitor possible changes of the PXRD patterns as a function of water content. It is found that such changes were minor and a total phase change was not observed.

[0469] In some embodiments, Form 1 is a diphosphate dihydrate.

[0470] 1H-NMR investigation of the Form 1 (in D2O) confirmed the chemical integrity of the sample. Since methanol was used as the solvent for production of this Form 1 sample, it was of interest as to whether the residual methanol content could be assessed by NMR. This appears to be the case, however, based on the obtained1H-NMR spectrum depicted in Figure 8, no methanol was detected.

[0471] The TG-FTIR thermogram of the Form 1 after drying is depicted in Figure 41. A first mass loss is observed from about 40°C to 160°C and corresponds to about 4.5%. An additional 4.5% mass loss is observed from 160°C to 300°C and both steps are attributable to water. The second mass loss step is likely due to decomposition of the dihydrogen phosphate ion.

[0472] A Raman spectrum of diphosphate salt Form 1 was recorded with a dispersive Raman instrument from 100 to 2000 cm-1. The Raman spectrum is depicted in Figure 9. 69. ASBLomond.24.0001.W

[0473] The DVS result for diphosphate Form 1 is presented in Figure 10 and Figure 11. The sample contains approx. 4.3% of water at 50% r.h. at the start of the experiment. At 0% r.h., the sample lost approx. 4% of water to reach a minimum water content of about 0.3%. Upon storage at 95% of r.h. the total water content reaches about 7.5%. Figure 11 shows that both cycles are largely identical without hysteresis. The water content at the beginning of the measurement was determined from the first step of the TG-FTIR result.

[0474] In the Table 11 presented approximate solubility determination data for Form 1 and Form 6.

[0475] Table 11. # Form Solvent Solubility, mg / mL 1 1 Acetic acid S~15

[0476] Suspension equilibration experiments were used to obtain thermodynamically stable forms (polymorphs or solvates) in a given solvent system. An appropriate amount of solvent or solvent mixture was typically added to a given amount of the starting material and equilibrated. Equilibrations experiments were conducted in different organic solvents, but also at different water activities using mixtures of organic solvent and water. The experiments at room temperature were conducted over several days. A summary of the suspension experiments is provided in Table 12.

[0477] Table 12. Summary of the suspension equilibration experiments. 70. ASBLomond.24.0001.W Starting # Solvent System Conditions Result / Remark Form y th w of al

[0478] Form 1 appeared to be very stable. 71. ASBLomond.24.0001.W

[0479] Description of the PXRD pattern for Form 1 is provided in Table 13.

[0480] Table 13. Description of the PXRD pattern for Form 1. Angle 2θ d value, Å Intensity* Relative intensity, % 5.95 14.84 s 5472. ASBLomond.24.0001.W

[0481] Form 2 is an elusive and poorly crystalline phase.

[0482] Form 3 appears to be the stable form at very high-water activities (wa> 0.9); for instance, in pure water at room temperature and in mixtures with water and THF or other solvents when the water activity is greater than 0.9. Form 3 was found as the solid residue after solubility tests with Form 1 and Form 6.

[0483] The phosphorus content by ICP-OES for Form 3 was 7.8% and TG-FTIR suggests a water content of about 6.9%. A simulation of the elemental composition would suggest 1.5 phosphate and 2.5 hydrate, which correspond to Formula (I-C-F3): .

[0484] Description 14.

[0485] Table 14. Description of the PXRD pattern for Form 3. Angle 2θ d value, Å Intensity* Relative intensity, %73. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 19.22 4.61 s 31

[0486] Form 4 was discovered when debocylation of compound 5 was carried out with a 39-fold excess of phosphoric acid. Determination of the phosphorus content of a sample of Form 4 revealed 12.9% phosphorus which roughly corresponds to three equivalents of phosphoric acid. Therefore, Form 4 is rather a triphosphate than a diphosphate salt and this explains why Form 4 was exclusively obtained when at least three equivalents of phosphoric acid were present in the system, which correspond to Formula (I-C-F4): 74. ASBLomond.24.0001.W .

[0487] The17 to 19 mg / mL, which is significantly higher than the solubility of Form 6.

[0488] Form 4 can serve as an intermediate to produce the stable Form 6 because by leaching out one equivalent of phosphoric acid to a liquid phase it can be converted to a diphosphate salt form.

[0489] The TG-FTIR thermogram of Form 4 shown in Figure 16 reveals a water content of about 1.4% that occurs from rt to 150°C. Thermal decomposition leads to additional mass loss above about 200°C. Since the water loss begins readily upon heating it is believed that Form 4 is a hygroscopic anhydrous form rather than a hydrate.

[0490] DVS experiment was carried out for Form 4 using a double humidity cycle with a scan rate of 5% r.h. per hour at 25°C. The thick trace in Figure 17 shows the applied measurement program and the thin curve shows the estimated water content. Based on the TG-FTIR result, the water content curve was adjusted to reflect the amount of water present in the sample. It appears that at 0% r.h. all water was removed while at 95% r.h. about 6% of water is adsorbed. However, it is readily noted from the figures that the water sorption would continue upon extended exposure to high relative humidity levels.

[0491] Description of the PXRD pattern for Form 4 is provided in Table 15.

[0492] Table 15. Description of the PXRD pattern for Form 4. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 16.99 5.21 m 23ASBLomond.24.0001.W *- “vs”-very strong; “s”-strong; “m”-medium; “w”-weak.

[0493] Form 5 was also obtained from debocylation of compound 5 in 2-MeTHF. The phosphorus content of Form 5 by ICP-OES was 15.7% which suggests that Form 5 is a tetraphosphate salt of Formula (I-C-F5): .

[0494] Form 5 is excess of phosphoricacid can be –

[0495] Form 5 is not a diphosphate salt, and therefore, it would be evident that it was never obtained in polymorph screening experiments when the starting material was a diphosphate salt, unless more phosphoric acid is added.

[0496] Form 5 is an important intermediate form that is generated during the debocylation of compound 5 in 2-MeTHF with an excess of phosphoric acid. In a competitive suspension experiment in acetone / H2O 9:1 Form 4 was obtained and phosphorus-content determination of the obtained sample showed a P-content of 12.9%; i.e., one equivalent of phosphoric acid was extracted to the solvent phase during the experiment. A quick solubility estimation showed that almost 30 mg / mL of Form 5 can be dissolved in pure water at 70°C.

[0497] The TG-FTIR thermogram of Form 5 is depicted in Figure 22 and suggests a water content of about 2.0% that is released upon heating from rt to about 150°C.

[0498] Description of the PXRD pattern for Form 5 is provided in Table 16.

[0499] Table 16. Description of the PXRD pattern for Form 5. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 13.97 6.34 s 30

[0500] Form 6 was discovered when an exploratory debocylation experiment was carried out in 2-MeTHF. In a later experiment Form 6 was obtained from an experiment with free base as the starting material. In this experiment, 2.5 eq of phosphoric acid was used in a mixture of EtOH / H2O 3:1. Form 6 was characterized by PXRD, PLM, DVS, TG-FTIR, NMR, solubility in pure water and P-OES content. A phosphorus content of 9.6% was determined, which is consistent with a diphosphate salt of Formula (I-C-F6): 78. ASBLomond.24.0001.W .

[0501] The 5 mg / mL and the equilibrated6 is lower than the solubility of Form 1 and competitive suspension experiments with Form 1 and Form 6 resulted in Form 6. Form 6 is therefore thermodynamically more stable than Form 1.

[0502] Form 6 appears to be the thermodynamically most stable form of the compound of Formula (I-C) diphosphate and it is a monohydrate with a water content of 2.8%.

[0503] Form 6 shows a good physicochemical profile which makes it suitable for formulation to a drug product.

[0504] Examination of Form 6 by DVS showed that while it is possible to remove all the water by drying under nitrogen, the water content at relative humidities between 20% and 80% remains relatively constant. The variation is less than 1% under kinetic conditions.

[0505] Based upon DVS testing, Form 6 can be regarded as slightly hygroscopic.

[0506] Solubility determination for Form 6 in pure water results is a pH value of the saturated solution of about 2 and a solubility of 3.2 mg / mL. Form 3 was found as the solid residue in the suspension with the saturated solution.

[0507] The chemical and physical stability of (I-C) Form 6 were tested under two different conditions for 15 days. The conditions were 40°C / 75% r.h. in an open vial and 60°C in a closed vial that was sealed under ambient conditions. The HPLC purity of “starting material, t = 0” sample was 99.4%. From the summary in Table 17 it is noted neither a form changed nor a change of the chemical purity could be observed.

[0508] Table 17. # Condition Duration HPLC purity (Δ) PXRD

[0509] Description of the PXRD pattern for Form 6 is provided in Table 18.

[0510] Table 18. Description of the PXRD pattern for Form 6. 79. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 5.37 16.46 m 18ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 28.70 3.11 m 1981. ASBLomond.24.0001.W

[0511] Form 7 was obtained in a new approach to produce diphosphate salt from the free base as the starting material was explored. The free base (I-A) was dissolved in MeOH / DCM 1:1 and 2.25 eq of phosphoric acid were added in form of a 1 M aqueous solution at 40°C. Surprisingly this led to a different solid form from the previous procedure that was used to produce Form 1. In contrast to the case of Form 1 where concentrated phosphoric acid was used, use of a small excess of 1 M phosphoric acid led to Form 7. Determination of the phosphorus content by ICP-OES revealed a P content of 9.2% which is consistent with a diphosphate salt of Formula (I-C-F7): .

[0512] Competitive to Form 6. Therefore,Form 6 is thermodynamically more stable than Form 7. Form 7 was characterized by PXRD, P- OES content, TG-FTIR and Raman spectroscopy. Form 7 is an important intermediate to produce Form 6 from Form 5. Under certain conditions, for instance in EtOH / H2O 3:1, Form 5 transforms into Form 7, and Form 7 can be converted to the stable form of the diphosphate salt, which is Form 6.

[0513] Polarized Light Microscopy (PLM) showed that Form 7 appears as nearly spherical particles in suspension whereas Form 6 typically forms very fine needles.

[0514] TG-FTIR was carried out for Form 7 and thermogram shown in Figure 29 reveals a mass loss of approx. 11.5% from rt to 310°C. However, this mass loss includes the decomposition of the dihydrogen phosphate ion. The actual mass loss that is due to water in Form 7 according to this measurement is likely about 6 to 8% and complete at about 150°C. Therefore Form 7 is a trihydrate

[0515] Description of the PXRD pattern for Form 7 is provided in Table 19.

[0516] Table 19. Description of the PXRD pattern for Form 7. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 18.44 4.81 w 10

[0517] Competitive slurry experiments were performed in different solvent systems at various water activities. The purpose was to determine the thermodynamically stable form at the given experimental conditions. A summary of all competitive slurry experiments is provided in Table 20.

[0518] Table 20. Summary of the competitive slurry experiments. # Starting Forms Solvent System Conditions ResultsASBLomond.24.0001.W 11 Forms 1, 4 & 5 Acetone / H2O 9:1 (aw~ 0.75) 1 day at rt Form 4 12 Forms 1, 6 & 7 EtOH / H2O 3:1 (aw~ 0.75) 3 days at rt Form 6ere vacuum dried at elevated temperatures and the samples were retested by PXRD. A summary of the drying experiments is provided in Table 21. No form conversion was observed for experiments. These forms are therefore stable upon the drying conditions applied for these experiments

[0520] Table 21. Summary of the drying experiments. # Starting Forms Drying conditions Results 1 F 1 2 d t 50°C 10 b F 1

[0521] Experiments with the free base as the starting material were performed in different solvent mixtures under various slurry conditions. Specifically, it was of interest as to how an excess of H3PO4, process temperature, and water activity would influence the formation of the various salt forms. These experiments are summarized in Table 22.

[0522] Table 22. Summary of experiments performed with the free base (I-A) as the starting material. # Solvent H3PO4, eq Slurry conditions Result84. ASBLomond.24.0001.W 4 DCM / MeOH 1:1 2 1 day at rt Form 1 1 day at rt;by debocylation in strongly acidic environments. Initially debocylation was carried out in HCl and the product was a dihydrochloride salt (I-B). It was soon found that debocylation with phosphoric acid was viable process to obtain phosphate salts (I-C). Large excesses of phosphoric acid and elevated temperatures are required for an efficient process. However, Form 6 is not directly generated. Form 5, which seems to be a tetraphosphate salt is typically obtained first. Subsequently Form 5 has to be converted to Form 6. These experiments are summarized in Table 23.

[0524] Table 23. Summary of debocylation experiments with Compound 5. # Solvent H3PO4, eq Slurry conditions Results

[0525] Table 24 provides some results from solubility tests in pure water.

[0526] Table 24. 85. ASBLomond.24.0001.W # Form tested Solubility, mg / mL pH End form Compound (I-C);

[0527] Description of the PXRD pattern for the crystalline Form D1 of the compound of Formula (I-D) is provided in Table 25.

[0528] Table 25. Description of the PXRD pattern for the compound of Formula (I-D), Form D1. Angle 2θ d value, Å Intensity* Relative intensity, %

[0529] Description of the PXRD pattern for the crystalline Form D2 of the compound of Formula (I-D) is provided in Table 26.

[0530] Table 26. Description of the PXRD pattern for the compound of Formula (I-D), Form D2. Angle 2θ d value, Å Intensity* Relative intensity, %. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 5.2 16.9 s 40

[0531] Description of the PXRD pattern for the crystalline Form D3 of the compound of Formula (I-D) is provided in Table 27.

[0532] Table 27. Description of the PXRD pattern for the compound of Formula (I-D), Form D3. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 17.6 5.0 s 49Crystallization and screening the compound of Formula (I-E)

[0533] In some embodiments, the compound of Formula (I-E) is a maleate salt of Formula (I-E- 1): , solvate, hydrate,

[0534] In some embodiments, the compound of Formula (I-E-1) is a maleate salt of Formula (I-E- 1*): ,ASBLomond.24.0001.W polymorph or cocrystal thereof.

[0535] In some embodiments, the compound of Formula (I-E-1) is a maleate salt of Formula (I-E- 1**): ,some a of Formula (I-E-1- a): a), solvate, hydrate,from 0.5 to 1.2.

[0537] In some embodiments, index “a” is selected from 0.8 to 0.9.

[0538] In some embodiments, index “a” is 0.84.

[0539] Description of the PXRD pattern for the crystalline Form E1 of the compound of Formula (I-E-1) is provided in Table 28.

[0540] Table 28. Description of the PXRD pattern for the compound of Formula (I-E-1), Form E1. Angle 2θ d value, Å Intensity* Relative intensity, %89. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 17.95 4.94 s 35, p ): 2), solvate, hydrate,

[0542] Description of the PXRD pattern for the crystalline Form E2 of the compound of Formula (I-E-2) is provided in Table 29.

[0543] Table 29. Description of the PXRD pattern for the compound of Formula (I-E-2), Form E2. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 15.17 5.84 w 8

[0544] Description of the PXRD pattern for the crystalline Form E3 of the compound of Formula (I-E-1*) is provided in Table 30.

[0545] Table 30. Description of the PXRD pattern for the compound of Formula (I-E-1*), Form E3. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 15.88 5.58 s 46ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 37.62 2.39 w 10re than 99%.

[0547] In some embodiments, purity of the compound of Formula (I-E-1*) in Form E3 is about 99.5%.

[0548] In some embodiments, purity of the compound of Formula (I-E-1*) in Form E3 is 99.5%.

[0549] Description of the PXRD pattern for the crystalline Form E4 of the compound of Formula (I-E-1**) is provided in Table 31.

[0550] Table 31. Description of the PXRD pattern for the compound of Formula (I-E-1**), Form E4. Angle 2θ d value, Å Intensity* Relative intensity, %. ASBLomond.24.0001.W *- “vs”-very strong; “s”-strong; “m”-medium; “w”-weak.

[0551] In some embodiments, purity of the compound of Formula (I-E-1**) in Form E4 is more than 98%.

[0552] In some embodiments, purity of the compound of Formula (I-E-1**) in Form E4 is about 98.8%.

[0553] In some embodiments, purity of the compound of Formula (I-E-1**) in Form E4 is 98.8%.

[0554] Description of the PXRD pattern for the crystalline Form E5 of the compound of Formula (I-E) is provided in Table 32.

[0555] Table 32. Description of the PXRD pattern for the compound of Formula (I-E), Form E5. Angle 2θ d value, Å Intensity* Relative intensity, % 367 2406 m 27. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 24.08 3.69 m 22ula (I-E) is provided in Table 33.

[0557] Table 33. Description of the PXRD pattern for the compound of Formula (I-E), Form E6. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 19.26 4.60 w 13Crystallization and screening the compound of Formula (I-F)

[0558] In some embodiments, the compound of Formula (I-F) is a fumarate salt of Formula (I-F- 2): 2), solvate, hydrate,

[0559] Description of the PXRD pattern for the crystalline Form F1 of the compound of Formula (I-F-2) is provided in Table 34.

[0560] Table 34. Description of the PXRD pattern for the compound of Formula (I-F-2), Form F1. 96. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 7.64 11.56 s 58Crystallization and screening the compound of Formula (I-G)

[0561] Description of the PXRD pattern for the crystalline Form G1 of the compound of Formula (I-G) is provided in Table 35.

[0562] Table 35. Description of the PXRD pattern for the compound of Formula (I-G), Form G1. Angle 2θ d value, Å Intensity* Relative intensity, %

[0563] Description of the PXRD pattern for the crystalline Form G2 of the compound of Formula (I-G) is provided in Table 36.

[0564] Table 36. Description of the PXRD pattern for the compound of Formula (I-G), Form G2. 97. ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 3.45 25.57 vs 87Crystallization and screening the compound of Formula (I-H)

[0565] Description of the PXRD pattern for the crystalline Form H1 of the compound of Formula (I-G) is provided in Table 37.

[0566] Table 37. Description of the PXRD pattern for the compound of Formula (I-G), Form H1. Angle 2θ d value, Å Intensity* Relative intensity, %ASBLomond.24.0001.W Angle 2θ d value, Å Intensity* Relative intensity, % 15.63 5.67 s 43p , p p p g p ve (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0568] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N, and18O. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0569] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0570] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium. 99. ASBLomond.24.0001.W

[0571] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[0572] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0573] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0574] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0575] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis. Pharmaceutical Compositions

[0576] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. 100. ASBLomond.24.0001.W

[0577] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0578] A polymorph form of Formula I, may be formulated in accordance with standard pharmaceutical practice and according to procedures of Example 85, for use in therapeutic treatment (including prophylactic treatment) in mammals including humans. The present disclosure provides a pharmaceutical composition comprising the Formula (I) compound in association with one or more pharmaceutically acceptable carrier, glidant, diluent, or excipient.

[0579] The formulations may be prepared using conventional dissolution and mixing procedures. The compound of the present disclosure is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0580] Pharmaceutical formulations of a polymorph form of Formula (I) compound may be prepared for various routes and types of administration with pharmaceutically acceptable diluents, carriers, excipients, glidants or stabilizers (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA), in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, 1.e., carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.

[0581] The pharmaceutical formulation is preferably sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0582] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, 101. ASBLomond.24.0001.W colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0583] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0584] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0585] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0586] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof. 102. ASBLomond.24.0001.W

[0587] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β- cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β- cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β- cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β- cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0588] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0589] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl- p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0590] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0591] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0592] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols 103. ASBLomond.24.0001.W (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0593] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0594] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0595] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0596] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient 104. ASBLomond.24.0001.W such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0597] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0598] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0599] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0600] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0601] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an FMS-like tyrosine kinase 3 (FLT3) related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0602] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an FMS-like tyrosine kinase 3 (FLT3) related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0603] The size of the dose for therapeutic or prophylactic purposes of a compound of Formulae disclosed herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine.

[0604] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article 105. ASBLomond.24.0001.W for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. Methods of Use

[0605] In some aspects, the present disclosure provides a method of inhibiting FMS-like tyrosine kinase 3 (FLT3) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0606] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0607] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0608] In some embodiments, the disease or disorder is associated with disfunction or malfunction of FMS-like tyrosine kinase 3 (FLT3). In some embodiments, the disease or disorder is a disease or disorder in which the FMS-like tyrosine kinase 3 (FLT3) is implicated.

[0609] The compounds of the invention are also useful in treating diseases associated with disfunctions of FMS-like tyrosine kinase 3 (FLT3). For example, diseases and conditions treatable according to the methods of the invention include cancer, acute myeloid leukemia (AML), cytogenetically normal acute myeloid leukemia (CN-AML).

[0610] In some embodiments, the disease or disorder is a cancer.

[0611] In some embodiments, the disease or disorder is acute myeloid leukemia (AML).

[0612] In some embodiments, the disease or disorder is cytogenetically normal acute myeloid leukemia (CN-AML).

[0613] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. 106. ASBLomond.24.0001.W

[0614] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing acute myeloid leukemia (AML) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0615] In some aspects, the present disclosure provides a method of treating, ameliorating or preventing cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0616] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0617] In some aspects, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0618] In some aspects, the present disclosure provides a method of treating cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0619] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting FMS-like tyrosine kinase 3 (FLT3) (e.g., in vitro or in vivo).

[0620] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0621] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0622] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing a cancer in a subject in need thereof. 107. ASBLomond.24.0001.W

[0623] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing acute myeloid leukemia (AML) in a subject in need thereof.

[0624] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating, ameliorating or preventing cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof.

[0625] In some aspects, the present disclosure provides a crystalline form of the present disclosure for use in treating a cancer in a subject in need thereof.

[0626] In some aspects, the present disclosure provides a crystalline form of the present disclosure for use in treating a cancer in a subject in need thereof.

[0627] In some aspects, the present disclosure provides a crystalline form of the present disclosure for use in treating acute myeloid leukemia (AML) in a subject in need thereof.

[0628] In some aspects, the present disclosure provides a crystalline form of the present disclosure for use in treating cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof.

[0629] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of FMS-like tyrosine kinase 3 (FLT3) (e.g., in vitro or in vivo).

[0630] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0631] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0632] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a cancer in a subject in need thereof.

[0633] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing acute myeloid leukemia (AML) in a subject in need thereof.

[0634] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof. 108. ASBLomond.24.0001.W

[0635] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cancer in a subject in need thereof.

[0636] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating acute myeloid leukemia (AML) in a subject in need thereof.

[0637] In some aspects, the present disclosure provides use of a crystalline form of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cytogenetically normal acute myeloid leukemia (CN-AML) in a subject in need thereof.

[0638] The present disclosure provides compounds that function as inhibitors of FMS-like tyrosine kinase 3 (FLT3) (e.g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of FMS-like tyrosine kinase 3 (FLT3) in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0639] In some embodiments, the inhibitor of FMS-like tyrosine kinase 3 (FLT3) is a crystalline form of the present disclosure.

[0640] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0641] The present disclosure also provides a method of treating a disease or disorder in which FMS-like tyrosine kinase 3 (FLT3) is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0642] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Routes of Administration

[0643] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0644] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, 109. ASBLomond.24.0001.W intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES Instrumental - Typical Measurement Conditions.

[0645] Powder X-Ray Diffraction (option 1): Measurements with a Bruker D8 Advance powder X-ray diffractometer was performed in reflection (Bragg-Brentano) geometry. 2θ values usually are accurate within an error of ^0.1-0.2°. The samples were generally prepared without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holder for polymorph screening, 0.1 mm depth. Normally samples were measured uncovered. The electric current in an X-ray tube operating at 40 kV is 40 mA. The PXRD diffractometer is equipped with a LynxEye detector. A variable divergence slight was used with a 3° window. The step size was 0.02° 2θ with a step time of 37 seconds. The samples were rotated at 0.5 rps during the measurement. All samples were prepared and measured in an ambient air atmosphere.

[0646] Powder X-Ray Diffraction (option 2): Stoe Stadi P equipped with a Mythen1K Detector; Cu-K^^ radiation; standard measurement conditions: transmission; 40 kV and 40 mA tube power; curved Ge monochromator; 0.02° 2^ step size, 12s or 48s step time, 1.5- 50.5° 2^ scanning range; detector mode: step scan; 1° 2^ detector step. The samples (10 - 20 mg of powder) were measured between two acetate foils or Kapton foils. No special treatment was used in preparing the samples other than the application of slight pressure to distribute the powder over the irradiated surface area. An ambient air atmosphere was used for all measurements, and each sample was rotated during the measurement. For presentation of overlays, the diffractograms are offset in the y- direction for purpose of comparison.

[0647] 1H-NMR: Bruker DPX300 spectrometer;1H-NMR spectra were recorded using a proton frequency of 300.13 MHz; 30° excitation pulse; recycle delay of 1 s; accumulation of 16 scans, and deuterated DMSO as the solvent. The chemical shifts were referenced relative to TMS at 0 ppm.

[0648] DSC: Differential scanning calorimetry measurements were carried out with a TA Instruments Q2000 instrument or a TA Instruments DSC 2500. The hermetic sealed gold pans were filled with sample under ambient conditions. The measurements were conducted with a heating rate of 20°C / min. The melting point is understood as the peak maximum. 110. ASBLomond.24.0001.W

[0649] TG-FTIR: Thermogravimetric measurement was carried out with a Netzsch Thermo- Microbalance TG 209 coupled to a Bruker FT-IR Spectrometer Vector 22. Aluminum sample pan with a pinhole, N2 atmosphere, heating rate of 10°C / min.

[0650] Microscopy: Polarized light microscopy was performed on a Leitz Orthoplan polarized microscope part #130880, generally a 10x10 magnification was applied.

[0651] DVS: Dynamic vapor sorption was carried out with a proUmid SPS11-100n instrument. The following program was applied to all DVS measurements: 50% r.h. - 0% r.h. - 95% r.h. - 0% r.h. - 95% r.h. - 50% r.h., scan rate of 5% r.h. per hour, T = 25°C. Hygroscopicity is classified according to the European Pharmacopoeia: (1) very hygroscopic (vh): increase of the mass ≥ 15%; (2) hygroscopic (h): increase of the mass is less than 15% and equal or greater than 2%; (3) slightly hygroscopic (sh): increase of the mass is less than 2% and equal or greater than 0.2%; (4) not hygroscopic (nh): increase of the mass is less than 0.2%; (5) deliquescent (d): sufficient water is absorbed to form a liquid. Classified compared to the starting material (at ambient conditions).

[0652] Solubility: Approximate solubilities were determined by incremental addition of solvent to approx.10 mg of the solid compound. If the substance was not dissolved by addition of a total of at least 10 mL of solvent, the solubility is indicated as < 1 mg / mL. Due to the experimental error inherent in this method, the solubility values are intended to be regarded as rough estimates and are to be used solely for the design of crystallization experiments.

[0653] Solvents: Fluka, Sigma-Aldrich, Merck, or ABCR analytical grade solvents were used.

[0654] Filtration: Filtrations are typically carried out with a fritted glass filter of porosity 4, or with 2 mL centrifuge filter units either PVDF or PTFE (0.22 µm) with the following conditions: 5000 rpm, 25°C, 5-10 min.

[0655] Abbreviations used in the following examples and elsewhere herein are: ACN (MeCN) acetonitrile aq. aqueous aw water activity DCM dichloromethane DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide dp dried powder DSC differential scanning calorimetry DVS dynamic vapor sorption eq equivalent g gram, gas h hour(s) HPLC high pressure (or performance) liquid chromatography ICP-OES inductively coupled plasma - optical emission spectrometry L liter 111. ASBLomond.24.0001.W LCMS liquid chromatography mass spectrometry MHz megahertz min minutes ml, mL milliliter NMR nuclear magnetic resonance PLM polarized light microscopy prf paraffin oil PXRD powder X-ray diffraction r.h. relative humidity rt room temperature S solubility s solid sat. saturated t temperature, triplet TG-FTIR thermogravimetry coupled with Fourier transform infrared spectroscopy THF tetrahydrofuran 2-MeTHF 2-methyl tetrahydrofuran Experiments description

[0656] Experiment 1. Salt I-B conversion to free base I-A (Form C), Sample I-A-a-1. Conversion 1.0 g (1.96 mmol) of the compound of Formula (I-B) to free base: Neutralized dihydrochloride in an aq. solution with NaOH and the compound of Formula (I-A) in the Form C was extracted with DCM. PXRD to Form C. H-NMR spectrum is consistent with structure of the compound of Formula (I-A).

[0657] Experiment 2. Salt I-B conversion to free base I-A (amorphous), Sample I-A-b. Conversion 1.0 g (1.96 mmol) of the compound of Formula (I-B) to free base: Neutralized dihydrochloride in an aq. solution with NaOH and filtered of the solid material, washed with water. PXRD to amorphous form. H-NMR spectrum is consistent with structure of the compound of Formula (I-A).

[0658] Experiment 3. Salt I-B conversion to free base I-A (Form A), Sample I-A-d-1. Conversion 1.0 g (1.96 mmol) of the compound of Formula (I-B) to free base: Neutralized dihydrochloride in an aq. solution with NaOH and filtered of the solid material, washed with water, but was added THF to promote crystallization.

[0659] Experiment 4. Stability study: Compound of Formula (I-A), Form A. 40.9 mg of the compound of Formula (I-A) was weighed and placed into a 4 ml Supelco vial for storage at 60°C for 2 weeks. The sample was submitted to HPLC (purity determination) and also to PXRD. HPLC showed 98.0% of purity. PXRD pattern unchanged and consistent with Form A. 112. ASBLomond.24.0001.W

[0660] Experiment 5. Stability study: Compound of Formula (I-A), Form A. 40.1 mg of the compound of Formula (I-A) was weighed and placed into a 4 mL Supelco vial for storage at 40°C and 75% of relative humidity for 2 weeks. The sample was submitted to HPLC (purity determination) and also to PXRD. HPLC showed 97.9% of purity. PXRD pattern unchanged and consistent with Form A.

[0661] Experiment 6. Salt I-B conversion to free base I-A (mesomorphic phase), Sample I-A-c. 20 g (0.0396 mol) of the compound of Formula (I-B) was dissolved in 2 L of water and neutralized with 1N NaOH solution. A thick suspension was obtained after the NaOH addition. 400 mL of THF was added and the suspension was stirred at rt. After overnight stirring, the suspension was filtered over a fritted glass filter (porosity 4). The solid was washed three times with 200 mL of water and solid dried under vacuum at rt. Yield ~ 16 g. Concentration of solid: 8 mg / ml. PXRD pattern corresponds to mesomorphic phase. Purity according to HPLC 99.30%.

[0662] Experiment 7. Preparation of Form E, Sample I-A-e-1. 2.0 ml of methanol was added to 124 mg of the compound of Formula (I-A)(mixture of Form A and mesomorphic) and the suspension was stirred at rt. After five days, the suspension was filtered by centrifugal filtration and the solid product submitted for PXRD. PXRD pattern corresponds to Form E. TG-FTIR shows 6.1% water.

[0663] Experiment 8. Preparation of Sample I-A-d-2. 2.0 ml of THF was added to 123 mg of the compound of Formula (I-A) (mixture of Form A and mesomorphic) and the suspension was stirred at r.t. After five days, the suspension was filtered by centrifugal filtration and the solid product submitted for PXRD. PXRD pattern corresponds to Form A.

[0664] Experiment 9. Preparation of Sample I-A-g-1. 3.0 ml of ethanol was added to 152 mg of the compound of Formula (I-A) (mixture of Form A and mesomorphic) and the suspension was stirred at 50°C. After four days, the suspension was filter by centrifugal filtration and the solid product submitted for PXRD. PXRD pattern corresponds to Form F.

[0665] Experiment 10. Free base sample preparation (I-A), mesomorphic phase. 20.194 g of I-B (0.0396 mol) was dissolved in 2 L of Millipore water under stirring at rt. After 20 minutes of stirring, a yellowish solution was obtained (pH 3-4 with pH paper). 39.6 mL (1 eq) of an aqueous 1 M NaOH solution was slowly added under stirring. A fine suspension was obtained after the addition. After 15 minutes of stirring, a solution was obtained (pH 4 with pH paper).39.6 mL (1 eq) of an aq.1 M NaOH solution was slowly added under stirring. A thick colorless solution 113. ASBLomond.24.0001.W was obtained after the addition. 400 mL of THF was added and the suspension was stirred at rt. After overnight stirring, the suspension was filtered over a fritted glass filter (porosity 4). The obtained mother liquor was a clear solution. The solid was washed three times with 200 mL of water. The filter cake was dried on the filter with applied vacuum for 30 minutes, and then further dried under vacuum at rt. After four days of drying, 16.133 g of colorless powder was obtained. The solid product was further characterized by PXRD and HPLC. PXRD pattern corresponds to mesomorphic form. HPLC showed 99.30% purity.

[0666] Experiments 11-19. Slurry / Evaporation Experiments at Room Temperature. PXRD Experiment Solvent Procedure Results ty e, e, ty. ASBLomond.24.0001.W white solution after ~4 h stirring, opened for evaporation, off-white solid after overnight us e,pe e s - . u y apoa o pe e s a . PXRD Experiment Solvent Procedure e,115. ASBLomond.24.0001.W stirring, centrifuged to recover solids, analyzed by PXRDre. Anti- PXRD Experiment Solvent Procedure solvent Results y, y,

[0669] Experiments 28-32. Drying and Post-Drying PXRD. 116. ASBLomond.24.0001.W Anti- Exp. Solvent Procedure PXRD (1) PXRD (2) solvent117. ASBLomond.24.0001.W Anti- Exp. Solvent Procedure PXRD (1) PXRD (2) solvent y, s r

[0670] Experiment 33. Boc deprotection in 2-MeTHF, preparation I-C, Form 5. tert-Butyl 7-(3-(3,4-dimethoxyphenyl)-1H-pyrazolo[4,3-c]quinolin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (40 mg, 0.075 mmol, compound 5) was added to a mixture of 2-MeTHF (Volume: 0.5 mL, Source: Thommen-Furler) and H3PO4(0.051 mL, 0.745 mmol) at rt, a precipitate was formed. The reaction was heated up to Ta=90°C. A precipitate was formed after overnight reaction and full conversion was reached. PXRD pattern essentially corresponds to Form 5.

[0671] Experiment 34. Preparation of compound of Formula (I-C), Form 1. 118. ASBLomond.24.0001.W 299.7 mg (0.69 mmol) of compound of Formula (I-A) was dissolved in 19 mL of DCM / MeOH 1:1 at rt under stirring. A solution of 94.7 µL of an 85%-wt. phosphoric acid solution in water (~ 2 eq) was then slowly added to the solution of (I-A) in two steps. The first equivalent was slowly added and after a short break, the second equivalent was also slowly added. A yellow precipitate was immediately formed. The obtained yellow suspension was then left under stirring at rt in a closed vial for the weekend. The suspension was then filtered over a fritted glass (porosity 4) under vacuum. The obtained wet yellow solid material was dried overnight at rt before being submitted to PXRD. 361.7 mg of I-C sample was recovered (yield ~ 79%). PXRD pattern corresponds to Form 1.

[0672] Experiment 35. Preparation of compound of Formula (I-C), Form 1. 1.0198 g of compound of Formula (I-A, Mixture of amorphous, Form A, and unknown mesoform type) (2.34 mmol) was dissolved in 65 mL of DCM / MeOH 1:1 at rt under stirring in a 100 mL vessel within the EasyMax. The free drug completely dissolved quite quickly, in a few minutes. Then, 322 µL of a solution of 85%-wt. phosphoric acid in water (~ 2 eq) was slowly added to the solution of I-A solution in two steps. A yellow precipitate was immediately formed and seeding was conducted with some amount of compound of Formula I-C (Form 1). The obtained yellow suspension was then stirred at rt in a closed container in the EasyMax. After overnight stirring, PLM investigation revealed small crystalline particles. After approximately 4 h of stirring, an in- process sample was recovered for PXRD. After additional 24 hours of stirring, the suspension was filtered over a fritted glass (porosity 4) and two filter papers with vacuum. The recovered wet yellow solid material was dried over a weekend at rt 1.3883 g of powder was recovered (yield ~ 89%). PXRD corresponds to Form 1.

[0673] Experiment 36. Preparation of compound of Formula (I-C), Form 3. 81.9 mg of compound of Formula (I-C, Form 1) was suspended in 2 mL of THF / H2O 4:1 at rt. A thick yellow suspension was obtained, and additional 1 mL of the THF / H2O mixture was added. After overnight stirring, a thick suspension was still observed and 3 mL of the THF / H2O mixture was added again. After four days of stirring, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 3.

[0674] Experiment 37. Preparation of compound of Formula (I-C), Form 4. 87.1 mg of compound of Formula (I-C, Form 1) was suspended in 2 mL of 2-propanol. To the yellow suspension 3 mL of 2-propanol was added and the mixture was stirred at 60°C for one day. The suspension was filtered using a centrifugal unit filter and the recovered yellow solid material 119. ASBLomond.24.0001.W was then submitted to PXRD. PXRD corresponds to Form 4, poorly crystalline, additional reflections at 7.9°, 9.8°,11.5° 2θ.

[0675] Experiment 38. Preparation of compound of Formula (I-C), Form 3 & Form 6. ~ 95 mg of Form 5, ~ 10 mg of Form 1, some Form 6, ~ 10 mg of Form 3 of the compound of Formula (I-C) were mixed with 4 mL of DMF / H2O 3:1 (aw~ 0.5). The obtained yellow suspension was then stirred at rt in a closed vial. After overnight stirring, ~ 10 mg of Form 4 was added to the mixture. After two additional days of stirring, the suspension was filtered using a centrifugal unit filter (PTFE, 0.22 µm, 5000 rpm, 25°C, 5 min) and the recovered yellow solid material was submitted to PXRD. PXRD corresponds mainly to Forms 3 and 6.

[0676] Experiment 39. Preparation of compound of Formula (I-C), Form 4. 99.5 mg of compound of Formula (I-C, Form 5), 10.4 mg of compound of Formula (I-C, Form 1), some of compound of Formula (I-C, Form 6), 9.8 mg of compound of Formula (I-C, Form 3) and 10.4 mg of compound of Formula (I-C, Form 4) were mixed with 2 mL of an acetone / H2O 24:1 mixture (aw ~ 0.5). The obtained yellow suspension was then stirred at rt in a closed vial. After one day of stirring, a thick suspension was obtained. Therefore, 1 mL of the acetone / H2O 24:1 mixture was added. After six additional days of stirring, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 4.

[0677] Experiment 40. Drying of compound of Formula (I-C), Form 5. 20.3 mg of compound of Formula (I-C, Form 5) was dried at 40°C under vacuum (< 10 mbar). After two days of drying, the sample was submitted to PXRD. PXRD corresponds to Form 5. No form conversion.

[0678] Experiment 41. Slurry in THF / H2O 4:1 of Form 1. 81.9 mg of compound of Formula (I-C) (Form 1) was suspended in 2 mL of THF / H2O 4:1 at rt. A thick yellow suspension was obtained, and additional 1 mL of the THF / H2O mixture was added. After overnight stirring, a thick suspension was still observed and 3 mL of the THF / H2O mixture was added again. After 4 days of stirring, the suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 3. TG-FTIR: ~ 10% of water loss in 2 steps from rt to 300°C, decomposition above 300°C. P-OES: 7.76% of phosphorus content determined.

[0679] Experiment 42. Slurry in MeOH / H2O 7:3 of Form 1. 82.5 mg of compound of Formula (I-C) (Form 1) was suspended in 2 mL of MeOH / H2O 7:3 at rt. A thick yellow suspension was obtained and 1 mL of the MeOH / H2O 7:3 mixture was added. After 120. ASBLomond.24.0001.W 5 days of stirring, the suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 1.

[0680] Experiment 43. Slurry in MeOH / H2O 9:1 of Form 1. 81.1 mg of compound of Formula (I-C) (Form 1) was suspended in 2 mL of MeOH / H2O 9:1 at rt. A thick yellow suspension was obtained and 1 mL of the MeOH / H2O 9:1 mixture was added. After 5 days of stirring, the suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 1 (with one reflection shifted at 18.3°2θ).

[0681] Experiment 44. Slurry in 2-PrOH of Form 1. 87.1 mg of compound of Formula (I-C) (Form 1) was suspended in 2 mL of 2-propanol. To the yellow suspension 3 mL of 2-propanol was added and the mixture was stirred at 60°C for one day. The suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 4. TG-FTIR: ~ 8.3% of water loss in 2 steps (from rt to 300°C). Decomposition starts at approximately 300°C.

[0682] Experiment 45. Slurry in water at high temperature of Form 1. 82.5 mg of compound of Formula (I-C) (Form 1) was suspended in 2 mL of water and heated up to 60°C under stirring in a closed vial. A thick suspension was obtained after a few minutes and 2 mL of water was added to the mixture. After approximately 2 h, the temperature was then increased to 100°C. The sample was not dissolved, and additional 2 mL of water was added. The temperature was decreased to 80°C and a suspension was still observed after 2 h of stirring. The suspension was then cooled to rt. After 4 days of stirring, the suspension was filtered using a centrifugal unit filter. The recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 3 with an additional reflection at 7.9°2θ.

[0683] Experiment 46. Competitive slurry of I-C in DMF / H2O 3:1. ~ 95 mg of Form 5, ~ 10 mg of Form 1, some Form 6, ~ 10 mg of Form 3 were mixed with 4 mL of DMF / H2O 3:1 (aw ~ 0.5). The obtained yellow suspension was then stirred at rt in a closed vial. After overnight stirring, ~ 10 mg of Form 4 was added to the mixture. After two additional days of stirring, the suspension was then filtered using a centrifugal unit filter (PTFE, 0.22 µm, 5000 rpm, 25°C, 5 min) and the recovered yellow solid material was submitted to PXRD. PXRD corresponds mainly to Forms 3 and 6.

[0684] Experiment 47. Competitive slurry in acetone / H2O 24:1. 99.5 mg of Form 5, 10.4 mg of Form 1, some Form 6, 9.8 mg of Form 3 and 10.4 mg of Form 4 were mixed with 2 mL of an acetone / H2O 24:1 mixture (aw ~ 0.5). The obtained yellow 121. ASBLomond.24.0001.W suspension was then stirred at r.t. in a closed vial. After one day of stirring, a thick suspension was obtained. Therefore, 1 mL of the acetone / H2O 24:1 mixture was added. After six additional days of stirring, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 4.

[0685] Experiment 48. Vacuum drying of Form 5. 20.3 mg of Form 5 was dried at 40°C under vacuum (< 10 mbar). After two days of drying, the sample was submitted to PXRD. PXRD corresponds to Form 5. No form conversion.

[0686] Experiment 49. Vacuum drying of Form 4. 16.5 mg of Form 4 was dried at 40°C under vacuum (< 10 mbar). After two days of drying, the sample was submitted to PXRD. PXRD corresponds to Form 1. Form conversion.

[0687] Experiment 50. Vacuum drying of Form 3. 15.2 mg of Form 3 was dried at 40°C under vacuum (< 10 mbar). After two days of drying, the sample was submitted to PXRD. PXRD corresponds to Form 3. No form conversion.

[0688] Experiment 51. Competitive slurry in 2-MeTHF / H2O 99:1. 40.2 mg of Form 5, 39.3 mg of Form 1, some Form 6, some Form 3 and some Form 4 were mixed with 2 mL of 2-MeTHF / H2O 99:1 (awroughly about 0.7 as 4% would be miscible). The obtained yellow suspension was then stirred at rt in a closed vial. After 5 days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 4. TG-FTIR: Two steps of water loss from rt to 150°C (~ 1.4%) and from 150 to 320°C (~ 6.1%). Decomposition starts at approximately 320°C. P-OES: P content is 12%, which corresponds to three H3PO4.

[0689] Experiment 52. Boc deprotection with H3PO4. 134 mg of Boc compound 5 was mixed with 500 µL of a solution of 85%-wt. phosphoric acid in water, 5 mL of methanol and 200 µL of water. A yellow suspension was obtained and further stirred at 75°C in a closed vial for approximately 30 min and seeded with some Form 1. Then, the suspension was cooled to rt. After five days of stirring, the suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD shows poorly crystalline material, no match with any known form, possibly incomplete conversion.

[0690] Experiment 53. Competitive slurry in EtOH / H2O 24:1. 100 mg of Form 1 and Form 3 were suspended in 5 mL of EtOH / H2O 24:1 (aw~ 0.3). The obtained yellow suspension was then stirred at rt in a closed vial. After 5 days, the suspension was 122. ASBLomond.24.0001.W filtered by centrifugal filtration and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 1.

[0691] Experiment 54. Boc deprotection with H3PO4. 103 mg of Boc compound 5 was mixed with 500 µL of a solution of 85%-wt. phosphoric acid in water, 8 mL of 2-propanol and 400 µL of water. A yellow suspension was obtained and further stirred at 75°C in a closed vial for approximately 1 h and seeded with Form 1. Then, the suspension was cooled to rt and 500 µL of water was added again. After five days of stirring, the suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD: Predominantly amorphous, one reflection at 25.8°2θ. Conversion possibly incomplete.

[0692] Experiment 55. Competitive slurry in 2-PrOH / H2O 5:1. 311 mg of mixture Forms 1 and 4 was suspended in 6 mL of a 2-PrOH / H2O 5:1 mixture (aw ~ 0.85). The obtained yellow suspension was then stirred at rt. After 5 days, the suspension was filtered using a centrifugal filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 1.

[0693] Experiment 56. Vacuum drying. 30.4 mg of Form 4 was dried at 40°C under vacuum (< 10 mbar). After one day of drying, the sample was submitted to PXRD. PXRD corresponds to Form 4. No form conversion.

[0694] Experiment 57. Vacuum drying. The remaining amount of sample from experiment 56 was further dried at 75°C under vacuum (< 10 mbar). After one day of drying, the sample was submitted to PXRD. PXRD corresponds to Form 4. No form conversion. Solubility in water ~ 17-19 mg / mL at rt, pH (5 mg / mL) = 2.58 at rt.

[0695] Experiment 58. Competitive slurry in EtOH / H2O 24:1. 78.3 mg of Form 5 and 9.9 mg of Form 1 were suspended in 2 mL of EtOH / H2O 24:1 (aw~ 0.3). The obtained yellow suspension was further stirred at rt in a closed vial. After 4 days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 4.

[0696] Experiment 59. Slurry in Acetone / H2O 24:1. 80.8 mg of Form 1 was suspended in 2 mL of acetone / H2O 24:1 (aw~ 0.5). The obtained yellow suspension was further stirred at rt in a closed vial. After 4 days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 1.

[0697] Experiment 60. Slurry in Acetone / H2O 24:1. 123. ASBLomond.24.0001.W The remaining amounts of samples from experiments 52 and 54 were mixed with 2 mL of 85%- wt. phosphoric acid solution in water. A viscous yellow suspension was obtained which was further stirred at rt. After approximately 2 h of stirring, the material was almost completely dissolved. Some particles were stuck on the vial wall.5 mL of 2-MeTHF was added to the solution and precipitation occurred immediately. A yellow suspension was obtained and further stirred at rt in a closed vial. After three days of stirring, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 5.

[0698] Experiment 61. Competitive slurry in EtOH / H2O 3:1. 46.6 mg of Form 1 and 45.3 mg of Form 4 were suspended in 2 mL of EtOH / H2O 3:1 (aw~ 0.75). The obtained yellow suspension was further stirred at rt. After one days of stirring, a thick suspension was obtained. Therefore, 1 mL of EtOH / H2O 3:1 was added to the suspension. After one additional day, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 1.

[0699] Experiment 62. Competitive slurry in EtOH / H2O 24:1. 221.6 mg of mixture of Forms 1 and 4 was suspended in 5 mL of EtOH / H2O 24:1 (aw ~ 0.3). The obtained yellow suspension was further stirred at rt in a closed vial. After one day, an in-process sample was recovered for PXRD. After five additional days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to a mixture of Forms 1 and 4.

[0700] Experiment 63. Competitive slurry in acetone / H2O 9:1. Form 5 and about 80 mg of mixture of Forms 1 and 4 were slurried in acetone / H2O 9:1 (aw~ 0.75) at rt in a closed vial. After one day, an in-process sample was recovered for PXRD. The remaining part of the suspension was stirred at rt for 2 days before the solid was separated by centrifugal filtration and submitted for PXRD. PXRD corresponds to Form 4. P-OES: P content is 12.9%, which corresponds to three H3PO4.

[0701] Experiment 64. Production of Form 7. 505.9 mg of compound of Formula (I-A) (1.16 mmol) was dissolved in 10 mL of EtOH / DCM 1:1 at 50°C under stirring. Then, the solution was seeded with some Form 4 and 240 µL of 85%-wt. phosphoric acid in water diluted in 1 mL of ethanol (3 eq). Precipitation occurred immediately and a thick yellow suspension was obtained. Therefore, 2 mL of EtOH / DCM 1:1 was added to the suspension which was further stirred at rt in a closed vial. After one day, a thick suspension was still observed and an in-process sample was recovered for PXRD (1). The suspension was seeded again with some Form 4 sample. Then, 1 mL of ethanol and 2 mL of water were added to the 124. ASBLomond.24.0001.W suspension which was further stirred at 40°C with the vial open to allow solvent evaporation. Solvent quickly evaporated and a wet yellow solid material was obtained. After one night, 3 mL of ethanol and 6 mL of water were added and the obtained suspension stirred again at rt in a closed vial. An in-process sample was then recovered for PXRD (2). After 3 additional days, the suspension was filtered over a fritted glass and the recovered yellow solid material was further dried at rt After one day of drying, the yellow solid material was submitted to PXRD (3). PXRD (1) does not correspond to any of the known forms. PXRD (2) is new, designated as Form 7. PXRD (3) corresponds to Form 7. TG-FTIR: ~ 7% of water loss from rt to approximately 150°C before the decomposition starts. KF: 9.5% H2O.

[0702] Experiment 65. Slurry in EtOH / H2O 3:1. To 120 mg of Form 4 was added 4 mL of mixture EtOH / H2O 3:1 (aw ~ 0.75). The resultant yellow suspension was stirred at rt for three days and an in-process control sample was taken for PXRD (1). The remainder of the suspension was stirred at rt until the next day. Then the solid was filtered off and vacuum dried at rt for about 1 h and submitted to PXRD (2). PXRD (1) corresponds to Form 1. PXRD (2) corresponds to Form 1.

[0703] Experiment 66. Production of Form 6. To 444 mg of compound (I-A) were added 5 mL of ethanol, 2.5 mL of a 1 M phosphoric acid solution (~ 2.5 eq) and 2.5 mL of ethanol. The resultant suspension was very inhomogeneous with yellow and white material. Then the suspension was stirred overnight at 75°C and on the next day, the suspension was homogeneous and yellow. Stirring was continued at 40°C for 2 days and an in-process sample was recovered for PXRD (1). The remainder of the suspension was stirred at rt for one more day and then filtered over a fritted glass filter and vacuum dried at rt for about 1 h. Yield ~ 548 mg (~ 82%). The sample was then submitted to PXRD (2). PXRD (1) corresponds to Form 6. PXRD (2) corresponds to Form 6. TG-FTIR: Water loss of about 6.9% in two steps. P- OES: P content is 9.6%, which corresponds to two H3PO4. HPLC: purity is 99.5%. Approximately aqueous solubility S ~ 5 mg / mL at rt.

[0704] Experiment 67. Production of Form 7. To 465 mg of compound (I-A) were added 10 mL of DCM / MeOH 1:1 and the mixture was heated to 40°C to dissolve the free base. Then 2.25 mL of a 1 M phosphoric acid solution (~ 2.25 eq) was added to the solution and a very bulky precipitate formed immediately. The suspension was stirred at 40°C for two days and an in-process sample was recovered for PXRD (1). The remainder of the suspension was stirred at rt for one more day and then filtered over a fritted glass filter and vacuum dried at rt for about 1 h. Yield ~ 778 mg (> 100%, probably not dry yet). The sample was then submitted to PXRD (2). PXRD (1) and PXRD (2) corresponds to Form 7. TG-FTIR: 32% mass 125. ASBLomond.24.0001.W loss (methanol and water), sample not sufficiently dried. P-OES: P content is 9.2%, which corresponds to two H3PO4.

[0705] Experiment 68. Production of Form 1. 5.1003 g of compound of Formula (I-A) (11.7 mmol) was dissolved in 325 mL of DCM / MeOH 1:1 at rt under stirring in a 1 L vessel. The free base dissolved within a few minutes. Then, 1.61 mL of 85% phosphoric acid was added to the solution in two steps. A yellow precipitate was formed and seeding was conducted with some Form 1. The obtained yellow suspension was then stirred at rt in the closed vessel. The suspension was then filtered over a fritted glass with two filter papers and the recovered yellow solid material was further dried at rt under vacuum (< 10 mbar) for one night.7.2983 g of the yellow solid material of Form 1 was recovered. PXRD corresponds to Form 1. TG-FTIR: ~ 4.4% of water and methanol loss (rt to 180°C) and ~ 4.6% of water loss (180 to 320°C).

[0706] Experiment 69. Drying of Form 1 (Experiment 68). Some methanol was still found within the sample of Form 1 which was then further dried at 40°C under vacuum (< 10 mbar) for approximately 8 h and then at rt under vacuum over a weekend to remove the methanol. The sample was then recovered and examined by HPLC and P-OES. P- OES: P content is 9.92%, which corresponds to two H3PO4. HPLC: Purity 99.3%. KF: 1.9% H2O.

[0707] Experiment 70. Slurry in 2-PrOH / H2O 4:1. 126.3 mg of Form 6 was suspended in 3 mL of 2-PrOH / H2O 4:1. The obtained yellow suspension was then stirred at rt. After 2 days of stirring, the suspension was filtered suing a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 6.

[0708] Experiment 71. Slurry in 2-PrOH / H2O 4:1. 126.3 mg of Form 7 was suspended in 3 mL of 2-PrOH / H2O 4:1. The obtained yellow suspension was then stirred at rt in a closed vial. After one day of stirring, a thick suspension was obtained. Therefore, 1 mL of 2-PrOH / H2O 4:1 was added to the suspension. After one additional day of stirring, the suspension was filtered by centrifugal filtration and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to a mixture of Forms 6 and 7.

[0709] Experiment 72. Competitive slurry in EtOH / H2O 3:1. 42.5 mg of Form 1, 40.3 mg of Form 7 and 42.0 mg of Form 6 were suspended in 3 mL of EtOH / H2O 3:1 (aw ~ 0.75). The obtained yellow suspension was then stirred at rt in a closed vial over the weekend. The suspension was further stirred at rt and after one day, the suspension was 126. ASBLomond.24.0001.W filtered using a centrifugal unit filter and the recovered yellow solid material was further dried at rt for one additional day. PXRD corresponds to Form 6.

[0710] Experiment 73. Competitive slurry in Acetone / H2O 4:1. To 200 mg of Form 1 was added 5 mL of acetone / H2O 4:1. Then, some amount of compounds in Forms 6 and 7 was added to the suspension which was then stirred at 40°C in a closed vial. After 3 days, a thick suspension was obtained. The suspension was further stirred for a few hours and then filtered using a centrifugal unit filter. The recovered yellow solid material was further dried at rt under vacuum (< 10 mbar) for two days. The dried yellow solid material was then recovered and submitted to PXRD. PXRD corresponds to Form 6.

[0711] Experiment 74. Competitive slurry in EtOH / H2O 24:1. 50.4 mg of Form 1 and 50.4 mg of Form 6 were suspended in 2 mL of EtOH / H2O 24:1 (aw ~ 0.3). The obtained yellow suspension was then stirred at rt in a closed vial. After 3 days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 6.

[0712] Experiment 75. Competitive slurry in EtOH / H2O 24:1. 51.5 mg of Form 1 and 50.2 mg of Form 6 were suspended in 2 mL of EtOH / H2O 9:1 (aw ~ 0.5). The obtained yellow suspension was then stirred at rt in a closed vial. After 3 days, the suspension was filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds to Form 6.

[0713] Experiment 76. Produce Form 6. 250.5 mg of compound of Formula (I-A) (0.57 mmol) was dissolved in 12 mL of EtOH / DCM 1:1 at rt under stirring. The solution was then seeded with some sample of Form 6. Then, 87 µL of 85%-wt. phosphoric acid solution in water was diluted in 2 mL of water (~ 2.2 eq) and slowly added to the solution of compound of Formula (I-A). Precipitation occurred immediately and a slightly yellow suspension was obtained which was further stirred at rt in a closed vial. After overnight stirring, an in-process sample was recovered for PXRD (1). After a few hours of stirring, the vial was opened and the temperature was increased up to 40°C to evaporate the dichloromethane. After approximately 2 h, a thick suspension was obtained and 8 mL of EtOH / H2O 3:1 was added (~ 15 mg / mL). A homogeneous suspension was obtained and further stirred at 75°C in a closed vial. After approximately 2 h at 75°C, a sample was examined by PLM and a small amount was placed onto a steel sample holder for Raman IPC. After overnight stirring at 75°C, a quite thick suspension was obtained and an in-process sample was recovered for PXRD (2). The remaining suspension was then filtered over a fritted glass and the recovered yellow solid material was further dried at rt. After drying over the weekend, the sample was further dried at rt 127. ASBLomond.24.0001.W under vacuum (< 10 mbar) for approximately 2 h before being recovered. PXRD (1) corresponds to Form 6. Raman IPC after 2 h at 75°C corresponds to Form 6. Microscopy shows long needle- shaped particles. PXRD (2) corresponds to Form 6.

[0714] Experiment 77. Stability study on Form 6. 46.8 mg of Form 6 was kept at 40°C with 75% r.h. for 2 weeks. PXRD corresponds to Form 6. HPLC: Purity 99.4%.

[0715] Experiment 78. Stability study on Form 6. 47.5 mg of Form 6 was kept at 60°C for 2 weeks. PXRD corresponds to Form 6. HPLC: Purity 99.4%.

[0716] Experiment 79.5g-Scale experiment to produce Form 6. 5.0656 g of compound of Formula (I-A) (~ 11.6 mmol) was suspended in approximately 173 mL of ethanol and the obtained white suspension was heated up to 75°C in a 500 mL vessel. A homogeneous white suspension was observed at 75°C. Then, 25.4 mL of a 1 M phosphoric acid solution in water (~ 2.2 eq) was slowly added to the suspension. A homogeneous yellow suspension was obtained after the addition.32.4 mL of water was also added to the suspension to obtain a EtOH / H2O v / v ratio of 3:1. The suspension was then seeded with some Form 6 sample. The suspension was then further stirred at 75°C in a closed vessel for approximately 4 h and finally cooled to rt. After stirring at rt over the weekend, an in-process sample was recovered for PXRD. The suspension was then filtered over a fritted glass with vacuum and the recovered yellow solid powder was dried at rt under vacuum (< 10 mbar). After overnight drying, 7.1578 g of the sample of Form 6 was recovered. PXRD and Raman IPC samples correspond to Form 6. TG-FTIR: ~ 2.9% of water loss from rt to 170°C and ~ 3.6% loss of water and some ethanol from 170 to 300°C. P-OES: P content is 10.1%. HPLC: Purity of 99.5 area-%. NMR: complies with structure. KF: 10.2% H2O.

[0717] Experiment 80. Slurry in water of Form 6. 100.2 mg of Form 6 was suspended in 2 mL of water. The obtained yellow suspension was then stirred at rt in a closed vial at 25°C for 24 h. The suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was submitted to PXRD. PXRD corresponds essentially to Form 3 with some Form 6.

[0718] Experiment 81. Boc compound (5) deprotection with 10 eq of H3PO4. 398.2 mg of compound 5 (~0.74 mmol) was suspended in 15 mL of 2-MeTHF and a brown homogeneous suspension was obtained. The suspension was then heated up to 75°C and a clear and slightly brown solution was obtained. The solution was then seeded with some Form 6 sample 128. ASBLomond.24.0001.W and 0.5 mL of 85%-wt. phosphoric acid in water (~10 eq) was slowly added and a thick and brown / yellow suspension was immediately obtained. Stirring at 75°C in a closed vial was then continued. After overnight stirring, a yellow homogeneous suspension was obtained. An in- process sample was then recovered for Raman analysis. The remaining suspension was then filtered over a fritted glass and the recovered yellow solid material was dried at rt under vacuum (< 10 mbar) for approximately 2 h. The sample was then submitted to PXRD. Raman spectrum corresponds to Form 5. PXRD corresponds to Form 5.

[0719] Experiment 82. Attempted conversion of Form 5 to Form 6 in EtOH / H2O 3:1. Approximately 30 mg of the sample from Experiment 81 was suspended in 1 mL of water and the obtained suspension was heated up to 70°C. Then, 3 mL of ethanol was added and a clear solution was obtained. The solution was then seeded with some Form 6 sample, cooled and further stirred at rt in a closed vial. After stirring over a weekend, a yellow suspension was obtained which was then filtered using a centrifugal unit filter. The recovered yellow solid material was then submitted to PXRD. PXRD corresponds to Form 6.

[0720] Experiment 83. Boc compound deprotection with 10 eq of H3PO4. 400.2 mg of compound 5 (~ 0.74 mmol) was suspended in 8 mL of 2-MeTHF / H2O 99:1 and the obtained suspension was heated up to 75°C. After a few minutes of stirring, a quite turbid and brown solution was obtained. The solution was then seeded with some Form 6 sample and 0.5 mL of 85%-wt. phosphoric acid in water (~ 10 eq) was slowly added and a very thick and yellow suspension was immediately obtained. The suspension was seeded again with some Form 6 and further stirred at 75°C in a closed vial. After overnight stirring, a yellow and homogeneous suspension was obtained and PLM revealed small crystalline particles. An in-process sample was then recovered for PXRD (1). After Form 5 was identified with the in-process sample, the whole amount was filtered over a fritted glass filter, dried at 50°C for one hour and filled into a vial; yield 474 mg. PXRD was then recorded (2). Microscopy shows nearly spherical particles 5-10 µm. PXRD (1) corresponds to Form 5. PXRD (2) corresponds to Form 5.

[0721] Experiment 84. Slurry in 2-PrOH / H2O 4:1. 0.8 mL of water was added to 200 mg of Form 5 and the mixture was heated to 75°C for a few minutes, then 3.2 mL of isopropanol was added. The suspension was seeded with a few mg of Form 6 and stirred at 50°C for about 20 h. PLM showed nearly spherical crystalline particles. The temperature was raised to 80°C and stirring was continued for 4 h and about 2 mL of the suspension was filtered off and the obtained solid was submitted for PXRD (1). The remaining fraction was allowed to cool to rt, 1 mL of water was added, and the suspension was further stirred at rt over a 129. ASBLomond.24.0001.W weekend before the solid was filtered off by centrifugal filtration and submitted for PXRD (2). PXRD (1) corresponds to Form 7. PXRD (2) corresponds to Form 6.

[0722] Experiment 85. Boc compound deprotection with 3 eq of H3PO4. 399.6 mg of compound 5 (~0.74 mmol) was suspended in 8 mL of 2-MeTHF and the obtained suspension was heated up to 75°C. After a few minutes of stirring, a quite turbid and brown solution was obtained. The solution was then seeded with some Form 6 sample and 0.15 mL of 85%-wt. phosphoric acid in water (~3 eq) was slowly added and a very thick and yellow suspension was immediately obtained. The suspension was seeded again with some Form 6 and further stirred at 75°C in a closed vial. After overnight stirring, the suspension was still very thick. Therefore, 2 mL of 2-MeTHF was added to the suspension which was then further stirred at 75°C before being cooled to rt and further stirred over the weekend. The suspension was then filtered over a fritted glass with vacuum and the recovered yellow solid material was further dried at rt under vacuum (< 10 mbar) for approximately 1 h before being submitted to PXRD. PXRD mainly amorphous.

[0723] Experiment 86. Attempted conversion of Form 7 to Form 6. 111 mg of Form 7 was suspended in 2 mL of EtOH / H2O 3:1. The obtained yellow suspension was seeded with some Form 6 sample and then further stirred at 60°C in a closed vial. After overnight stirring at 60°C, an in-process sample was recovered for Raman analysis. The suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. Raman spectrum corresponds to Form 6. Needle-shaped crystalline particles. PXRD corresponds to Form 6.

[0724] Experiment 87. Attempted conversion of Form 7 to Form 6. 159 mg of Form 7 was suspended in 3 mL of 2-PrOH / H2O 3:1. The obtained yellow suspension was seeded with some Form 6 sample and then further stirred at 60°C in a closed vial. After overnight stirring at 60°C, an in-process sample was recovered for Raman analysis. The suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material was then submitted to PXRD. Raman spectrum corresponds to Form 6. PXRD corresponds to Form 6.

[0725] Experiment 88. Attempted conversion of Form 7 to Form 6. 122 mg of Form 7 was suspended in 2 mL of 2-PrOH / H2O 4:1. The obtained yellow suspension was seeded with some Form 6 sample and then further stirred at 60°C in a closed vial. After overnight stirring at 60°C, an in-process sample was recovered for Raman analysis. The suspension was then filtered using a centrifugal unit filter and the recovered yellow solid material 130. ASBLomond.24.0001.W was then submitted to PXRD. Raman spectrum corresponds to Form 6. PXRD corresponds to Form 6.

[0726] Experiment 89. Attempted conversion of Form 5 to Form 6. 101.5 mg of Form 5 was suspended in 2 mL of 2-PrOH / H2O 2:1. The obtained yellow suspension was seeded with some Form 3 and Form 6 samples and then further stirred at rt in a closed vial. After overnight stirring, the suspension was then further stirred at 60°C. PXRD corresponds to Form 7.

[0727] Experiment 90. Formulation of crystalline Formula (I) compound. After crystallization, polymorph forms of Formula (I) compound, may be formulated by dry granulation using a roller compactor, followed by a tableting operation. Additional ingredients in the tablets may include microcrystalline cellulose (Avicel® PH, FMC BioPolymer), lactose (FastFlo®, Foremost Farms USA), sodium starch glycolate (EXPLOTAB®, JRS Pharma), or magnesium stearate (Hyqual®, Macron Fine Chemicals). Equivalents

[0728] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 131. ASB

Claims

Lomond.24.0001.W CLAIMS What is claimed is:

1. A crystalline compound of Formula (I): , in the form of free hydrate, polymorph orcocrystal thereof.

2. The crystalline compound of claim 1, wherein the compound is a free base of Formula (I- A): , or a solvate, hydrate,3. The crystalline compound of claim 2, selected from: a Form A polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.5, 6.9, 7.1, 10.2, 10.6, 10.9, 12.9, 13.8, 14.2, 14.9, 16.4, 17.6, 18.1, 18.6, 19.3, 19.4, 20.1, 20.5, 21.3, 22.0, 22.6, 23.1, 23.3, 23.8, 24.2, 24.9, 25.5, 25.7, 26.6, 27.3, 27.7, 28.6, 29.7, 30.1, 30.4, 30.8, 31.8, 32.3, 32.6, 33.3, 34.2, 35.7, 36.4, 36.6, 37.1, 37.9, 39.0 and 39.7; a Form B polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.3, 7.5, 8.8, 11.4, 13.4, 14.8, 15.1, 16.6, 16.6, 17.5, 17.6, 17.9, 18.0, 18.9, 19.4, 19.9, 21.1, 21.4, 22.5, 23.5, 24.0, 24.7, 24.9, 26.3, 26.8, 27.5, 28.3, 28.7, 30.2, 31.9, 32.3, 32.9, 34.3, 35.6, 36.5 and 38.3; a Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 7.6, 9.8, 10.4, 13.8, 15.1, 17.6, 18.5, 19.3, 132. ASBLomond.24.0001.W 20.2, 20.9, 21.8, 22.2, 22.8, 23.8, 24.5, 25.1, 25.6, 26.1, 26.7, 27.9, 29.4, 29.8, 30.6, 31.5, 32.3, 32.8, 33.8, 37.3, and 38.1; a Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.1, 6.6, 8.5, 9.4, 10.6, 12.2, 12.5, 13.5, 13.9, 14.2, 14.7, 15.3, 16.0, 16.4, 18.0, 19.4, 20.7, 21.0, 21.8, 22.2, 22.9, 24.0, 24.4, 25.2, 25.6, 26.2, 26.8, 28.1, 28.6, 30.7, 31.9, and 32.2; a Form E polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.4, 7.6, 8.9, 9.7, 10.2, 13.7, 15.2, 17.7, 18.1, 18.8, 19.3, 20.1, 20.9, 22.1, 22.4, 23.0, 23.4, 23.9, 24.4, 25.6, 26.0, 27.5, 28.5, 30.6, 32.1, 35.7 and 38.0; a Form F polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.2, 8.1, 9.7, 10.6, 11.7, 12.6, 15.0, 16.3, 17.5, 18.5, 19.7, 20.9, 21.3, 22.0, 22.8, 23.7, 24.2, 24.7, 25.4, 25.7, 26.4, 28.3, 28.6, 31.2, 32.4, and 35.

4.

4. The crystalline compound of claim 1, wherein the compound is a hydrochloride salt of Formula (I-B): , solvate, hydrate,selected from 1 to 4.

5. The crystalline compound of claim 4, in the form of dihydrochloride polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2- theta at approximately: 3.18, 6.38, 7.23, 9.26, 9.67, 11.19, 11.68, 12.88, 13.83, 14.52, 15.13, 16.20, 16.87, 17.11, 17.81, 18.72, 19.41, 20.29, 20.85, 21.80, 23.16, 23.49, 23.94, 24.31, 25.34, 26.50, 26.96, 27.37, 28.50, 29.76, 30.60, and 31.

73.

6. The crystalline compound of claim 1, wherein the compound is a phosphate salt of Formula (I-C):

133. ASBLomond.24.0001.W , solvate, hydrate, selected from 1 to 4.

7. The crystalline compound of claim 6, wherein the compound is a phosphate salt of Formula (I-C-1-a): a).

8. The crystalline compound of claim 6, selected from: a Form 1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.95, 9.26, 10.59, 11.94, 12.55, 14.84, 17.36, 17.95, 18.09, 18.61, 19.08, 20.02, 20.53, 21.56, 22.58, 23.05, 23.57, 23.96, 24.72, 25.27, 25.62, 26.39, 27.76, 28.90, 30.20, 31.45, 31.92, 33.64, 36.38, and 41.77; a Form 3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.61, 5.95, 8.92, 9.21, 9.99, 10.71, 11.13, 12.13, 12.66, 13.69, 15.09, 15.57, 16.77, 17.42, 17.94, 18.77, 19.22, 19.73, 20.42, 21.09, 21.41, 22.23, 22.82, 23.38, 23.69, 23.98, 24.94, 25.82, 26.40, 27.23, 27.90, 29.31, 30.16, 31.46, 32.26, 34.41, 35.94, 36.34, 36.98, 37.79, 38.06, and 40.11; a Form 4 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.93, 8.17, 8.71, 9.22, 11.88, 12.14, 12.51, 14.45, 14.89, 16.99, 17.49, 17.86, 18.43, 18.67, 19.36, 19.68, 20.32, 20.49, 21.17, 22.01, 22.21, 22.48, 23.08, 23.75, 24.79, 25.13, 25.76, 26.19, 26.53, 27.57, 29.15, 29.98, 30.34, 31.12, 33.53, 34.37, 36.19, 38.48, 39.28, 40.28, 42.47, and 48.77; a Form 5 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.22, 8.04, 9.19, 9.74, 10.57, 12.17, 14.43, 134. ASBLomond.24.0001.W 13.36, 13.97, 15.39, 15.79, 16.95, 18.28, 18.79, 19.12, 19.50, 20.02, 20.78, 21.29, 21.84, 24.02, 24.45, 24.64, 25.10, 25.67, 26.43, 26.98, 27.79, 30.85, 31.38, 32.62, and 33.18; a Form 6 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.37, 6.26, 7.62, 8.74, 9.28, 10.76, 12.54, 13.28, 15.31, 16.27, 17.54, 17.99, 18.51, 18.78, 19.02, 19.37, 19.82, 20.27, 20.55, 21.03, 21.28, 21.63, 22.63, 23.05, 23.91, 24.49, 25.42, 25.73, 26.21, 26.73, 27.13, 27.82, 28.44, 28.70, 29.09, 29.44, 29.84, 30.01, 31.12, 31.84, 32.54, 34.04, 34.43, 34.80, 35.65, 36.12, 36.57, 36.97, 37.49, 37.81, 38.54, 39.24, 39.95, 40.25, 40.70, 41.42, 42.75, 43.30, 44.89, 45.57, 46.47, 47.44, 47.88 and 49.46; a Form 7 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.48, 7.08, 12.90, 15.10, 16.54, 18.44, 19.46, 20.03, 21.28, 21.77, 22.22, 23.18, 25.05, 25.46, 26.42, 27.32, 29.26, 30.74, 32.60, 42.94 and 44.21 9. The crystalline compound of claim 1, wherein the compound is a tartrate salt of Formula (I-D): , solvate, hydrate,from 1 to 4.

10. The crystalline compound of claim 9, selected from: a Form D1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.2, 9.7, 12.9, 16.4, 18.6, 19.7, 21.0, 21.8, 22.7, 23.7, 24.3, 24.8, and 25.4; a Form D2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.9, 5.2, 8.2, 9.7, 10.4, 12.6, 15.6, 16.5, 17.6, 18.3, 19.2, 19.7, 20.5, 21.8, 22.6, 23.1, 23.6, 24.4, 24.9, 26.1, 26.4, 27.4, and 30.2; a Form D3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.8, 8.1, 9.6, 10.3, 15.6, 16.4, 17.6, 18.1, 19.1, 19.6, 20.4, 22.5, 23.0, 23.5, 24.3, 24.8, 26.0, 26.3, and 27.

3.

135. ASBLomond.24.0001.W 11. The crystalline compound of claim 1, wherein the compound is a maleate salt of Formula (I-E): , solvate, hydrate, from 1 to 4.

12. The crystalline compound of claim 11, selected from: a Form E1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 8.12, 13.33, 15.24, 16.28, 17.51,17.95, 19.17, 20.27, 21.11, 21.86, 22.30, 23.40, 24.01, 25.41, 25.98, 27.09, and 28.22; a Form E2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 4.85, 5.54, 6.77, 12.69, 13.16, 14.56, 15.17, 15.97, 19.21, 20.36, 20.77, 21.86, 22.13, 22.61, 25.51, 25.84, 26.20, 26.47, 26.80, 28.23, 37.93, and 44.40; a Form E3 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 4.84, 6.75, 7.44, 8.10, 8.31, 9.99, 10.33, 12.94, 14.67, 15.25, 15.88, 16.29, 17.23, 17.63, 17.92, 18.33,18.80, 19.52, 20.08, 20.65, 21.27, 22.19, 22.43, 22.91, 23.44, 23.71, 24.30, 24.61, 25.12, 25.64, 26.09, 26.46, 26.78, 28.56, 28.86, 29.76, 30.78, 31.25, 31.88, 33.00, 34.39, 35.00, 36.46, 37.62, 38.45, 39.19, and 39.88; a Form E4 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.71, 7.69, 9.08, 11.25, 12.57, 14.04, 15.47, 16.43, 17.29, 18.54, 19.36, 20.73, 21.25, 22.74, 23.28, 24.58, 26.11, and 28.35; a Form E5 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.67, 5.29, 7.06, 7.73, 8.79, 9.11, 10.62, 11.13, 12.36, 13.83, 15.48, 16.53, 17.17, 18.02, 18.49, 18.82, 19.43, 19.69, 20.11, 20.80, 21.33, 22.04, 22.79, 23.20, 24.08, 24.62, 25.08, 26.22, 26.93, 27.61, 28.05, 28.92, 29.36, and 30.39; a Form E6 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 2.49, 4.55, 6.23, 6.69, 7.17, 136. ASBLomond.24.0001.W 7.95, 9.11, 10.40, 11.25, 12.50, 13.24, 13.69, 15.20, 15.71, 17.41, 17.85, 18.16, 18.79, 19.26, 19.51, 20.56, 21.63, 22.18, 22.49, 23.10, 23.91, 24.89, 25.41, 25.60, 26.23, 26.62, 27.70, 28.19, 31.42, and 31.

89.

13. The crystalline compound of claim 1, wherein the compound is a maleate salt of Formula (I-F): 4.a Form F1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 7.64, 9.17, 11.19, 12.26, 14.94, 15.40, 18.09, 19.99, 21.13, 22.48, 23.37, 25.72, 26.26, and 29.

02.

15. The crystalline compound of claim 1, wherein the compound is a maleate salt of Formula (I-G): 4.a Form G1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.74, 12.75, 13.60, 14.29, 15.24, 20.39, 25.86, and 26.30; a Form G2 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.45, 7.88, 9.04, 10.94, 12.17, 137. ASBLomond.24.0001.W 13.60, 15.26, 17.52, 18.20, 18.86, 20.33, 21.22, 22.39, 23.73, 24.64, 25.84, 26.41, 27.63, and 28.

86.

17. The crystalline compound of claim 1, wherein the compound is a maleate salt of Formula (I-H): , solvate, hydrate, selected from 1 to 4.

18. The crystalline compound of claim 17, selected from: a Form H1 polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.15, 4.50, 5.55, 6.22, 9.02, 9.86, 13.81, 14.17, 15.63, 17.04, 17.80, 18.73, 19.46, 20.63, 22.95, 24.60, 25.66, 25.92, and 26.

96.

19. The crystalline compound of claim 1, wherein the compound is in substantially pure form.

20. The crystalline compound of claim 1, wherein the X-ray powder diffraction pattern 1s made using CuKαl radiation.

21. The Form B polymorph of claim 3 characterized by the X-ray powder diffraction pattern shown in Figure 43.

22. The Form D polymorph of claim 3 characterized by the X-ray powder diffraction pattern shown in Figure 44.

23. The polymorph of claim 5 characterized by the X-ray powder diffraction pattern shown in Figure 3.

24. The Form 1 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 7.

25. The Form 3 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 12.

26. The Form 4 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 15.

27. The Form 5 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 20.

138. ASBLomond.24.0001.W 28. The Form 6 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 23.

29. The Form 7 polymorph of claim 8 characterized by the X-ray powder diffraction pattern shown in Figure 28.

30. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline polymorph of any one of claims 1-29, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

31. The pharmaceutical composition of claim 30, , further comprising an additional pharmaceutically active agent.

32. The pharmaceutical composition of any one of claims 30, 31 in the form of a tablet.

33. The pharmaceutical composition of any one of claims 30, 31 wherein the therapeutically effective amount is from 1 to 200 mg.

34. An amorphous compound of Formula (I): , in the form of freehydrate thereof.

35. The amorphous compound of claim 34, wherein the compound is a free base of Formula (I-A): , or a solvate, hydrate36. The amorphous compound of claim 34, wherein the compound is a hydrochloride salt of Formula (I-B):

139. ASBLomond.24.0001.W , or solvate, hydrate37. The amorphous compound of claim 34, wherein the compound is a phosphate salt of Formula (I-C): , or solvate, hydrate38. The amorphous compound of claim 34, wherein the compound is a tartrate salt of Formula (I-D): , or solvate,39. The amorphous compound of claim 34, wherein the compound is a maleate salt of Formula (I-E):

140. ASBLomond.24.0001.W ,salt of Formula (I-F): F),salt of Formula (I-G): ,salt of Formula (I-H):

141. ASBLomond.24.0001.W , or solvate, hydrate142. ASB

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