Crystalline polymorphs of 1-thiazol-2-yl-pyrazole-5-carboxylic acid derivative

Abstract

To provide crystalline polymorphs of a thiazolylpyrazole derivative, pharmaceutical compositions comprising them, and methods of using the crystalline polymorphs and their compositions.SOLUTION: Provided are crystalline polymorphs of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of its salt and / or hydrate or solvate.SELECTED DRAWING: None

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 855,671, filed May 31, 2019, which is incorporated herein by reference in its entirety. [Technical Field]

[0002] TECHNICAL FIELD This disclosure relates generally to crystalline polymorphs of thiazolylpyrazole derivatives, pharmaceutical compositions containing them, and methods of using the crystalline polymorphs and compositions. [Background technology]

[0003] Cancer, the uncontrolled proliferation of cells, is a multifactorial disease characterized by tumor formation, proliferation, and, in some cases, metastasis. In the United States, more than 1.5 million people will be diagnosed with cancer this year, and more than 500,000 will die from it. Overall, at least one in three people will develop some form of cancer during their lifetime. There are more than 200 histopathologically distinct types of cancer, with breast, colorectal, and prostate cancer accounting for more than half of all new cases in the United States. Current cancer treatments vary depending on the location and stage of the cancer but generally include surgery, systemic therapy, radiation therapy, and chemotherapy. Despite the efforts that have been made to develop anticancer therapies, many of these remain ineffective against specific cancers.

[0004] The uncontrolled cell proliferation that characterizes cancer involves not only the chaotic control of cell proliferation but also the corresponding adjustment of energy metabolism to stimulate cell growth and division. Reprogramming of cellular metabolism has emerged as a key molecular hallmark of cancer cells. Under aerobic conditions, normal cells process glucose via glycolysis in the cytosol, first to pyruvate and then to carbon dioxide in the mitochondria. Under aerobic conditions, glycolysis is favored, and only relatively small amounts of pyruvate are exported to the oxygen-consuming mitochondria. When growth factors and nutrients are abundant, oncogenic signaling processes direct enhanced metabolism, leading to increased synthesis of macromolecules such as lipids, proteins, and nucleic acids. The net effect is support for cell growth and proliferation. However, during tumorigenesis, a harsh, anoxic, nutrient-poor environment exists, challenging cells and their ability to maintain metabolic homeostasis. Cancer cells can reprogram their glucose metabolism, and therefore their energy production, by restricting their energy metabolism primarily to glycolysis, a process that was deemed primitive and inefficient by early biochemists. Despite these early theories, the metabolic signature of cancer cells is not a passive response to damaged mitochondria but rather results in oncogene-directed metabolic reprogramming necessary to support anabolic growth. Oncogene mutations that enable increased and more efficient utilization of scarce nutrients present unique targets for cancer treatment.

[0005] Particularly useful thiazolylpyrazole compounds, such as 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (identified herein as Compound 1), have been disclosed in International Publication Nos. WO 2018 / 102452 and WO 2018 / 102453 for the treatment of cancer. These compounds are believed to be active against cancer cells by arresting the cell cycle at the G0 / G1 phase, thereby inducing apoptosis in the cancer cells. These compounds are also believed to inhibit glutathione synthesis in cancer cells. Thus, these thiazolylpyrazole compounds show promise for the treatment of cancer.

[0006] Nevertheless, specific crystalline (morphological or polymorphic) forms of known compounds are important in drug discovery. For example, some polymorphic forms may exhibit improved thermodynamic stability, solubility, dissolution, etc., compared to other forms. As a result, some polymorphic forms may be more suitable than others in formulated pharmaceutical compositions.

[0007] Thus, there remains a need for improved forms of particularly useful anti-cancer compounds, and especially improved forms of thiazolylpyrazole compounds. Summary of the Invention

[0008] One aspect of the present disclosure provides a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (identified herein as Compound 1), optionally in the form of a hydrate or solvate thereof.

[0009] Another aspect of the disclosure provides crystalline polymorphs of different salts of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of hydrates or solvates thereof. In certain embodiments of this aspect, the salt is the potassium, sodium, magnesium, urea, L-arginine, or L-proline salt of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid.

[0010] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline, optionally in the form of a hydrate or solvate thereof.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising the crystalline polymorphs or salts described herein.

[0012] In another aspect, the present disclosure provides a method of treating a hyperproliferative disorder, such as cancer, in a subject in need thereof, the method comprising administering to the subject an effective amount of a crystalline polymorph or salt described herein.

[0013] In another aspect, the present disclosure provides a crystalline polymorph or salt described herein for use in the treatment of a hyperproliferative disorder, such as cancer.

[0014] In another aspect, the disclosure provides the use of a crystalline polymorph or salt described herein for the preparation of a medicament for the treatment of a hyperproliferative disorder, such as cancer.

[0015] In certain embodiments of the various aspects of the present disclosure, the hyperproliferative disorder is a hematopoietic cancer. In certain alternative embodiments of the present disclosure, the hyperproliferative disorder is a solid tumor.

[0016] In certain embodiments of the various aspects of the disclosure, the hyperproliferative disorder is a cancer (e.g., a solid tumor such as colorectal cancer, lung cancer, or pancreatic cancer) with a mutant KRAS gene, e.g., a heterozygous mutant KRAS gene.

[0017] Another aspect of the present disclosure provides a method for inhibiting cell cycle progression in cancer cells. The method comprises contacting cancer cells with an effective amount of the crystalline polymorph or salt described herein. In certain such embodiments, the cancer cells are hematopoietic cancer cells. In other such embodiments, the cancer cells are cancer cells of solid tumors (e.g., pancreatic cancer, lung cancer, or colorectal cancer). In certain such embodiments, the cancer cells have a heterozygous mutant KRAS gene. Cell cycle progression can be inhibited, for example, at the G0 / G1 phase.

[0018] Another aspect of the present disclosure provides a method for inducing apoptosis in cancer cells. The method comprises contacting the cancer cells with an effective amount of a crystalline polymorph or salt described herein. In certain such embodiments, the cancer cells are hematopoietic cancer cells.

[0019] Another aspect of the present disclosure provides a method for inducing cytotoxic effects in cancer cells. The method comprises contacting cancer cells with an effective amount of the crystalline polymorph or salt described herein. In certain such embodiments, the cancer cells are hematopoietic cancer cells. In other such embodiments, the cancer cells are cancer cells of solid tumors (e.g., pancreatic cancer, lung cancer, or colorectal cancer). In certain such embodiments, the cancer cells have a heterozygous mutant KRAS gene.

[0020] Another aspect of the present disclosure provides a method for inhibiting glutathione synthesis in cancer cells. The method comprises contacting cancer cells with an effective amount of a crystalline polymorph or salt described herein. In certain such embodiments, the cancer cells are hematopoietic cancer cells. In other such embodiments, the cancer cells are cancer cells of a solid tumor (e.g., pancreatic cancer, lung cancer, or colorectal cancer). In certain such embodiments, the cancer cells have a heterozygous mutant KRAS gene.

[0021] Other aspects and embodiments of the present disclosure will be apparent from consideration of the detailed description provided herein.

[0022] The accompanying drawings are included to provide a further understanding of the compositions and methods of the present disclosure, and are incorporated into and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the detailed description, serve to explain the principles and operation of the present disclosure. [Brief explanation of the drawings]

[0023] [Figure 1A] 1 shows the X-ray powder diffraction (XRPD) pattern for crystalline polymorph Form 1 (Example 2). [Figure 1B-1C] 1 shows the differential scanning calorimetry (DSC) profile and thermogravimetric analysis (TGA), respectively, for crystalline polymorph Form 1. [Figure 1D] 1 shows the Fourier transform infrared (FTIR) spectrum for crystalline polymorph Form 1. [Figure 1E] 1 shows Form 1 before and after dynamic vapor sorption (DVS) measurements. [Figure 1F] 1 shows an overlay of the XRPD pattern of Form 1 of Example 1 with the two crystalline forms obtained after crystallization of Example 3. [Figure 2] 1 shows the XRPD pattern for crystalline polymorph Form 2 (Example 5). [Figure 3A] 1 shows the XRPD pattern for crystalline polymorph Form 3 (Example 6). [Figure 3B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 3. [Figure 4A] 1 shows the XRPD pattern for crystalline polymorph Form 4 (Example 7). [Figure 4B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 4. [Figure 5A] 1 shows the XRPD pattern for crystalline polymorph Form 5 (Example 8). [Figure 5B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 5. [Figure 5C] 1 shows an overlay of XRPD patterns of a competition experiment between Form 1 and Form 5. [Figure 6A] 1 shows the XRPD pattern for crystalline polymorph Form 6 (Example 10). [Figure 6B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 6. [Figure 7A] 1 shows the XRPD pattern for crystalline polymorph Form 7 (Example 11). [Figure 7B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 7. [Figure 8] 1 shows the XRPD pattern for crystalline polymorph Form 8 (Example 12). [Figure 9A] 1 shows the XRPD pattern for crystalline polymorph Form 9 (Example 13). [Figure 9B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 9. [Figure 10A] 1 shows the XRPD pattern for crystalline polymorph Form 10 (Example 14). [Figure 10B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 10. [Figure 11A] 1 shows the XRPD pattern for crystalline polymorph Form 11 (Example 15). [Figure 11B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 11. [Figure 12A] 1 shows the XRPD pattern for crystalline polymorph Form 12 (Example 17). [Figure 12B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 12. [Figure 13A] 1 shows the XRPD pattern for crystalline polymorph Form 13 (Example 19). [Figure 13B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 13. [Figure 14A] 1 shows the XRPD pattern for crystalline polymorph Form 14 (Example 20). [Figure 14B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 14. [Figure 15A] 1 shows the XRPD pattern for crystalline polymorphic Form 15 (Example 21). [Figure 15B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 15. [Figure 16A] 1 shows the XRPD pattern for crystalline polymorphic Form 16 (Example 22). [Figure 16B] 1 shows the TGA and DSC profiles for crystalline polymorph Form 16. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present inventors have discovered a novel crystalline polymorph useful for the treatment of cancer. Accordingly, one aspect of the present disclosure provides a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a hydrate or solvate thereof.

[0025] The ability of a compound to exist in different crystal structures is known as polymorphism. As used herein, "polymorph" refers to crystalline forms that have the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystal. Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, and dissolution. Polymorphs of a compound can be identified in the laboratory by X-ray diffraction spectroscopy, such as XRPD, and other methods, such as infrared spectroscopy (IR). Furthermore, polymorphs of the same drug substance or active pharmaceutical ingredient, whether administered alone or formulated as a drug product (pharmaceutical composition), are well known in the pharmaceutical industry to affect, for example, the solubility, stability, flowability, handleability, compressibility of the drug substance, and the safety and efficacy of the drug product (see Brittain, H. (Ed.). (1999). Polymorphism in Pharmaceutical Solids. Boca Raton: CRC Press, and Hilfiker, Rolf (ed.). (2006) Polymorphism in the Pharmaceutical Industry. Weinheim, Germany: Wiley-VCH).

[0026] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (i.e., as the free acid), referred to herein as "Form 1." In certain embodiments, the Form 1 crystalline polymorph is anhydrous / solvent-free (i.e., does not contain solvent or water in its crystalline structure). Such a crystalline polymorph can be characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.1, 7.1, 9.4, 12.7, 18.8, 21.3, and 22.3 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorphs can be characterized as providing an XRPD pattern comprising six or more (e.g., each) peaks selected from 6.1, 7.1, 9.4, 12.7, 18.8, 21.3, and 22.3 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorphs of the present disclosure are characterized as providing an XRPD pattern according to that shown in FIG. 1A.

[0027] In certain embodiments, the crystalline polymorph of the present disclosure, referred to herein as Form 1, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 123±2° C. In certain embodiments, the crystalline polymorph of Form 1 of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0028] In certain embodiments, the crystalline polymorph of the present disclosure, referred to herein as Form 1, has a crystalline polymorphic peak of 2930 (broad) ± 2 cm -1 , 1709±2cm -1 , 1539±2cm -1 , 1359±2cm -1 , 1238±2cm -1 , 1165±2cm -1 , 1112±2cm -1 , 987±2cm -1 , 875±2cm -1 , 772.50±2cm-1 , and 690±2cm -1 In certain embodiments, the crystalline polymorph has an FTIR spectrum including six or more (e.g., seven or more, eight or more, or nine or more) peaks selected from the following: -1 , 1709±2cm -1 , 1539±2cm -1 , 1359±2cm -1 , 1238±2cm -1 , 1165±2cm -1 , 1112±2cm -1 , 987±2cm -1 , 875±2cm -1 , 772.50±2cm -1 , and 690±2cm -1 In certain embodiments, the crystalline polymorph is characterized in that it provides an FTIR spectrum comprising 10 or more peaks selected from the peak: 1709±2 cm -1 , 1539±2cm -1 , 1359±2cm -1 , 1238±2cm -1 , 1165±2cm -1 , 1112±2cm -1 , 987±2cm -1 , 875±2cm -1 , 772.50±2cm -1 , and 690±2cm -1 In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an FTIR spectrum according to that shown in FIG.

[0029] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, referred to herein as "Form 2." In certain embodiments, the Form 2 crystalline polymorph is an anhydrous / solvent-free product. Such a crystalline polymorph can be characterized in that the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.2, 6.6, 7.5, 10.9, 12.4, and 13.3 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 6.2, 6.6, 7.5, 10.9, 12.4, and 13.3 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in FIG.

[0030] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, referred to herein as "Form 5." In certain embodiments, the crystalline polymorph of Form 5 is an anhydrous / solvent-free product. Such crystalline polymorphs are characterized in that the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 7.1, 17.7, 18.8, 19.3, and 22.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising six or more (e.g., each) peaks selected from 6.4, 7.1, 17.7, 18.8, 19.3, and 22.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 5A.

[0031] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 5, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 142±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0032] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, referred to herein as "Form 8." In certain embodiments, the crystalline polymorph of Form 8 is an anhydrous / solvent-free product. Such crystalline polymorphs are characterized in that the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 9.1, 14.3, 16.6, 18.4, 20.1, and 21.9 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 6.4, 9.1, 14.3, 16.6, 18.4, 20.1, and 21.9 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 8.

[0033] The present disclosure is also directed to a novel crystalline polymorph of a hydrate or solvate of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (i.e., as the free acid).

[0034] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (e.g., as a hydrate or solvate), designated herein as "Form 3." Such crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 14.4, 16.2, 17.5, 19.1, 22.8, and 24.0 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that it provides an XRPD pattern comprising six or more (e.g., each) peaks: 6.4, 14.4, 16.2, 17.5, 19.1, 22.8, and 24.0 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that it provides an XRPD pattern according to that shown in Figure 3A.

[0035] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 3, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 91±2° C. and 118±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0036] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (e.g., as a hydrate or solvate), referred to herein as "Form 4." Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 9.9, 14.9, 19.4, 21.4, 23.5, and 24.1 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the peaks: 9.9, 14.9, 19.4, 21.4, 23.5, and 24.1 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 4A.

[0037] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 4, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 49±2° C. and 73±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0038] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (e.g., as a hydrate or solvate), referred to herein as "Form 6." Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.8, 11.5, 14.5, 17.3, 20.8, and 22.0 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 5.8, 11.5, 14.5, 17.3, 20.8, and 22.0 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 6A.

[0039] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 6, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 64±2° C. and 120±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0040] In certain embodiments, the crystalline polymorph of the present disclosure is a novel crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (e.g., as a hydrate or solvate), referred to herein as "Form 7." Such a crystalline polymorph can be characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.7, 7.0, 11.5, 13.1, 14.4, 17.2, and 22.1 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph can be characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 6.7, 7.0, 11.5, 13.1, 14.4, 17.2, and 22.1 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 7A.

[0041] In certain embodiments, the crystalline polymorph of the present disclosure, referred to herein as Form 7, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 58±2° C. and 108±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG. 7B.

[0042] Another aspect of the present disclosure provides crystalline polymorphs of salts of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of hydrates or solvates thereof. For example, in certain embodiments, the present disclosure provides crystalline polymorphs of potassium, sodium, magnesium, urea, L-arginine, or L-proline salts.

[0043] The crystalline polymorph of the present disclosure is, in certain embodiments, a crystalline polymorph of potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof.

[0044] In certain embodiments, the crystalline polymorph of the present disclosure is potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, referred to herein as "Form 9." Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 7.1, 10.2, 12.2, 14.2, 19.0, 19.4, and 24.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 6.4, 7.1, 10.2, 12.2, 14.2, 19.0, 19.4, and 24.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 9A.

[0045] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 9, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 113±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0046] In certain embodiments, the crystalline polymorph of the present disclosure is potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (e.g., as a hydrate or solvate), referred to herein as "Form 10." Such a crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.6, 5.8, 7.4, 9.5, 12.8, 15.5, and 19.5 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 5.6, 5.8, 7.4, 9.5, 12.8, 15.5, and 19.5 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 10A.

[0047] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 10, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 62±2° C. and 144±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0048] The crystalline polymorph of the present disclosure, in certain embodiments, is a crystalline polymorph of sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally a hydrate or solvate thereof.

[0049] In certain embodiments, the crystalline polymorph of the present disclosure is sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, referred to herein as "Form 11." Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 7.0, 10.4, 12.2, 13.1, 14.0, 18.8, and 24.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising each of the following peaks: 7.0, 10.4, 12.2, 13.1, 14.0, 18.8, and 24.5 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 11A.

[0050] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 11, is characterized in that the crystalline polymorph provides a (e.g., broad) DSC thermogram with an exothermic peak at 76±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0051] In certain embodiments, the crystalline polymorph of the present disclosure is sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, referred to herein as "Form 12." In certain embodiments, the Form 12 crystalline polymorph is anhydrous / solvent-free. Such crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 3.8, 7.5, 13.0, 16.2, 17.0, 17.8, 20.0, 22.7, and 23.7 (±0.1 degrees 2θ). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern that includes six or more, or seven or more, or each of the following peaks: 3.8, 7.5, 13.0, 16.2, 17.0, 17.8, 20.0, 22.7, and 23.7 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 12A.

[0052] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 12, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 153±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0053] The crystalline polymorph of the present disclosure, in certain embodiments, is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, optionally in the form of a hydrate or solvate thereof. For example, in certain embodiments, the crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine is referred to herein as "Form 13." In certain embodiments, the crystalline polymorph of Form 13 is anhydrous / solvent-free. Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 10.3, 16.6, 18.7, 20.7, 21.3, 25.0, and 28.2 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising six or more, or each, of the following peaks: 10.3, 16.6, 18.7, 20.7, 21.3, 25.0, and 28.2 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 13A.

[0054] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 13, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 231±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0055] The crystalline polymorph of the present disclosure, in certain embodiments, is a crystalline polymorph of magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof. For example, in certain embodiments, the crystalline polymorph of magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate is referred to herein as "Form 14." Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.4, 15.8, 16.8, 18.7, 25.1, and 38.2 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that it provides an XRPD pattern comprising six or more, or each, of the following peaks: 5.4, 15.8, 16.8, 18.7, 25.1, and 38.2 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 14A.

[0056] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 14, is characterized in that the crystalline polymorph provides a DSC thermogram with endothermic peaks at 105±2° C. and 137±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0057] The crystalline polymorph of the present disclosure, in certain embodiments, is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, optionally in the form of a hydrate or solvate thereof. For example, in certain embodiments, the crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea is referred to herein as "Form 15." In certain embodiments, the crystalline polymorph of Form 1 is anhydrous / solvent-free. Such a crystalline polymorph is characterized in that it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.7, 9.8, 16.5, 17.3, 17.8, 20.0, 21.1, 23.5, and 26.1 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that the crystalline polymorph provides an XRPD pattern comprising six or more, or seven or more, or each of the following peaks: 5.7, 9.8, 16.5, 17.3, 17.8, 20.0, 21.1, 23.5, and 26.1 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 15A.

[0058] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 15, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 136±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0059] The crystalline polymorph of the present disclosure, in certain embodiments, is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline, optionally in the form of a hydrate or solvate thereof. For example, in certain embodiments, the crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline is referred to herein as "Form 16." Such a crystalline polymorph is characterized in that it provides an XRPD pattern that includes four or more (e.g., five or more) peaks selected from 7.7, 7.9, 11.9, 15.9, 17.4, 19.7, and 21.4 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph is characterized in that it provides an XRPD pattern that includes six or more, or each, of the following peaks: 7.7, 7.9, 11.9, 15.9, 17.4, 19.7, and 21.4 (2θ±0.1 degrees). In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides an XRPD pattern according to that shown in Figure 16A.

[0060] In certain embodiments, the crystalline polymorph of the present disclosure, designated herein as Form 16, is characterized in that the crystalline polymorph provides a DSC thermogram with an endothermic peak at 168±2° C. In certain embodiments, the crystalline polymorph of the present disclosure is characterized in that the crystalline polymorph provides a DSC thermogram according to that shown in FIG.

[0061] Another aspect of the present disclosure is a method for manufacturing a semiconductor device comprising: potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline, optionally in the form of a hydrate or solvate thereof.

[0062] In certain embodiments, potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate is in the form of a hydrate or solvate thereof. In certain embodiments, sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate is in the form of a hydrate or solvate thereof. In certain embodiments, magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate is in the form of a hydrate or solvate thereof. In certain embodiments, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline is in the form of a hydrate or solvate thereof.

[0063] Therapeutic methods of the present disclosure As mentioned above, mutations that allow for increased and more efficient utilization of scarce nutrients are favored during tumorigenesis. Oncogenic Ras stimulates both glucose uptake via increased expression of GLUT1 and its utilization through anabolic pathways and its conversion to glutathione, the major cellular antioxidant. Ras also regulates glutamine metabolism, specifically directing glucose and glutamine carbons to pathways that support biosynthesis, redox homeostasis, and ultimately cell survival and proliferation. In addition to these effects on cellular metabolism, Ras has also been described to influence cell progression through the cell cycle. Specifically, Ras has been implicated in driving cell progression through the early G1 and even G2 restriction points. Ras activity at the G1 restriction point is particularly important because this event is a critical integration point for growth factor signaling, which commits cells to further division or entry into G0, or quiescence. Ras coordinates growth factor signaling to regulate the levels of cyclins, cyclin-dependent kinases, and competitive cyclin-dependent kinase inhibitors. Ras-related oncogenes, particularly KRAS (also known as k-Ras or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), have also been shown to directly affect cellular metabolism, resulting in global rearrangements of metabolic pathways. KRAS has been shown to have pleiotropic effects on glucose utilization, glutathione synthesis, redox balance, and glutamine metabolism. Glutathione, a ubiquitous intracellular peptide, has diverse functions, including regulating cell proliferation, detoxification, and antioxidant defense. Increased glutathione levels are associated with early proliferative responses (e.g., stimulating cells to shift from G0 to G1 phase of the cell cycle) and are essential for cells to enter S phase. Glutathione is also involved in regulating cell death, possibly regulating both apoptosis and necrosis. Additionally, increased glutathione levels have been reported in many tumors and are implicated in conferring drug and / or radiation resistance and interfering with chemotherapy. Therefore, inhibitors of glutathione synthesis represent unique chemotherapeutic targets.

[0064] Without intending to be bound by theory, the inventors believe that the crystalline polymorphs or salts described herein are active against cancer cells by arresting the cell cycle at the G0 / G1 phase. Thus, as alluded to above, the crystalline polymorphs or salts described herein can be employed in a variety of methods and uses. For example, in certain embodiments of the present disclosure, a method for treating a hyperproliferative disorder in a subject in need thereof comprises administering to the subject an effective amount of a crystalline polymorph or salt described herein. In other embodiments of the present disclosure, the crystalline polymorphs or salts described herein are provided for use in treating a hyperproliferative disorder. In other embodiments of the present disclosure, a use of the crystalline polymorphs or salts described herein for preparing a medicament for treating a hyperproliferative disorder is provided. In each of these embodiments, the hyperproliferative disorder may be, for example, cancer.

[0065] The inventors have determined that, in certain embodiments, the presently described crystalline polymorphs or salts inhibit cell cycle progression in cancer cells. Accordingly, another embodiment of the present disclosure provides a method for inhibiting cell cycle progression in cancer cells, the method comprising contacting cancer cells with an effective amount of the crystalline polymorphs or salts described herein. In certain such embodiments, cell cycle progression is inhibited at the G0 / G1 phase.

[0066] Inhibiting cell cycle progression at the G0 / G1 phase can, in certain embodiments, induce apoptosis in cancer cells. Accordingly, another embodiment of the present disclosure provides a method for inducing apoptosis in cancer cells, such as hematopoietic cancer cells. The method comprises contacting the cancer cells with an effective amount of a crystalline polymorph or salt described herein. However, in other embodiments, for example, in certain solid tumors, apoptosis may not be necessary for a significant therapeutic effect to be present.

[0067] The inventors have determined that the crystalline polymorphs or salts described herein can, in certain embodiments, induce a cytotoxic effect on cancer cells (e.g., through the apoptotic mechanisms described above or through alternative mechanisms). Accordingly, another embodiment of the present disclosure provides a method for inducing a cytotoxic effect on cancer cells. The method comprises contacting cancer cells with an effective amount of the crystalline polymorphs or salts described herein.

[0068] The inventors have determined that the crystalline polymorphs or salts described herein can, in certain embodiments, inhibit glutathione synthesis in cancer cells. Accordingly, another embodiment of the present disclosure provides a method for inhibiting glutathione synthesis in cancer cells. The method includes contacting cancer cells with an effective amount of the crystalline polymorphs or salts described herein.

[0069] The methods, crystalline polymorphs or salts, and uses described herein can be used for a variety of different types of cancer or cells of a variety of different types of cancer. For example, in certain embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is a hematopoietic cancer. In other embodiments, the cancer is a solid tumor.

[0070] In certain embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is a lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL)). In other such embodiments, the cancer is a leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia. In other such embodiments, the cancer is a plasma cell neoplasm (e.g., multiple myeloma).

[0071] However, one of ordinary skill in the art will understand from the disclosure provided herein that the methods, crystalline polymorphs or salts, and uses described herein can be used in a variety of other types of cancer. For example, in certain embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is selected from the group consisting of appendix cancer, bone cancer (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), bronchial tumors, cancer of unknown primary, chronic myeloproliferative neoplasms, colon and rectal cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)), leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myeloid leukemia (CMML), advanced NK cell leukemia, acute biliary tract cancer (ALC), and leukemia (LEC). and multiple cell leukemia), acute and chronic T-cell and B-cell leukemia), lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL)), plasma cell neoplasms (such as multiple myeloma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and chronic myeloproliferative neoplasms, pancreatic cancer and pancreatic neuroendocrine tumors (e.g., pancreatic islet cell tumors), small intestine cancer, soft tissue sarcoma, and squamous cell carcinoma.

[0072] And in other embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is selected from the group consisting of adrenocortical carcinoma, adrenocortical carcinoma, AIDS-related cancers (e.g., Kaposi's sarcoma, AIDS-related lymphoma, Burkitt's lymphoma, etc. and primary CNS lymphoma), anal cancer, adnexal cancer, astrocytoma (e.g., childhood cerebellum or cerebrum), bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, bone cancer (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumors (e.g., neuroblastoma multiforme, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma), and the like. tumors, oligodendroglioma, supratentorial primitive neuroectodermal tumor, and visual pathway and hypothalamic glioma), brain stem glioma, breast cancer, bronchial tumor, gastrointestinal carcinoma-like tumor, carcinoma-like tumor, carcinoma of unknown primary, cardiac (heart) tumor, central nervous system cancer (e.g., atypical teratoma / rhabdoid tumor, embryonal tumor, and germ cell tumor), cervical cancer, childhood cancer, chondrosarcoma, chronic myeloproliferative neoplasm, colon and rectal cancer, craniopharyngioma, desmoplastic small round cell tumor, ductal carcinoma in situ (DCIS), endometrial cancer, acanthoma, epithelial hemangioendothelioma (EHE), esophageal cancer, nasal neuroblastoma, extracranial germ cell tumor tumors, extragonadal germ cell tumors, eye cancer (e.g., intraocular melanoma, retinoblastoma), fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease (GTD), glioma, hairy cell leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), hepatocellular (liver) cancer, histiocytosis, Langerhans cell, hypopharyngeal cancer, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLH), Myeloid leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute biphenotypic leukemia, and polycythemia erythrocytosis), acute and chronic T-cell and B-cell leukemia), lip and oral cavity cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung carcinoma, and lung squamous cell carcinoma), lung cancer-like tumors, lymphomas (e.g., Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma,Cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL), male breast cancer, meningioma, mesothelioma, midline duct carcinoma containing the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, plasma cell neoplasms (e.g., multiple myeloma), fungal infections, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and chronic myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma (NPC), neuroblastoma, oral cavity cancer, lip and oral cavity cancer and oropharyngeal cancer, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (e.g., pancreatic islet cell tumors), paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumors, pleuropulmonary blastoma, primary peritoneal cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sezary syndrome, skin cancer (e.g., basal cell carcinoma and squamous cell carcinoma, Merkel cell carcinoma, and melanoma), small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, testicular cancer, throat cancer, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer and sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0073] For example, in some particular embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is a solid tumor, which in various embodiments can be, for example, lung cancer, colorectal cancer, or pancreatic cancer.

[0074] In certain embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer is diffuse large B-cell lymphoma.

[0075] KRAS mutations are found in >90% of pancreatic cancers, 50% of colon cancers, and 25% of lung adenocarcinomas. Thus, in certain embodiments of the methods, crystalline polymorphs or salts, and uses otherwise described herein, the cancer has a mutant KRAS gene, e.g., a heterozygous mutant.

[0076] Those skilled in the art will be able to determine effective amounts and dosages of the crystalline polymorphs or salts described herein based on this disclosure, taking into account the current state of the art.

[0077] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0078] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0079] As used herein, the phrase "therapeutically effective amount" or "effective amount" means an amount of an active crystalline polymorph that elicits the biological or medical response sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician.

[0080] In certain embodiments, the effective amount is: (i) To inhibit disease progression; (ii) prophylactic uses, e.g., to prevent or limit the onset of a disease, condition, or disorder in individuals who have been previously diagnosed with, or who may otherwise be at risk for, the disease, condition, or disorder, but who have not yet experienced or exhibited the symptoms or full manifestations of the disease; (iii) To inhibit a disease, e.g., inhibiting a disease, condition, or disease in an individual experiencing or exhibiting the symptoms or symptoms of the disease, condition, or disease; (iv) to alleviate the referenced disease, e.g., to alleviate the disease, condition, or disorder (i.e., to reverse the symptoms and / or symptoms) in an individual experiencing or exhibiting the symptoms or symptoms of the disease, condition, or disorder, e.g., to reduce the severity of the disease; or (v) may be in an amount suitable to elicit the referenced biological effect.

[0081] As used herein, the terms "treatment" and "treating" mean (i) alleviating the referenced disease, condition, or disorder (or a symptom thereof), such as alleviating the disease, condition, or disorder (i.e., reversing or ameliorating the disease and / or symptoms) in an individual experiencing or exhibiting the symptoms or symptoms of the disease, condition, or disorder, e.g., reducing the severity of the disease or a symptom thereof, or inhibiting the progression of the disease, or (ii) eliciting the referenced biological effect (e.g., inducing apoptosis or inhibiting glutathione synthesis). Pharmaceutical Compositions and Dosage Forms

[0082] The crystalline polymorphs or salts described herein can be usefully provided in the form of pharmaceutical compositions.Such compositions comprise the polymorphs according to any one of the above-mentioned aspects or embodiments described herein, together with pharmaceutically acceptable excipients, diluents or carriers.The pharmaceutical compositions can be, for example, in the form of tablets, capsules or parenteral preparations, but those skilled in the art will understand that the crystalline polymorphs can be provided in a variety of pharmaceutical compositions.

[0083] The crystalline polymorphs or salts of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray, or rectally, for example, in dosage unit forms containing one or more pharmaceutically acceptable carriers, diluents, or excipients. As used herein, the term "parenteral" includes transdermal, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques, etc. The medicament containing the crystalline polymorphs of the present disclosure can be provided in any suitable formulation and dosage form as described herein.

[0084] Pharmaceutical compositions can be made using the crystalline polymorphs or salts disclosed herein. For example, in one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent, or excipient, and the crystalline polymorph described above with reference to any one of the structural formulas.

[0085] In the pharmaceutical compositions disclosed herein, one or more crystalline polymorphs or salts of the present disclosure can be present in association with one or more pharmaceutically acceptable carriers, diluents, or excipients, and, if desired, other active ingredients. Pharmaceutical compositions containing the crystalline polymorphs or salts of the present disclosure can be present in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0086] Compositions intended for oral use can be prepared according to any suitable method for preparing pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known techniques. In some cases, such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0087] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0088] Formulations for oral use may also be presented as lozenges.

[0089] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents, such as naturally occurring phospholipids, phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0090] Oily suspensions can be prepared by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.Sweeteners and flavoring agents can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0091] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0092] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the above partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavoring agents.

[0093] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water comprises less than 50% of the composition. In some embodiments, a composition containing less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content is present in trace amounts in the composition.

[0094] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, alcohol comprises less than 50% of the composition. In some embodiments, compositions containing less than 50% alcohol have at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments, the alcohol content is present in trace amounts in the composition.

[0095] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations can also contain demulcents, preservatives, flavoring agents, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to the art using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, systemically acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be used as solvents or suspending media. For this purpose, any non-irritating, fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, find use in the preparation of injectable solutions.

[0096] The crystalline polymorph or salt of the present disclosure can also be administered in the form of suppositories, for example, for rectal administration of drugs. These compositions can be prepared by mixing the crystalline polymorph with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby dissolving in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol.

[0097] The crystalline polymorph or salt of the present disclosure can also be administered systemically in a sterile medium.Depending on the vehicle and concentration used, the drug can be either suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle.

[0098] The compositions can be formulated in unit dosage forms of the active ingredient. The term "unit dosage form" means physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0099] The active crystalline polymorph can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of crystalline polymorph actually administered will typically be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual crystalline polymorph being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0100] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the crystalline polymorphs described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the crystalline polymorphs described herein.

[0101] Tablets or pills can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action.For example, tablets or pills, oral contraceptives, can comprise an inner and outer component, the latter being in the form of an envelope surrounding the former.The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release.Various materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids, such as shellac paint, cetyl alcohol, and cellulose acetate.

[0102] The amount of crystalline polymorph or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, e.g., prophylactic or therapeutic, the condition of the patient, the method of administration, etc. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending clinician, depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0103] The compositions administered to patients can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for ready use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the crystalline polymorph preparation is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0104] The therapeutic dosage of a crystalline polymorph or salt can vary depending, for example, on the specific use for which the treatment is being administered, the method of administration of the crystalline polymorph, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a crystalline polymorph described herein in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the crystalline polymorph or salt described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% (weight / volume) of the crystalline polymorph. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage will likely depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected crystalline polymorph, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0105] The crystalline polymorphs described herein can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, etc.

[0106] One of skill in the art would formulate the crystalline polymorphs or salts described herein as pharmaceutical formulations based, for example, on the physicochemical properties of the crystalline polymorph, the amount of the crystalline polymorph or salt required for a pharmaceutically effective amount, and the desired route of administration. [Example]

[0107] The preparation of the crystalline polymorphs or salts of the present disclosure is further illustrated by the following examples, which should not be construed as limiting the disclosure in scope or spirit to the specific procedures and crystalline polymorphs or salts described therein.

[0108] Example 1: Preparation of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Compound 1) Compound 1 is described as Compound No. 5 in International Patent Application Publication No. WO2018 / 102453, which is incorporated herein by reference in its entirety.

[0109] 3-(2-bromo-5-chlorophenoxy)oxetane Diisopropyl diazocarboxylate (292 mg, 1.45 mmol) was added to a solution of 2-bromo-5-chlorophenol (200 mg, 0.964 mmol), oxetan-3-ol (89 mg, 1.2 mmol), and triphenylphosphine (379 mg, 1.45 mmol) in THF (4.2 mL). The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate was added, and the mixture was washed with 1N NaOH (3×). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (10%) to give the title compound (208 mg, 0.789 mmol, 82%).

[0110] 2-(4-chloro-2-(oxetan-3-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Degassed dioxane was added to a mixture of 3-(2-bromo-5-chlorophenoxy)oxetane (100 mg, 0.379 mmol), pinacoldiborane (116 mg, 0.455 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (28 mg, 0.038 mmol), and potassium acetate (112 mg, 1.14 mmol). The reaction mixture was cooled to 85°C. o C for 18 hours. The mixture was filtered over Celite and the pad was washed with dioxane. The filtrate was evaporated to give the title compound (219 mg, 186%, 50 w / w% from NMR analysis), which was used as is.

[0111] 2-chloro-5-(isopropylthio)thiazole A 2.5 M solution of n-BuLi in hexane (20.5 mL, 51.2 mmol) was dissolved in a solution of 2-chlorothiazole (4.9 g, 41.0 mmol) in THF (117 mL) at -78°C. o C. The reaction mixture was stirred at the same temperature for 30 minutes. Diisopropyl disulfide (13.1 mL, 82.0 mmol) was added to the reaction mixture and stirred at the same temperature for 1.5 hours. Water was added to quench the reaction, followed by the addition of Et.sub.2O. The reaction mixture was transferred to a separatory funnel, and the aqueous layer was extracted with Et.sub.2O (3.times.). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (dry-packed) using a solution of EtOAc in hexanes (0-5% gradient) to afford the title compound (2.31 g, 11.9 mmol, 29%) as a yellow liquid.

[0112] 4-Bromo-2-chloro-5-(isopropylthio)thiazole A 2 M solution of bromine (72.7 μL, 1.42 mmol) in dichloromethane (“DCM”) was added dropwise to a solution of 2-chloro-5-(isopropylthio)thiazole (250 mg, 1.29 mmol) in DCM. The reaction was stirred at room temperature for 3 h. A solution of NaSO was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (dry-loaded) using a solution of DCM in hexanes (50–100% gradient) to afford the title compound (271 mg, 0.99 mmol, 77%) as a yellow liquid.

[0113] 4-Bromo-2-hydrazinyl-5-(isopropylthio)thiazole DIPEA (64 μL, 0.37 mmol) was added to hydrazine hydrochloride (13.0 mg, 0.18 mmol) and 4-bromo-2-chloro-5-(isopropylthio)thiazole (50.0 mg, 0.18 mmol) in NMP (2 mL) in a glass microwave vial. The vial was sealed and heated under microwave irradiation for 150 min. o The mixture was heated to C for 1 h. The crude product was purified by reverse flash chromatography (C18, using a gradient of 0–40–70% MeCN in HO with 10 mM NHCOH buffer), extracted with EtO, and concentrated in vacuo to give the title compound 29.0 mg, 0.11 mmol, 59%) as a yellow solid.

[0114] 2-(Methoxyimino)-3-(2-nitrobenzyl)-4-oxopentanoic acid methyl ester Methyl acetopyruvate (1.0 g, 6.94 mmol), methoxyhydroxylamine hydrochloride (0.58 g, 6.94 mmol), and molecular sieves (2.5 g) were placed in a flame-dried round-bottom flask equipped with a nitrogen inlet. Dry DMF (23 mL) was added, the round-bottom flask was covered with foil, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL), and the organic phase was washed with water (3 × 50 mL) and brine (1 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.07 g, 6.16 mmol, 89%) as a red liquid.

[0115] 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate methyl ester Methyl 2-(methoxyimino)-3-(2-nitrobenzyl)-4-oxopentanoate (4.00 g, 23.1 mmol) was dissolved in MeOH (115 mL). 4-Bromo-2-hydrazinyl-5-(isopropylthio)thiazole (6.19 g, 23.1 mmol) was added, followed by dropwise addition of 12 N HCl (7.70 mL, 92.4 mmol) to the reaction mixture. The reaction mixture was heated to reflux overnight. The crude product was concentrated in vacuo and purified by flash chromatography (dry-packed) on silica gel using a solution of EtOAc in hexanes (5-20% gradient) and twice by flash chromatography (dry-packed) on silica gel using a solution of DCM in hexanes (10-50% gradient) to give the title compound (1.89 g, 5.02 mmol, 22%) as an orange oil.

[0116] 4-Bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate A 2 M solution of bromine in MeCN (3.32 mL, 6.64 mmol) was added dropwise to a solution of methyl 1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (500 mg, 1.33 mmol) in a solution of DCM / MeCN (7 mL, 1:1). The reaction was stirred at room temperature for 5 h. NaSO solution was added and the aqueous layer was extracted with EtO (3×). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a solution of DCM in hexanes (20%) to give the title compound (421 mg, 0.93 mmol, 70%) as an orange solid.

[0117] 4-Bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate Place methyl 4-bromo-1-(4-bromo-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (100 mg, 0.220 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)-1,3,2-dioxaborolane (51.6 mg, 0.187 mmol), and KCO (152 mg, 1.10 mmol) in a 5 mL glass microwave vial equipped with a magnetic stir bar and a nitrogen flow at room temperature. 、 Nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through the solution in THF (2 mL), and the solution was then added to a microwave vial, followed by the addition of catalyst Pd(dtbpf)Cl2 (14.3 mg, 0.022 mmol). The vial was capped and placed in a 90 °C oil bath for 16 h. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography on silica gel (dry-packed) using a solution of EtOAc in hexanes (0-10% gradient) to afford the title compound (47.4 mg, 0.090 mmol, 41%) as a yellow oil.

[0118] 4-(3-Fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid Place methyl 4-bromo-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (47.4 mg, 0.090 mmol), 3-fluorophenylboronic acid (15.2 mg, 0.108 mmol), and NaCO (47.9 mg, 0.452 mmol) in a 5 mL glass microwave vial equipped with a magnetic stir bar and a nitrogen flow at room temperature. 、Nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a dioxane / water solution (2 mL, 4:1), then the solution was added to a microwave vial, followed by the addition of catalyst Pd(PPh3)4 (10.4 mg, 0.009 mmol). The vial was capped and placed in an oil bath at 85 °C for 16 h. The reaction mixture was diluted with EtOAc and transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. THF / MeOH (2 mL, 1:1) and 1 M NaOH (181 μL, 0.181 mmol) were added, and the reaction was stirred at room temperature for 16 h. The product was purified using HPLC-MS (column X-Bridge 30 × 50, 55–75% MeCN / NH4CO2H 10 mM, pH 3.8 / flow rate 45 ml / min / 11 min) to give the title compound (12.8 mg, 0.024 mmol, 27%) as a yellow solid after lyophilization.

[0119] 1 H NMR (500MHz, DMSO) δ7.53-7.42(m, 1H), 7.30-7.23(m, 2H), 7.22-7.15(m, 1H), 6.41(s, 1H), 3.32-3.22(m, 1H), 2.74-2.60(m, 1H), 2.50 -2.33(m, 3H), 2.26(s, 3H), 2.23-2.15(m, 1H), 2.07-1.97(m, 1H), 1.57-1.46(m, 1H), 1.23(dd, J=6.7, 3.4Hz, 6H);MS(m / z):526.3[M+1] + .

[0120] Sodium 4-(3-fluorophenyl)-2-[5-isopropylsulfanyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylate 4-(3-Fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid can be converted to its sodium salt by treatment with sodium hydroxide in tetrahydrofuran, followed by evaporation of the solvent and washing the solid with water to provide the crude sodium salt. Alternatively, saponification of the methyl ester can be carried out under conditions that directly provide the crude sodium salt.

[0121] The crude sodium salt can then be recrystallized. In one preparation, 56 g (0.10 mol) of the crude sodium salt was dissolved in tetrahydrofuran (500 mL) and filtered. To this solution, acetonitrile (250 mL) was added, and the solution was concentrated to 350 mL under reduced pressure at 50°C. Acetonitrile (250 mL) was added again, and the resulting solution was concentrated to 300 mL under reduced pressure at 50°C, allowing crystallization. To this mixture, acetonitrile (250 mL) was added, and the resulting solution was concentrated to 500 mL under reduced pressure at 50°C again. The mixture was then allowed to stand at 50°C for 1 hour, then cooled to 20°C for 1 hour, and then cooled to 0°C for 30 minutes. The resulting mixture was filtered, and the solid was washed with cold acetonitrile (2 x 100 mL, 0°C) and dried under reduced pressure at 35°C to give the sodium salt (54.7 g, 98%). MS (m / z): 525.85 [M-Na+2] + . 1 H NMR (500 MHz, DMSO-d 6 )δ14.16(br s, 1H), 7.50-7.55(m, 1H), 7.23-7.31(m, 3H), 6.44(m, 1H), 3.32(m, 1H), 2.68-2.74(m, 1H), 2.55-2.64(m, 1H), 2 .43-2.55(m, 1H), 2.30(s, 3H), 2.20-2.30(m, 1H), 2.02-2.09(m, 1H), 1.50-1.60(m, 1H), 1.26(d, 6H, J=7.5Hz). 13 C NMR (126 MHz, DMSO-d 6)δ163.51, 162.37, 161.58, 157.70, 154.94, 150.62, 133.49, 132.86, 132.79, 131.44, 131.23, 131.16, 129.80, 127.98, 127.59 , 125.55, 125.52, 125.38, 122.20, 120.09, 116.14, 115.96, 115.35, 115.19, 42.50, 26.71, 24.56, 23.15, 23.07, 21.64, 12.76.

[0122] 4-(3-Fluorophenyl)-2-[5-isopropylsulfanyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]thiazol-2-yl]-5-methyl-pyrazole-3-carboxylic acid (1) A 5 L flask was charged with the above sodium salt (52.0 g, 94.9 mmol) and 10% acetonitrile in deionized water (1.0 L). The mixture was warmed to 50 °C and then treated dropwise with 0.1 N HCl (1.0 equiv.). As the addition proceeded, the slurry was observed to change and become thicker. As the addition approached 1.0 equiv., the pH dropped to approximately 3; the target pH to ensure complete protonation is below 4. After 2 h, the mixture was cooled to 22 °C, filtered, washed with water, and air-dried to give the title compound 1 as crystalline Form 1 (51.76 g, 99% yield). 1 H NMR (500 MHz, DMSO-d 6 )δ14.16(s, 1H), 7.50-7.55(m, 1H), 7.25-7.30(m, 3H), 6.44(s, 1H), 3.28-3.34(quint, 1H), 2.69-2.73(d, 1H), 2.44-2.48(m, 2H), 2.29(s, 3H) 2.24-2.27(m, 2H), 2.04-2.08(m, 1H), 1.51-1.59(m, 1H), 1.26(d, 6H). 13C NMR (500MHz, CDCl3) δ163.46, 162.46, 161.51, 156.70, 152.70, 152.35, 133.41, 132.85, 131.94, 1 31.03, 129.76, 125.39, 121.61, 116.79, 115.22, 42.69, 37.92, 26.89, 24.68, 23.02, 21.48, 12.30. 19 F NMR (500 MHz, CDCl3) δ -73.62 (s), -113.17 (quintated). MS (m / z): 526.3 [M+1] + .

[0123] Example 2: Crystalline Polymorph Form 1 The crystalline polymorphic Form 1 of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid (Compound 1) was characterized by XRPD. Figure 1A provides the XRPD pattern, and Figure 1D provides the FTIR spectrum. This crystalline polymorph was also characterized by TGA, DSC, and polarized light microscopy (PLM). As shown by DSC and TGA in Figures 1B and 1C, respectively, Form 1 exhibited a melting endotherm onset at 101.2 °C, an endothermic peak at 123.4 °C, and negligible weight loss before 150 °C. PLM images showed Form 1 as needle-shaped birefringent crystals. Based on these results, Form 1 was considered an anhydrate.

[0124] Example 3: Large-scale antisolvent crystallization of polymorph 1 Compound 1 (2.088 g) obtained in Example 1 was placed in a 20 mL vial and dissolved in 2 mL of acetone at 50° C., then filtered. The filtrate was seeded with 103.1 mg of crystalline polymorphic form 1 from Example 2. To the seeded filtrate, 12 mL of water was slowly added, and the resulting suspension was stirred at room temperature overnight.

[0125] Temperature cycling was then used to improve the crystallinity. The suspension was maintained at 50°C for 30 minutes, then the temperature was decreased to 20°C at a rate of 0.1°C / min, and then increased to 50°C at a rate of 0.5°C / min. The temperature was then decreased to 20°C at a rate of 0.1°C / min, and then increased to 50°C at a rate of 0.5°C / min. Finally, the temperature was decreased to 20°C at a rate of 0.1°C / min and maintained at 20°C before isolating the solid. Antisolvent addition crystallization yielded approximately 1.5 g (approximately 67%) of the crystalline polymorph, which matched the Form 1 reference.

[0126] TGA and DSC measurements showed a weight loss of 0.1% at 150 °C and an endothermic peak at 120.0 °C. PLM images showed that the sample contained D 10 =0.16μm, D 50 = 0.36 μm, and D 90 = 3.72 μm (after 5 min of sonication, D 10 =0.16μm, D 50 = 0.35 μm, and D 90 The sample exhibited rod-shaped birefringent crystals with a particle size distribution (PSD) of 1.42 μm (Figure 1E). Dynamic vapor sorption (DVS) showed a water absorption rate of 0.6% at 25 °C / 80% relative humidity, indicating that Form 1 is slightly hygroscopic. As shown in Figure 1E, no change in morphology was observed before or after DVS.

[0127] Reverse antisolvent addition crystallization was also successful at a scale of approximately 1.1 g in 1 mL of acetone at 50°C. The dissolved compound was filtered, and the filtrate was slowly added (approximately 50 μL / sec) to an aqueous solution pre-seeded with crystalline polymorph Form 1 from Example 2 (97 mg of seeds in 6 mL of water). The resulting suspension was stirred at room temperature for 24 hours, filtered, washed with water, and air-dried for 2 days. Reverse antisolvent addition crystallization yielded approximately 1 g (approximately 85%) of the crystalline polymorph, which matched the Form 1 reference. As provided in Figure IF, both antisolvent addition crystallization and reverse antisolvent addition crystallization yielded crystalline polymorphs consistent with the Form 1 reference.

[0128] Example 4: Solubility and Stability of Crystalline Polymorph Form 1 The solubility of crystalline polymorph Form 1 was tested in biologically relevant media: water, simulated gastric fluid (SGF), fasting simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF). For example, the polymorph was suspended in the solvent and stirred at 400 rpm at 37°C for 1, 4, and 24 hours, followed by filtration. The supernatant concentration was measured by HPLC (mobile phase A: 0.1% NH in HO; mobile phase B: acetonitrile; flow rate: 0.8 mL / min; injection volume: 5 μL). The remaining solid was examined by XRPD. The solubility and pH are summarized in Table 1. Additionally, no shape change was observed in water, SGF, and FeSSIF, and one unknown peak at approximately 31 2θ degrees was observed for the FaSSIF polymorph. [Table 1]

[0129] Physical and chemical stability evaluations were performed on crystalline polymorph Form 1 under stress conditions. In the experiments, approximately 10 mg of the polymorph was placed in a 4 mL glass vial and stored at 40 °C / 75% RH for one week. HPLC was utilized to assess degradation, and XPRD was used to evaluate the crystalline polymorphism. Both studies showed that Form 1 was physically stable (i.e., the polymorphism remained unchanged and there was minimal or no degradation) for one week at 40 °C / 75% RH.

[0130] Example 5: Crystalline Polymorph Form 2 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2–0.9 mL of methyl tert-butyl ether (MTBE). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. The XRPD pattern, shown in Figure 2, suggested that Form 2 was metastable and partially converted to Form 1 upon drying under ambient conditions.

[0131] Example 6: Crystalline Polymorph Form 3 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2–0.9 mL of 1,4-dioxane:HO (1:3 volume ratio). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. Figure 3A provides the XRPD pattern for Form 3. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 3B, Form 3 exhibited endothermic peaks at 91.3 °C and 117.7 °C and a 3.8% weight loss by 100 °C. PLM images displayed Form 3 as rod-shaped, birefringent crystals. Based on these results, Form 3 was considered a hydrate or solvate.

[0132] Example 7: Crystalline Polymorph Form 4 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2–0.9 mL of dimethylformamide:HO (1:3 volume ratio). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. Figure 4A provides the XRPD pattern for Form 4. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 4B, Form 4 exhibited endothermic peaks at 49.4 °C and 72.9 °C and a 2.5% weight loss by 100 °C. PLM images displayed Form 4 as irregularly shaped, birefringent crystals. Based on these results, Form 4 was considered a hydrate or solvate.

[0133] Example 8: Crystalline Polymorph Form 5 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2–0.9 mL of 2-methyltetrahydrofuran:n-heptane (1:6 volume ratio). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. Figure 5A provides the XRPD pattern for Form 5. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 5B, Form 5 exhibited an endothermic peak at 141.9 °C and negligible weight loss before decomposition. PLM images displayed Form 5 as irregularly shaped, birefringent crystals. Based on these results, Form 5 was considered an anhydrous form.

[0134] Example 9: Conversion between Form 1 and Form 5 To determine the thermodynamic stability relationship between Form 1 and Form 5, a slurry conversion experiment was conducted. Specifically, a sample of Form 1 was added to 1.0 mL of HO:acetone (9:1 volume ratio) or 0.8 mL of HO:ethanol (3:1 volume ratio) at room temperature. After equilibration for 1 hour, the suspension was filtered to obtain a saturated solution of Form 1. A saturated solution of Form 1:Form 5 (1:1) was added. After stirring at room temperature for 2 or 3 days, the solid was isolated for XRPD analysis. As shown in Figure 5C, only Form 1 was observed. As a result, Form 1 was determined to be more thermodynamically stable than Form 5 at room temperature.

[0135] Example 10: Crystalline Polymorph Form 6 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2–0.9 mL of methanol:HO (937:63 volume ratio). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. Figure 6A provides the XRPD pattern for Form 6. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 6B, Form 6 exhibited endothermic peaks at 64.3 °C and 119.5 °C and a 2.9% weight loss by 80 °C. PLM images displayed Form 6 as irregularly shaped, birefringent crystals. Based on these results, Form 6 was considered to be a hydrate or solvate.

[0136] Example 11: Crystalline Polymorph Form 7 Crystalline polymorph Form 1 (15 mg) was suspended in 0.5 mL of acetone. The resulting visually clear solution was covered with Parafilm® with 5–10 pinholes and allowed to evaporate at room temperature. The remaining solid was isolated and subjected to XRPD. Figure 7A provides the XRPD pattern for Form 7. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 7B, Form 7 exhibited endothermic peaks at 52.2 °C and 108.4 °C, and a weight loss of 1.4% by 130 °C. PLM images displayed Form 7 as irregularly shaped, birefringent crystals. Based on these results, Form 7 was considered to be a hydrate or solvate.

[0137] Example 12: Crystalline Polymorph Form 8 Crystalline polymorph Form 1 (20 mg) was suspended in 0.2-0.9 mL of tetrahydrofuran:HO (1:9 volume ratio). The resulting slurry was stirred at room temperature for 4 days, after which the remaining solid was isolated and subjected to XRPD. The XRPD pattern, shown in Figure 8, suggested that Form 8 is metastable and partially converts to Form 1 upon drying under ambient conditions.

[0138] Example 13: 9 Crystalline Polymorphic Forms A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of KOH in ethyl acetate (1:1 molar ratio of KOH:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 9A shows the XRPD pattern of Form 9, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 9B, Form 9 exhibited an endothermic peak at 112.9 °C and a 1.2% weight loss by 130 °C. PLM images displayed Form 9 as rod-shaped, birefringent crystals. Based on these results, Form 9 was considered to be a hydrate or solvate.

[0139] Example 14: Crystalline Polymorph Form 10 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of KOH in methanol (1:1 molar ratio of KOH:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 10A shows the XRPD pattern of Form 10, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 10B, Form 10 exhibited endothermic peaks at 61.8 °C and 143.8 °C and a 4.3% weight loss by 150 °C. PLM images displayed Form 10 as irregularly shaped, birefringent crystals. Based on these results, Form 10 was considered to be a hydrate or solvate.

[0140] Example 15: Crystalline Polymorph Form 11 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of NaOH in ethyl acetate (1:1 molar ratio of NaOH:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 11A shows the XRPD pattern of Form 11, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 11B, Form 11 exhibited an endothermic peak at 75.6 °C and a 2.7% weight loss by 90 °C. PLM images displayed Form 11 as rod-shaped, birefringent crystals. Based on these results, Form 11 was considered to be a hydrate or solvate.

[0141] Example 16: Solubility of crystalline polymorphic form 11 The solubility of crystalline polymorph Form 11 was tested in biologically relevant media: water, SGF, FaSSIF, and FeSSIF. For example, the crystalline polymorph was suspended in the solvent and stirred at 400 rpm at 37°C for 1, 4, and 24 hours, followed by filtration. The supernatant was measured for concentration by HPLC, and the remaining solid was tested by XRPD. The solubility and pH are summarized in Table 2. Additionally, no form change was observed by XRPD in water and FaSSIF. Form 11 converted to Form 1 in SGF and FeSSIF. [Table 2]

[0142] Example 17: Crystalline Polymorph Form 12 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of NaOH in methanol (1:1 molar ratio of NaOH:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50°C for 2 hours and then subjected to XRPD. Figure 12A shows the XRPD pattern of Form 12, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 12B, Form 12 exhibited an endothermic peak at 152.8°C and a weight loss of 15.8% by 160°C. PLM images displayed Form 12 as irregularly shaped, birefringent crystals. Based on these results, Form 12 was considered anhydrous.

[0143] Example 18: Conversion between Form 11 and Form 12 To determine the thermodynamic stability relationship between Form 11 and Form 12, a slurry conversion experiment was conducted. Specifically, Form 12 (2.5 mg) was added to 1.0 mL of 4% dichloromethane at room temperature. After equilibration for 1 hour, the suspension was filtered to obtain a saturated solution of Form 12. Form 11:Form 12 (1:1) was added to each saturated solution. After stirring for 30 minutes at room temperature, the solid was isolated for XRPD analysis. As shown in Figure 12C, only Form 11 was observed. As a result, Form 11 was determined to be more thermodynamically stable than Form 12 at room temperature. The pH of Form 11 solution (2.5 mg in 1 mL of 4% dichloromethane) and Form 12 solution (2.5 mg in 1 mL of 4% dichloromethane) were measured to be 8.25 and 7.98, respectively.

[0144] Example 19: Crystalline Polymorph Form 13 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of L-arginine in methanol (1:1 molar ratio of L-arginine:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 13A shows the XRPD pattern of Form 13, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 13B, Form 13 exhibited endothermic peaks at 160.8 °C and 230.9 °C, and negligible weight loss before decomposition. PLM images displayed Form 13 as plate-like birefringent crystals. Based on these results, Form 13 was considered anhydrous.

[0145] Example 20: Crystalline Polymorph Form 14 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of Mg(OH)2 in methanol (1:1 molar ratio of Mg(OH)2:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 14A shows the XRPD pattern of Form 14, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 14B, Form 14 exhibited endothermic peaks at 104.5 °C and 137.2 °C and a 5.8% weight loss by 120 °C. PLM images displayed Form 14 as irregularly shaped, birefringent crystals. Based on these results, Form 14 was considered to be a hydrate or solvate.

[0146] Example 21: Crystalline Polymorph Form 15 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of urea in methanol (1:1 molar ratio of urea:Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50°C for 2 hours and then subjected to XRPD. Figure 15A shows the XRPD pattern of Form 15, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 15B, Form 15 exhibited an endothermic peak at 136.0°C and negligible weight loss before decomposition. PLM images displayed Form 15 as irregularly shaped, birefringent crystals. Based on these results, Form 15 was considered an anhydrate.

[0147] Example 22: Crystalline Polymorph Form 16 A solution of crystalline polymorph Form 1 (20 mg in 0.3 mL) was mixed with 0.3 mL of a solution of Mg(OH) in methanol (1:1 molar ratio of Mg(OH) to Form 1) and then stirred at room temperature for 2 to 5 days. The solid was isolated and subjected to XRPD. The wet solid was also dried under vacuum at 50 °C for 2 hours and then subjected to XRPD. Figure 16A shows the XRPD pattern of Form 16, in which no polymorphic change was observed during drying. This crystalline polymorph was also characterized by TGA, DSC, and PLM. As shown by the TGA and DSC data in Figure 16B, Form 16 exhibited an endothermic peak at 168.3 °C and a 1.0% weight loss by 170 °C. PLM images displayed Form 16 as irregularly shaped, birefringent crystals. Based on these results, Form 16 was considered to be a hydrate or solvate.

[0148] General Methodology and Equipment for Examples 2-22 X-ray powder diffraction data were obtained by standard techniques using a Panalytical X'Pert3 powder XRPD on a Si zero-background holder operated with a Cu Kα radiation source at 45 kV and 40 mA (Kα1 (Å): 1.540598, Kα2 (Å): 1.544426, Kα2 / Kα1 intensity ratio: 0.50). 2θ positions were calibrated against a Panalytical Si reference standard disk. Scanning parameters ranged from 3 to 40° 2θ (±0.0131°), with continuous scanning at a rate of approximately 0.04° 2θ / min.

[0149] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were all obtained by standard techniques using a TA Instruments TA Q500 or Q550 (for TGA) and a TA Q2000 (for DSC). The DSC was calibrated with an indium reference standard, and samples were analyzed using a temperature program from 25°C to 350°C at a rate of 10°C / min. The TGA was calibrated using a nickel reference standard, and samples were analyzed using a temperature program from 25°C to 350°C at a rate of 10°C / min.

[0150] Polarized light microscopy (PLM) images were captured on a Nikon DS-Fi2 upright microscope at room temperature.

[0151] Dynamic water vapor sorption (DVS) was measured on an SMS DVS Intrinsic from Surface Measurement Systems (London, United Kingdom) using the following parameters: temperature: 25 °C; sample size: 10–20 mg; gas and flow rate: N and 200 mL / min; dm / dt: 0.002% / min; min. dm / dt stability duration: 10 min; maximum equilibration time: 180 min; relative humidity (RH) range: 0% RH–95% RH–0% RH; RH step size: 10%.

[0152] The Fourier transform infrared spectroscopy (FTIR) spectral data disclosed herein is taken at 2 cm -1 The data were obtained by standard techniques using a Shimadzu FTIR spectrometer in attenuated total reflectance (ATR) mode operating at a resolution of 100 sq. m for a total of 20 scans.

[0153] Biological Example 1: Cell viability of BJAB cells BJAB cells (DSMZ) are maintained in RPMI1640 growth medium + 10% FBS at 37°C / 5% CO2 and used prior to passage 34. Cells are seeded into white Corning Costar 96-well assay plates at 2500 cells / well in 50 μL of medium. Serial dilutions of the test polymorphs are made in cell culture medium / FBS + 0.2% DMSO and transferred to the assay plate in a volume of 50 μL (final 0.1% DMSO). Plates are maintained at 37°C for 72 hours. The effect of compounds on cell proliferation is assessed using Cell Titer Glo reagent (Promega) according to the manufacturer's instructions. Briefly, 100 μL of reagent is added per well, and after 10 minutes of incubation, luminescence values ​​are determined using a plate reader (Tecan F200PRO). The percent of luminescence signal compared to the untreated control was calculated for each compound concentration, and the EC 50 Values ​​are determined from dose-response data by nonlinear regression analysis using Prism (GraphPad). Data are summarized in the composite table above. The mTor inhibitor Torin1 (Liu, et al. (2010) J. Med. Chem. 53, 7146.) is used as a control. Data are summarized in the composite table above.

[0154] Biological Example 2: Measurement of glutathione levels after treatment using three cell lines BJAB, HCT116, and normal human lung fibroblast (NHLF) cells were maintained in RPMI (Wisent), McCoy's (Wisent), or FGM-2 (Lonza) medium, respectively. For total glutathione measurements, 5,000 cells / well (BJAB or HCT116) or 10,000 cells / well (NHLF) were transferred to a clear-bottom 96-well assay plate (Thermo Fisher) in a volume of 50 μL. The plates were incubated overnight at 37°C in 5% CO2 in an unsealed plastic bag containing moist paper. The test polymorphic compound was serially diluted in medium plus 0.4% DMSO, and 50 μL of each dilution was transferred to the assay plate. The assay plate was then incubated at 37°C in 5% CO2 in an unsealed plastic bag containing moist paper for the specified time. For total glutathione measurements, prepare GSH-Glo™ Reagent (Promega) by diluting the provided luciferin-NT (1:100), glutathione S-transferase (1:100), and DTT (1 mM final) in GSH-Glo™ Reaction Buffer. Add 100 μL to the assay plate and incubate at room temperature for 30 minutes before adding 100 μL of luciferin detection reagent. Keep the plate in the dark at room temperature for 10 minutes. Luminescence is measured using a Tecan Infinite 200Pro.

[0155] Biological Example 3: Cell Cycle Analysis of Treated Cells HCT116 cells (3 x 10 ) grown in McCoy's medium supplemented with heat-inactivated fetal bovine serum 5Cells (individual cells) are seeded into 6-well plates and allowed to adhere overnight. Duplicate samples are prepared by serum-starving (0% FBS) cells and treating them with 5 μM of the test polymorph compound or DMSO vehicle control for 24 hours. Two hours before harvesting, replicating DNA is labeled with 10 μM EdU (5-ethynyl-2'-deoxyuridine, Thermo Fisher). Both adherent and suspension cells are harvested and fixed in 4% paraformaldehyde in PBS for 15 minutes at room temperature. Cells are then permeabilized in 0.25% (vol / vol) Triton X-100 / 0.5% BSA / PBS for 20 minutes at room temperature. This is followed by a click reaction with OG488-azide, which detects EdU incorporation as follows: Cells are incubated for 30 minutes in a reaction mixture containing 100 mM Tris-HCl pH 7.6, 4 mM CuSO4, 10 μM OG488-azide, and 100 mM ascorbic acid. Excess reagent is removed by repeated washing in 0.5% BSA / PBS wash buffer. Cells are resuspended in 500 μL of DAPI staining solution (1 μg / mL DAPI and 50 μg / mL RNAse A in PBS).

[0156] Flow cytometry analysis was performed on an LSRII flow cytometer (BD Biosciences) equipped with blue (488 nm), red (633 nm), and violet (405 nm) lasers. OG488 analysis was performed using 488 nm excitation and detection with a 505LP mirror and a 530 / 30BP filter. DAPI analysis was performed using 405 nm excitation and detection with a 442 / 16BP filter. The voltage settings were FSC = 324, SSC = 276, OG488 = 215, and DAPI = 351. Cell cycle analysis with DAPI was performed using a linear axis scale. A logarithmic scale was used for EdU. Data analysis was performed using FCS Express software version 6 (DeNovo Software).

[0157] Various exemplary embodiments of the present disclosure include, but are not limited to, the enumerated embodiments listed below, which can be combined in any number and in any combination that is not technically or logically inconsistent. Embodiment 1. A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a hydrate or solvate thereof. Embodiment 2. The crystalline polymorph of embodiment 1 in anhydrous / solvate-free form. Embodiment 3. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an X-ray powder diffraction (XRPD) pattern comprising four or more (e.g., five or more) peaks selected from 6.1, 7.1, 9.4, 12.7, 18.8, 21.3, and 22.3 (±0.1 degrees 2θ). Embodiment 4. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an X-ray powder diffraction (XRPD) pattern comprising six or more (e.g., each) peaks selected from 6.1, 7.1, 9.4, 12.7, 18.8, 21.3, and 22.3 (±0.1 degrees 2θ). Embodiment 5. The crystalline polymorph of any of embodiments 1-4, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 1A. Embodiment 6. The crystalline polymorph of any of Examples 1-5, characterized in that it provides a differential scanning calorimetry (DSC) thermogram having an endothermic peak at 123±2° C. Embodiment 7. The crystalline polymorph of any of embodiments 1-6, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 1B. Embodiment 8. The crystalline polymorph is 2930 (broad) ± 2 cm -1 , 1709±2cm -1 , 1539±2cm -1 , 1359±2cm -1 , 1238±2cm -1 , 1165±2cm-1 , 1112±2cm -1 , 987±2cm -1 , 875±2cm -1 , 772.50±2cm -1 , and 690±2cm -1 The crystalline polymorph of any one of embodiments 1 to 7, characterized in that it provides a Fourier transform infrared spectroscopy (FTIR) spectrum comprising six or more (e.g., seven or more, or eight or more, or nine or more) peaks selected from: Embodiment 9. The crystalline polymorph of any of embodiments 1-7, wherein the crystalline polymorph provides an FTIR spectrum according to that shown in Figure 1D. Embodiment 10. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.2, 6.6, 7.5, 10.9, 12.4, and 13.3 (±0.1 degrees 2θ). Embodiment 11. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 6.2, 6.6, 7.5, 10.9, 12.4, and 13.3. Embodiment 12. The crystalline polymorph of any of embodiments 1, 2, 10, and 11, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 2. Embodiment 13. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 7.1, 17.7, 18.8, 19.3, and 22.5 (±0.1 degrees 2θ). Embodiment 14. The crystalline polymorph of embodiment 1 or embodiment 2, characterized in that it provides an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 6.4, 7.1, 17.7, 18.8, 19.3, and 22.5. Embodiment 15. The crystalline polymorph of any of embodiments 1, 2, 13, and 14, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 5A. Embodiment 16. The crystalline polymorph of any of Examples 1, 2, and 13-15, characterized in that it provides a DSC thermogram having an endothermic peak at 142±2° C. Embodiment 17. The crystalline polymorph of any of embodiments 1, 2, and 13-16, wherein the crystalline polymorph is characterized by providing a DSC thermogram according to that shown in Figure 5B. Embodiment 18. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph is characterized by providing an X-ray powder diffraction (XRPD) pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 9.1, 14.3, 16.6, 18.4, 20.1, and 21.9 (2θ±0.1 degrees). Embodiment 19. The crystalline polymorph of embodiment 1 or embodiment 2, wherein the crystalline polymorph provides an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 6.4, 9.1, 14.3, 16.6, 18.4, 20.1, and 21.9. Embodiment 20. The crystalline polymorph of any of embodiments 1, 2, 18, and 19, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 8. Embodiment 21. The crystalline polymorph of embodiment 1, which is in the form of a hydrate or solvate of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid. Embodiment 22. The crystalline polymorph of embodiment 21, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 14.4, 16.2, 17.5, 19.1, 22.8, and 24.0 (±0.1 degrees 2θ). Embodiment 23. The crystalline polymorph of embodiment 21, wherein the crystalline polymorph provides an XRPD pattern comprising six or more (e.g., each) peaks selected from 6.4, 14.4, 16.2, 17.5, 19.1, 22.8, and 24.0 (±0.1 degrees 2θ). Embodiment 24. The crystalline polymorph of any of embodiments 21-23, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 3A. Embodiment 25. The crystalline polymorph of any of Examples 21-24, characterized in that it provides a DSC thermogram with endothermic peaks at 91±2°C and 118±2°C. Embodiment 26. The crystalline polymorph of any of embodiments 21 to 25, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 3B. Embodiment 27. The crystalline polymorph of embodiment 21, wherein it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 9.9, 14.9, 19.4, 21.4, 23.5, and 24.1 (±0.1 degrees 2θ). Embodiment 28. The crystalline polymorph of embodiment 21, wherein the crystalline polymorph provides an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 9.9, 14.9, 19.4, 21.4, 23.5, and 24.1. Embodiment 29. The crystalline polymorph of any of embodiments 21, 27, and 28, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 4A. Embodiment 30. The crystalline polymorph of any of Examples 21 and 27-29, characterized in that it provides a DSC thermogram with endothermic peaks at 49±2° C. and 73±2° C. Embodiment 31. The crystalline polymorph of any of Examples 21 and 27-30, characterized in that it provides a DSC thermogram according to that shown in Figure 4B. Embodiment 32. The crystalline polymorph of embodiment 21, wherein it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.8, 11.5, 14.5, 17.3, 20.8, and 22.0 (±0.1 degrees 2θ). Embodiment 33. The crystalline polymorph of embodiment 21, characterized in that it provides an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 5.8, 11.5, 14.5, 17.3, 20.8, and 22.0. Embodiment 34. The crystalline polymorph of any of embodiments 21, 32, and 33, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 6A. Embodiment 35. The crystalline polymorph of any of Examples 21 and 32-34, characterized in that it provides a DSC thermogram with endothermic peaks at 64±2°C and 120±2°C. Embodiment 36. The crystalline polymorph of any of embodiments 21 and 32-35, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 6B. Embodiment 37. The crystalline polymorph of embodiment 21, wherein it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.7, 7.0, 11.5, 13.1, 14.4, and 22.1 (±0.1 degrees 2θ). Embodiment 38. The crystalline polymorph of embodiment 21, wherein the crystalline polymorph can be characterized by providing an XRPD pattern comprising each of the following peaks (±0.1 degrees 2θ): 6.7, 7.0, 11.5, 13.1, 14.4, 17.2, and 22.1. Embodiment 39. The crystalline polymorph of any of embodiments 21, 37, and 38, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 7A. Embodiment 40. The crystalline polymorph of any of Examples 21 and 37-39, characterized in that it provides a DSC thermogram with endothermic peaks at 58±2°C and 108±2°C. Embodiment 41. The crystalline polymorph of any of embodiments 21 and 37-40, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 7B. Embodiment 42. A crystalline polymorph of potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof. Embodiment 43. The crystalline polymorph of embodiment 42, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 7.1, 10.2, 12.2, 14.2, 19.0, 19.4, and 24.5 (±0.1 degrees 2θ). Embodiment 44. The crystalline polymorph of embodiment 42, wherein the crystalline polymorph provides an XRPD pattern comprising each peak selected from 6.4, 7.1, 10.2, 12.2, 14.2, 19.0, 19.4, and 24.5 (±0.1 degrees 2θ). Embodiment 45. The crystalline polymorph of any of embodiments 42-44, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 9A. Embodiment 46. The crystalline polymorph of any of Examples 42-45, characterized in that it provides a DSC thermogram with an endothermic peak at 113±2° C. Embodiment 47. The crystalline polymorph of any of embodiments 42 to 46, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 9B. Embodiment 48. The crystalline polymorph of embodiment 42, wherein the crystalline polymorph is characterized by providing an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.6, 5.8, 7.4, 9.5, 12.8, 15.5, and 19.5 (2θ±0.1 degrees). Embodiment 49. The crystalline polymorph of embodiment 42, wherein the crystalline polymorph is characterized by providing an XRPD pattern comprising each of 5.6, 5.8, 7.4, 9.5, 12.8, 15.5, and 19.5 (2θ±0.1 degrees). Embodiment 50. The crystalline polymorph of any of embodiments 42, 48, and 49, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 10A. Embodiment 51. The crystalline polymorph of any of Examples 42 and 48-50, characterized in that it provides a DSC thermogram with endothermic peaks at 62±2°C and 144±2°C. Embodiment 52. The crystalline polymorph of any of embodiments 42 and 48-51, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 10B. Embodiment 53. A crystalline polymorph of sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof. Embodiment 54. The crystalline polymorph of embodiment 53, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 7.0, 10.4, 12.2, 13.1, 14.0, 18.8, and 24.5 (±0.1 degrees 2θ). Embodiment 55. The crystalline polymorph of embodiment 53, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 7.0, 10.4, 12.2, 13.1, 14.0, 18.8, and 24.5 (±0.1 degrees 2θ). Embodiment 56. The crystalline polymorph of any of embodiments 53-55, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 11A. Embodiment 57. The crystalline polymorph of any of Examples 53-56, characterized in that it provides a DSC thermogram with an endothermic peak at 76±2°C. Embodiment 58. The crystalline polymorph of any of embodiments 53 to 57, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 11B. Embodiment 59. The crystalline polymorph of embodiment 53, wherein it provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 3.8, 7.5, 13.0, 16.2, 17.0, 17.8, 20.0, 22.7, and 23.7 (±0.1 degrees 2θ). Embodiment 60. The crystalline polymorph of embodiment 53, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 3.8, 7.5, 13.0, 16.2, 17.0, 17.8, 20.0, 22.7, and 23.7 (±0.1 degrees 2θ). Embodiment 61. The crystalline polymorph of any of embodiments 53, 59, and 60, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 12A. Embodiment 62. The crystalline polymorph of any of Examples 53 and 59-61, characterized in that it provides a DSC thermogram with an endothermic peak at 153±2°C. Embodiment 63. The crystalline polymorph of any of embodiments 53 and 59-62, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 12B. Embodiment 64. A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, optionally in the form of a hydrate or solvate thereof. Embodiment 65. The crystalline polymorph of embodiment 64, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 10.3, 16.6, 18.7, 20.7, 21.3, 25.0, and 28.2 (±0.1 degrees 2θ) L-arginine. Embodiment 66. The crystalline polymorph of embodiment 64, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 10.3, 16.6, 18.7, 20.7, 21.3, 25.0, and 28.2 (±0.1 degrees 2θ) L-arginine. Embodiment 67. The crystalline polymorph of any of embodiments 64-66, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 13A. Embodiment 68. The crystalline polymorph of any of Examples 64-67, characterized in that it provides a DSC thermogram with an endothermic peak at 231±2° C. Embodiment 69. The crystalline polymorph of any of embodiments 64 to 68, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 13B. Embodiment 70. A crystalline polymorph of magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof. Embodiment 71. The crystalline polymorph of embodiment 70, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.4, 15.8, 16.8, 18.7, 25.1, and 38.2 (±0.1 degrees 2θ). Embodiment 72. The crystalline polymorph of embodiment 70, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 5.4, 15.8, 16.8, 18.7, 25.1, and 38.2 (±0.1 degrees 2θ). Embodiment 73. The crystalline polymorph of any of embodiments 70-72, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 14A. Embodiment 74. The crystalline polymorph of any of Examples 70-73, characterized in that it provides a DSC thermogram with endothermic peaks at 105±2°C and 137±2°C. Embodiment 75. The crystalline polymorph of any of embodiments 70-74, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 14B. Embodiment 76. A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, optionally in the form of a hydrate or solvate thereof. Embodiment 77. The crystalline polymorph of embodiment 76, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.7, 9.8, 16.5, 17.3, 17.8, 20.0, 21.1, 23.5, and 26.1 (±0.1 degrees 2θ). Embodiment 78. The crystalline polymorph of embodiment 76, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 5.7, 9.8, 16.5, 17.3, 17.8, 20.0, 21.1, 23.5, and 26.1. Embodiment 79. The crystalline polymorph of any of embodiments 76-78, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 15A. Embodiment 80. The crystalline polymorph of any of Examples 76-79, characterized in that it provides a DSC thermogram with an endothermic peak at 136±2°C. Embodiment 81. The crystalline polymorph of any of embodiments 76-80, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 15B. Embodiment 82. A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline, optionally in the form of a hydrate or solvate thereof. Embodiment 83. The crystalline polymorph of embodiment 82, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 7.7, 7.9, 11.9, 15.9, 17.4, 19.7, and 21.4 (±0.1 degrees 2θ). Embodiment 84. The crystalline polymorph of embodiment 82, wherein the crystalline polymorph provides an XRPD pattern comprising each of peaks selected from 7.7, 7.9, 11.9, 15.9, 17.4, 19.7, and 21.4 (±0.1 degrees 2θ). Embodiment 85. The crystalline polymorph of any of embodiments 82-84, wherein the crystalline polymorph provides an XRPD pattern according to that shown in Figure 16A. Embodiment 86. The crystalline polymorph of any of Examples 82-85, characterized in that it provides a DSC thermogram with an endothermic peak at 168±2°C. Embodiment 87. The crystalline polymorph of any of embodiments 82-86, wherein the crystalline polymorph provides a DSC thermogram according to that shown in Figure 16B. Embodiment 88. potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, Magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally a hydrate or solvate salt thereof, selected from 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline. Embodiment 89. A pharmaceutical composition comprising the crystalline polymorph described in any of embodiments 1-87 or the salt described in embodiment 88 together with a pharmaceutically acceptable excipient, diluent, or carrier. Embodiment 90. A method for treating a hyperproliferative disorder, e.g., cancer, in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline polymorph described in any of embodiments 1-87 or a salt described in embodiment 88. Embodiment 91. The crystalline polymorph of any of embodiments 1-87 or the salt of embodiment 88 for use in the treatment of a hyperproliferative disorder, such as cancer. Embodiment 92. Use of a crystalline polymorph according to any of embodiments 1 to 8 or a salt according to embodiment 88 for the preparation of a medicament for the treatment of a hyperproliferative disorder, such as cancer. Embodiment 93. A method for inhibiting cell cycle progression in cancer cells, comprising contacting the cancer cells with an effective amount of a crystalline polymorph of any of embodiments 1-87 or a salt of embodiment 88. Embodiment 94. The method of embodiment 93, wherein cell cycle progression is inhibited in the G0 / G1 phase of the cell cycle. Embodiment 95. A method for inducing apoptosis in cancer cells, comprising contacting cancer cells with an effective amount of the crystalline polymorph of any of embodiments 1-87 or the salt of embodiment 88. Embodiment 96. A method for inducing a cytotoxic effect on cancer cells, comprising contacting the cancer cells with an effective amount of the crystalline polymorph of any of embodiments 1-87 or the salt of embodiment 88. Embodiment 97. A method for inhibiting glutathione synthesis in cancer cells, comprising contacting cancer cells with an effective amount of the crystalline polymorph of any of embodiments 1-87 or the salt of embodiment 88. Embodiment 98. The method, crystalline polymorph, salt, or use of any one of embodiments 90 to 97, wherein the cancer is a hematopoietic cancer. Embodiment 99. The cancer is selected from the group consisting of lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL)), leukemia (e.g., acute lymphoblastic leukemia (ALL)), 98. The method, crystalline polymorph, salt, or use of any of embodiments 90-97, wherein the patient is selected from acute myeloid leukemia (AML), acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia (acute mixed lineage leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia), and plasma cell neoplasms (e.g., multiple myeloma). Embodiment 100. The cancer is selected from the group consisting of adrenocortical carcinoma, adrenocortical carcinoma, AIDS-associated cancers (such as, for example, Kaposi's sarcoma, AIDS-associated lymphoma, Burkitt's lymphoma, and primary CNS lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., childhood cerebellar or cerebral), bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, bone cancer (e.g., Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma), brain tumors (e.g., glioblastoma multiforme, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, oligodendroglioma, supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), and / or glioma. tumors), brain stem glioma, breast cancer, bronchial tumor, gastrointestinal carcinoid tumor, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumor, central nervous system cancer (e.g., atypical teratoma / rhabdomyosarcomatoid tumor, embryonal tumor, and germ cell tumor), cervical cancer, childhood cancer, chondrosarcoma, chronic myeloproliferative neoplasia, colon and rectal cancer, craniopharyngioma, desmoplastic small round cell tumor, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid hemangioendothelioma (EHE), esophageal cancer, esophageal neuroblastoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer (e.g., intraocular melanoma) , retinoblastoma), fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease (GTD), glioma, hairy cell leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), hepatocellular (liver) cancer, histiocytosis, Langerhans cell, hypopharyngeal cancer, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute myeloid leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myeloid leukemia (CMML), aggressive NK cell leukemia (acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia), lip cancer, oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma), pulmonary carcinoid tumor, lymphoma (e.g., Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma,diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL), male breast cancer, meningioma, mesothelioma, midline tract carcinoma involving the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, plasma cell neoplasms (e.g., multiple myeloma), mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia and chronic myeloproliferative neoplasia, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma (NPC), neuroblastoma, oral cavity cancer, lip cancer and oral and oropharyngeal cancer, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (e.g., pancreatic islet cell tumors), 98. The method, crystalline polymorph, salt, or use of any of embodiments 90 to 97, wherein the cancer is selected from the group consisting of paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sézary syndrome, skin cancer (e.g., basal and squamous cell carcinoma, Merkel cell carcinoma, melanoma), small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric (stomach) cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer and sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor. Embodiment 101. The cancer is selected from the group consisting of appendiceal cancer, osteosarcoma (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), bronchial tumor, cancer of unknown primary, chronic myeloproliferative neoplasia, colon and rectal cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)), leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia (acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia), lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and leukemia of unknown primary cancer). 98. The method, crystalline polymorph, salt, or use of any of embodiments 90-97, wherein the tumor is selected from the group consisting of lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL), plasma cell neoplasms (e.g., multiple myeloma), myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasia and chronic myeloproliferative neoplasia, pancreatic cancer and pancreatic neuroendocrine tumors (e.g., pancreatic islet cell tumors), small intestine cancer, soft tissue sarcoma, and squamous cell carcinoma. Embodiment 102. The method, crystalline polymorph, salt, or use of any one of embodiments 90-97, wherein the cancer is diffuse large B-cell lymphoma. Embodiment 103. The method, crystalline polymorph, salt, or use of any of embodiments 90 to 97, wherein the cancer is colorectal cancer. Embodiment 104. The method, crystalline polymorph, salt, or use of any one of embodiments 90 to 103, wherein the cancer has a mutant KRAS gene. Embodiment 105. The method, crystalline polymorph, salt, or use of any one of embodiments 90 to 103, wherein the cancer has a heterozygous mutant KRAS gene.

[0158] Throughout this specification, various references have been made to patents and printed publications. The cited references and printed publications are individually incorporated herein by reference in their entirety.

[0159] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Thus, the invention is not limited to that precisely as shown and described.

Claims

1. A crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a salt thereof and / or a hydrate or solvate thereof.

2. 2. The crystalline polymorph of claim 1, wherein said polymorph is a polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid based compound, optionally in the form of a salt thereof and / or a hydrate or solvate thereof.

3. The crystalline polymorph of claim 2 in anhydrous / solvate-free form.

4. The crystalline polymorph of claim 3, wherein the crystalline polymorph provides an X-ray powder diffraction (XRPD) pattern comprising four or more (e.g., five or more) peaks selected from 6.1, 7.1, 9.4, 12.7, 18.8, 21.3, and 22.3 (2θ±0.1 degrees).

5. The crystalline polymorph of claim 3, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.2, 6.6, 7.5, 10.9, 12.4, and 13.3 (2θ±0.1 degrees).

6. 4. The crystalline polymorph of claim 3, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 9.1, 14.3, 16.6, 18.4, 20.1, and 21.9 (2θ±0.1 degrees).

7. The crystalline polymorph of claim 1, which is in the form of a hydrate or solvate of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid.

8. 8. The crystalline polymorph of claim 7, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 14.4, 16.2, 17.5, 19.1, 22.8, and 24.0 (2θ±0.1 degrees).

9. 8. The crystalline polymorph of claim 7, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 9.9, 14.9, 19.4, 21.4, 23.5, and 24.1 (2θ±0.1 degrees).

10. 8. The crystalline polymorph of claim 7, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.8, 11.5, 14.5, 17.3, 20.8, and 22.0 (2θ±0.1 degrees).

11. 8. The crystalline polymorph of claim 7, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.7, 7.0, 11.5, 13.1, 14.4, 17.2, and 22.1 (2θ±0.1 degrees).

12. The crystalline polymorph of claim 1, which is a crystalline polymorph of potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof.

13. 13. The crystalline polymorph of claim 12, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 6.4, 7.1, 10.2, 12.2, 14.2, 19.0, 19.4, and 24.5 (2θ±0.1 degrees).

14. 13. The crystalline polymorph of claim 12, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.6, 5.8, 7.4, 9.5, 12.8, 15.5, and 19.5 (2θ±0.1 degrees).

15. The crystalline polymorph of claim 1, which is a crystalline polymorph of sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof.

16. 16. The crystalline polymorph of claim 15, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 7.0, 10.4, 12.2, 13.1, 14.0, 18.8, and 24.5 (2θ±0.1 degrees).

17. 16. The crystalline polymorph of claim 15, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 3.8, 7.5, 13.0, 16.2, 17.0, 17.8, 20.0, 22.7, and 23.7 (2θ±0.1 degrees).

18. The crystalline polymorph of claim 1, which is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, optionally in the form of a hydrate or solvate thereof.

19. 19. The crystalline polymorph of claim 18, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 10.3, 16.6, 18.7, 20.7, 21.3, 25.0, and 28.2 (2θ±0.1 degrees) L-arginine.

20. The crystalline polymorph of claim 1, which is a crystalline polymorph of magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, optionally in the form of a hydrate or solvate thereof.

21. 21. The crystalline polymorph of claim 20, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.4, 15.8, 16.8, 18.7, 25.1, and 38.2 (2θ±0.1 degrees).

22. The crystalline polymorph of claim 1, which is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, optionally in the form of a hydrate or solvate thereof.

23. 23. The crystalline polymorph of claim 22, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 5.7, 9.8, 16.5, 17.3, 17.8, 20.0, 21.1, 23.5, and 26.1 (2θ±0.1 degrees).

24. The crystalline polymorph of claim 1, which is a crystalline polymorph of 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline, optionally in the form of a hydrate or solvate thereof.

25. 25. The crystalline polymorph of claim 24, wherein the crystalline polymorph provides an XRPD pattern comprising four or more (e.g., five or more) peaks selected from 7.7, 7.9, 11.9, 15.9, 17.4, 19.7, and 21.4 (2θ±0.1 degrees).

26. potassium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, sodium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, magnesium 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid urea, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-arginine, 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in the form of a hydrate or solvate thereof, selected from 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid L-proline.

27. A pharmaceutical composition comprising the crystalline polymorph of any one of claims 1 to 25 or the salt of claim 26 together with a pharmaceutically acceptable excipient, diluent, or carrier.

28. 27. A method for treating a hyperproliferative disorder, such as cancer, in a subject in need thereof, comprising administering to said subject an effective amount of the crystalline polymorph of any of claims 1 to 25 or the salt of claim 26.

29. 27. A method for inhibiting cell cycle progression in cancer cells, said method comprising contacting said cancer cells with an effective amount of the crystalline polymorph of any of claims 1 to 25 or the salt of claim 26.

Images