Crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and uses thereof

Abstract

The present disclosure relates to crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and uses thereof. The present disclosure relates to crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido}-acetic acid. In particular, the present disclosure relates to a) a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ("Compound I"); b) a pharmaceutical composition comprising one or more crystalline forms of Compound I and optionally comprising a pharmaceutically acceptable carrier; c) methods of treating a type of diabetes or other condition by administering one or more crystalline forms of Compound I; and d) a process for preparing a crystalline form of Compound I.

Description

[0001] This application is a divisional application of the Chinese Patent Application No. 202180056233.1 with the title of “Crystalline Forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic Acid and Uses Thereof” filed on June 07, 2021, which corresponds to the PCT Application No. PCT / US2021 / 036082 with the filing date of June 07, 2021, both of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to a) crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (“Compound I” or “API”); b) pharmaceutical compositions comprising one or more crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and optionally a pharmaceutically acceptable carrier; and c) methods of treating a type of diabetes and other conditions by administering one or more crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid to a subject in need thereof. BACKGROUND

[0003] Glucokinase (“GK”) is a key regulator of glucose homeostasis and acts as a physiological glucose sensor, changing its conformation, activity, and / or intracellular location in parallel with changes in glucose concentration. GK has two major distinguishing features that make it an excellent choice for glycemic control. First, its expression is mostly restricted to tissues that require glucose sensing (mainly the liver and pancreatic beta cells). Second, GK is able to sense changes in serum glucose levels and modulate changes in hepatic glucose metabolism (which in turn modulate the balance between hepatic glucose production (HGP) and glucose consumption) and changes in beta cell insulin secretion. The concept of GK activation for the treatment of diabetes is attractive because it has been shown to be effective and safe in normalizing blood glucose in animal models of both type 1 and type 2 diabetes through a mechanism that is completely different from the actions of current marketed anti-diabetic therapies.

[0004] Although several small-molecule activators of GK are in clinical development, their initial therapeutic prospects are hampered by hypoglycemia, elevated triglyceride (TG) levels, and loss of efficacy over time. These adverse events (AEs) are associated with ongoing β-cell activation. Compound I (a liver-selective agent) does not induce similar antagonistic effects. (Vella et al., Science Translational Medicine, January 16, 2019).

[0005] Compound I is an orally administered, small-molecule, liver-selective glucokinase activator that improves glycemic control and, at therapeutically relevant doses, does not induce hypoglycemia, dyslipidemia, or pathological increases in glycogen and triglycerides in the liver. (Vella et al., Science Translational Medicine, January 16, 2019).

[0006] Not all compounds that act as GK activators possess the properties most likely to become useful therapeutic agents. Some of these properties include high affinity for glucokinase, duration of glucokinase activation, oral bioavailability, tissue distribution, and stability (e.g., ability to be formulated or crystallized, shelf life). Favorable properties can lead to improved safety, tolerability, efficacy, therapeutic index, patient compliance, cost-effectiveness, ease of manufacture, etc.

[0007] Furthermore, the isolation and commercial-scale preparation of the corresponding pharmaceutical formulation of Compound I, with acceptable solid-state properties (including chemical stability, thermal stability, solubility, hygroscopicity and / or particle size), compound manufacturability (including yield, impurity removal during crystallization, filtration properties, drying properties and grinding properties), and formulation feasibility (including stability relative to pressure or compression during tableting) present many challenges.

[0008] Therefore, there is a need for one or more crystalline forms of Compound I that possess these properties in an acceptable balance and can be used to prepare pharmaceutically acceptable solid dosage forms. Summary of the Invention

[0009] In one aspect, this disclosure relates to the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazolyl-5-ylthioalkyl}-acetic acid. In one aspect, the crystalline form is anhydrous. In another aspect, the crystalline form is solvated.

[0010] In one aspect, this disclosure relates to the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazolyl-5-ylthioalkyl}-acetic acid of formula (I).

[0011]

[0012] The crystalline form is selected from:

[0013] a) a crystalline form characterized by an XRPD pattern having peaks at 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees two-theta;

[0014] b) a crystalline form characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees two-theta;

[0015] c) a crystalline form characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees two-theta;

[0016] d) a crystalline form characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, and 26.4 ± 0.2 degrees two-theta;

[0017] e) a crystalline form characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.2 degrees two-theta;

[0018] f) a crystalline form characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, and 16.8 ± 0.2 degrees two-theta;

[0019] g) a crystalline form characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, and 21.9 ± 0.2 degrees two-theta;

[0020] h) a crystalline form characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, and 8.5 ± 0.2 degrees two-theta;

[0021] i) a crystalline form characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees two-theta; and

[0022] j) a crystalline form characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0023] In one aspect, the present disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees two-theta.

[0024] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an endothermic peak beginning at about 160 °C as determined by DSC.

[0025] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm -1 In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm

[0026] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm Figure 4 13 In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm

[0027] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about

[0028] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is Form A.

[0029] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees 2-theta.

[0030] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an endothermic peak beginning at about 166 °C as determined by DSC.

[0031] ​In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1310.1 ± 2.0, 1514.4 ± 2.0, and 1661.3 ± 2.0 cm -1 In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1310.1 ± 2.0, 1514.4 ± 2.0, and 1661.3 ± 2.0 cm

[0032] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1310.1 ± 2.0, 1514.4 ± 2.0, and 1661.3 ± 2.0 cm Figure 8 13 In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an IR pattern having peaks at 1310.1 ± 2.0, 1514.4 ± 2.0, and 1661.3 ± 2.0 cm

[0033] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell indexed as a simple monoclinic crystal system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell with an a value of about In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell with an a value of about In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell with a volume of about In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid has a unit cell with a volume of about

[0034] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is Form B.

[0035] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees 2-theta.

[0036] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is characterized by an endothermic peak beginning at about 149 °C as determined by DSC.

[0037] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl} -acetic acid is a dichloromethane solvate.

[0038] ​In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell indexed to the simple monoclinic system. In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with an a value of about an b value of about and a c value of about In another aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid has a unit cell with a volume of about

[0039] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form C.

[0040] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, and 26.4 ± 0.2 degrees two-theta.

[0041] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is characterized by an endothermic peak beginning at about 147 °C as determined by DSC.

[0042] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is characterized by a solid state NMR substantially as shown in Figure 13 13 C.

[0043] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form D.

[0044] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.2 degrees two-theta.

[0045] ​​In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is characterized by an endothermic peak starting at about 171 °C as determined by DSC.

[0046] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form E.

[0047] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, and 16.8 ± 0.2 degrees 2-theta.

[0048] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form F.

[0049] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, and 21.9 ± 0.2 degrees 2-theta.

[0050] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form G.

[0051] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, and 8.5 ± 0.2 degrees 2-theta.

[0052] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form H.

[0053] In one aspect, the present disclosure relates to a crystalline form of {2-[3- cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees 2-theta.

[0054] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form I.

[0055] In one aspect, the disclosure relates to a crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid characterized by an XRPD pattern having peaks at 5.9±0.2, 17.4±0.2, and 18.8±0.2 degrees two-theta.

[0056] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is characterized by an endothermic peak beginning at about 164 °C as determined by DSC.

[0057] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form J.

[0058] In some aspects, the crystalline form is substantially free of other polymorphic forms. In some aspects, the crystalline form has a polymorphic purity of at least about 80%.

[0059] In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. In one aspect, the crystalline form of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is Form A.

[0060] In some aspects, the disclosure relates to a pharmaceutical composition comprising any one or more of the crystalline forms discussed above and a pharmaceutically acceptable carrier, diluent, excipient, or mixture thereof.

[0061] In some aspects, the disclosure relates to a method of treating a type of diabetes or other condition, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition discussed above. In some aspects, the type of diabetes is Type 1 diabetes. In some aspects, the type of diabetes is Type 2 diabetes.

[0062] In some aspects, the pharmaceutical composition is administered orally. In some aspects, the pharmaceutical composition is administered as a tablet. In some aspects, up to about 2000 mg of {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid is administered to the patient per day.

[0063] In some aspects, the present disclosure provides a method of preparing a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid, wherein the crystalline form is selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 is a powder X-ray diffraction pattern ("XRPD") corresponding to crystalline Form A.

[0065] Figure 2A is a differential scanning calorimetry thermogram ("DSC") corresponding to crystalline Form A.

[0066] Figure 2B is a thermogravimetric analysis thermogram ("TGA") corresponding to crystalline Form A.

[0067] Figure 3 is an infrared ("IR") spectrum corresponding to crystalline Form A.

[0068] Figure 4 is a solid state NMR corresponding to crystalline Form A. 13 C Solid State NMR.

[0069] Figure 5 is an XRPD corresponding to crystalline Form B.

[0070] Figure 6A is a DSC corresponding to crystalline Form B.

[0071] Figure 6B is a TGA corresponding to crystalline Form B.

[0072] Figure 7 is an IR spectrum corresponding to crystalline Form B.

[0073] Figure 8 is a solid state NMR corresponding to crystalline Form B. 13 C Solid State NMR.

[0074] Figure 9 is an XRPD corresponding to crystalline Form C.

[0075] Figure 10A is a DSC corresponding to crystalline Form C.

[0076] Figure 10B is a TGA corresponding to crystalline Form C.

[0077] Figure 11 is an XRPD corresponding to crystalline Form D.

[0078] Figure 12A is a DSC corresponding to crystalline Form D.

[0079] Figure 12B is a TGA corresponding to crystalline Form D.

[0080] Figure 13 is a DSC corresponding to crystalline Form D. 13 C Solid State NMR.

[0081] Figure 14 is an XRPD corresponding to crystalline Form E.

[0082] Figure 15A is a DSC corresponding to crystalline Form E.

[0083] Figure 15B is a TGA corresponding to crystalline Form E.

[0084] Figure 16 is an XRPD corresponding to crystalline Form F.

[0085] Figure 17 is an XRPD corresponding to crystalline Form G.

[0086] Figure 18 is an XRPD corresponding to crystalline Form H.

[0087] Figure 19 is an XRPD corresponding to crystalline Form I.

[0088] Figure 20 is an XRPD corresponding to crystalline Form J.

[0089] Figure 21A is a DSC corresponding to crystalline Form J.

[0090] Figure 21B is a TGA corresponding to crystalline Form J. DETAILED DESCRIPTION

[0091] I. DEFINITIONS

[0092] To facilitate the understanding of the present disclosure set forth herein, a number of terms are defined below.

[0093] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0094] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), and the terms "one or more," and "at least one" are used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."

[0095] Further, as used herein, "and / or" shall

[0096] The term "Compound I" refers to the compound {2-[3-cyclohexyl-3-(trans-4- propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.

[0097] The term "subject" refers to an animal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "subject" and "patient" are used interchangeably herein, for example, to refer to a mammalian subject, such as a human subject.

[0098] The term "treatment" means including alleviating or abrogating one or more of the symptoms of a disorder, disease, or condition; or reducing the cause of the disorder, disease, or condition itself.

[0099] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable diluent," or "pharmaceutically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5thEd., Rowe et al. Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rdEd., Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference).

[0100] The terms "about" or "approximately" mean an acceptable limit of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain aspects, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" or "approximately" mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0101] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, for treating, delaying onset of, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" can be an optical isomer of a compound described herein.

[0102] The term "solvate" or "solvated" refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent, bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. Where the solvent includes ethanol, the compound can be an ethanol solvate.

[0103] The term "polymorph" as used herein refers to a crystalline form of a compound or a salt, hydrate or solvate thereof, in a specific crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein refers to a solid state form consisting of orderly arranged structural units. Different crystalline forms of the same compound or a salt, hydrate or solvate thereof, result from different packing of the molecules in the solid state, which leads to different crystal symmetries and / or cell parameters. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton PA, 173 (1990); United States Pharmacopeia, 23rd Ed., 1843-1844 (1995) (incorporated herein by reference).

[0104] Crystalline forms are most often characterized by X-ray powder diffraction (XRPD). The reflected XRPD pattern (peaks, usually expressed in degrees 2-theta) is often considered a fingerprint of a particular crystalline form. The relative intensities of the XRPD peaks can vary greatly depending on sample preparation techniques, crystal size distribution, filters, sample mounting procedures, and the particular instrument used, among others. In some cases, depending on the type or setting of the instrument, new peaks can be observed or existing peaks can disappear. In some cases, depending on the type or setting of the instrument, the sensitivity of the instrument, the measurement conditions, and / or the purity of the crystalline form, any particular peak in the XRPD pattern can appear as a single peak, a doublet, a triplet, a quartet, or a multiplet. In some cases, any particular peak in the XRPD can appear in a symmetrical shape or an asymmetrical shape, e.g., with a shoulder. Furthermore, instrument variations and other factors can affect the 2-theta values. Skilled artisans, with an understanding of these variations, are able to use XRPD, as well as using other known physico-chemical techniques, to discern or determine defining characteristics or properties of a particular crystalline form.

[0105] The term "anhydrous" or "anhydrous" as applied to a compound refers to a solid state in which the compound contains no structural water within the crystal lattice.

[0106] The use of the terms "including" and "containing" are based on a broad and inclusive basis and are used in their plain, ordinary sense, unless otherwise specifically noted. The use of the terms "comprising" and "comprise" are based on a broad and inclusive basis and are used in their plain, ordinary sense, unless otherwise specifically noted.

[0107] For all embodiments disclosed herein, peak position reproducibility is associated with values of 2-theta degrees (XRPD), ppm (1H NMR), and cm-1 (IR). Thus, it should be understood that all peaks disclosed herein have the value disclosed ± the peak position reproducibility associated with each analytical technique. XRPD peak position reproducibility is ± 0.2 degrees 2-theta. 13 1H NMR peak position reproducibility is ± 0.2 ppm. IR peak position reproducibility is ± 2 cm-1. -1 13 1H NMR peak position reproducibility is ± 0.2 ppm. IR peak position reproducibility is ± 2 cm-1. -1 .

[0108] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present application, including definitions, controls. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. All publications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference for all purposes.

[0109] II. Crystalline Forms

[0110] In one aspect, the present disclosure relates to crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid. In one aspect, the crystalline form is anhydrous, as determined by 1 H NMR. In another aspect, the crystalline form is solvated, as determined by 1 H NMR.

[0111] In one aspect, the present disclosure relates to crystalline forms of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid of Formula (I)

[0112]

[0113] The crystalline form is selected from:

[0114] a) a crystalline form characterized by an XRPD pattern having peaks at 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees 2-theta; ​

[0115] b) a crystalline form characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees 2-theta;

[0116] c) a crystalline form characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees 2-theta;

[0117] d) a crystalline form characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, and 26.4 ± 0.2 degrees 2-theta;

[0118] e) a crystalline form characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.2 degrees 2-theta;

[0119] f) a crystalline form characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, and 16.8 ± 0.2 degrees 2-theta;

[0120] g) a crystalline form characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, and 21.9 ± 0.2 degrees 2-theta;

[0121] h) a crystalline form characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, and 8.5 ± 0.2 degrees 2-theta;

[0122] i) a crystalline form characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees 2-theta; and

[0123] j) a crystalline form characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees 2-theta.

[0124] A. Crystalline Form A

[0125] In one aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees 2-theta. In one aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 8.7 ± 0.2, 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees 2-theta. In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 1. Figure 1

[0126] In one aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, expressed in degrees 2-theta and relative intensity, in Table 1:​

[0127] Table 1

[0128]

[0129]

[0130] Relative intensities can vary depending on crystal size and morphology.

[0131] In one aspect, the crystalline form of Compound I is characterized by an endothermic peak beginning at about 160 °C as determined by DSC. In one aspect, the crystalline form of Compound I is characterized by a DSC curve substantially as shown in Figure 2A In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in Figure 2B

[0132] In one aspect, the crystalline form of Compound I is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm -1 In one aspect, the crystalline form of Compound I is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, 1238.7 ± 2.0, and 1313.2 ± 2.0 cm -1 In one aspect, the crystalline form of Compound I is characterized by the following IR peaks in Table 2.

[0133] Table 2

[0134]

[0135]

[0136]

[0137] In one aspect, the crystalline form of Compound I is characterized by an IR pattern substantially as shown in Figure 3

[0138] In one aspect, the crystalline form of Compound I is characterized by a C solid state NMR substantially as shown in 13 Figure 4

[0139] In one aspect, the crystalline form is anhydrous, as determined by 1 H NMR.

[0140] In one aspect, the crystalline form of Compound I has a unit cell indexed to a simple monoclinic system. In another aspect, the crystalline form of Compound I has an a value of about b value of about​​​​ And the value of c is approximately The unit cell. In another aspect, the crystalline form of compound I has a volume of approximately... The unit cell.

[0141] In one respect, the crystalline form of compound I is form A.

[0142] B. Crystalline Form B

[0143] In one aspect, this disclosure relates to the crystalline form of compound I, characterized by XRPD plots showing peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees 2θ. In another aspect, this disclosure relates to the crystalline form of compound I, characterized by XRPD plots showing peaks at 11.0 ± 0.2, 11.6 ± 0.2, 17.8 ± 0.2, and 21.1 ± 0.2 degrees 2θ.

[0144] In one respect, the crystalline form of compound I is obtained by essentially as follows Figure 5 The XRPD diagram shown is used to characterize it.

[0145] In one respect, the crystalline form of compound I was characterized by the following XRPD plots in Table 3, expressed in terms of 2θ degrees and relative intensities:

[0146] Table 3

[0147]

[0148]

[0149] *Relative strength may vary depending on crystal size and morphology.

[0150] In one aspect, the crystalline form of compound I is characterized by an endothermic peak beginning at approximately 166 °C, as determined by DSC. In another aspect, the crystalline form of compound I is characterized by essentially as... Figure 6A The DSC curves shown are used for characterization. In one aspect, the crystalline form of compound I is characterized by essentially as follows: Figure 6B The TGA curve shown is used to characterize it.

[0151] In one respect, the crystalline form of compound I was determined by measurements at 1310.1±2.0, 1514.4±2.0, and 1661.3±2.0 cm⁻¹. -1 The crystalline form of compound I was characterized by IR spectroscopy with peaks at 1097.3 ± 2.0, 1310.1 ± 2.0, 1541.4 ± 2.0, and 1661.3 ± 2.0 cm⁻¹. -1 The crystalline form of compound I is characterized by the IR spectrum showing the peaks at each peak. In one respect, the crystalline form of compound I is characterized by the following IR peaks in Table 4.

[0152] Table 4

[0153]

[0154]

[0155] In one aspect, the crystalline form of Compound I is characterized by an IR pattern substantially as shown in FIG. 1. Figure 7

[0156] In one aspect, the crystalline form of Compound I is characterized by an IR pattern substantially as shown in FIG. 1. Figure 8 13 C solid state NMR.

[0157] In one aspect, the crystalline form is anhydrous, as determined by 1 H NMR.

[0158] In one aspect, the crystalline form of Compound I has a unit cell indexed to a simple monoclinic system. In another aspect, the crystalline form of Compound I has a unit cell with an a value of about a b value of about and a c value of about In another aspect, the crystalline form of Compound I has a unit cell with a volume of about In another aspect, the crystalline form of Compound I has a unit cell with a volume of about

[0159] In one aspect, the crystalline form of Compound I is Form B.

[0160] C. Crystalline Form C

[0161] In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees two-theta. In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 8.0 ± 0.2, 17.4 ± 0.2, and about 21.6 ± 0.2 degrees two-theta.

[0162] In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in FIG. 1. Figure 9

[0163] In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in FIG. 1.

[0164] Table 5

[0165]

[0166] ​​​

[0167] Relative intensities can vary depending on crystal size and morphology.

[0168] In one aspect, the crystalline form of Compound I is characterized by an endothermic peak beginning at about 149 °C as determined by DSC. In one aspect, the crystalline form of Compound I is characterized by a DSC curve substantially as shown in Figure 10A In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in Figure 10B

[0169] In one aspect, the crystalline form is a solvate as determined by H NMR. In one aspect, the crystalline form of Compound I is a dichloromethane solvate. 1

[0170] In one aspect, the crystalline form of Compound I has a unit cell indexed to a simple monoclinic system. In another aspect, the crystalline form of Compound I has a unit cell with an a value of about a b value of about and a c value of about In another aspect, the crystalline form of Compound I has a unit cell with a volume of about In another aspect, the crystalline form of Compound I has a unit cell with a volume of about

[0171] In one aspect, the crystalline form of Compound I is Form C.

[0172] D. Crystalline Form D

[0173] In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, and 26.4 ± 0.2 degrees two-theta. In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, 18.2 ± 0.2, and 26.4 ± 0.2 degrees two-theta.

[0174] In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 11

[0175] In one aspect, the crystalline form of Compound I is characterized by the following XRPD pattern expressed in degrees two-theta and relative intensity in Table 6:

[0176] Table 6

[0177]

[0178]

[0179] ​​​*Relative intensities can vary depending on crystal size and morphology.

[0180] In one aspect, the crystalline form of Compound I is characterized by an endothermic peak beginning at about 147 °C as determined by DSC. In one aspect, the crystalline form of Compound I is characterized by a DSC curve substantially as shown in Figure 12A In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in Figure 12B In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in

[0181] In one aspect, the crystalline form of Compound I is characterized by a solid state NMR substantially similar to that of Figure 13 13 C.

[0182] In one aspect, the crystalline form of Compound I is Form D.

[0183] E. Crystalline Form E

[0184] In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.2 degrees 2-theta. In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 20.7 ± 0.2 degrees 2-theta.

[0185] In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 14 In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in

[0186] In one aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, expressed in degrees 2-theta and relative intensity, in Table 7:

[0187] Table 7

[0188]

[0189]

[0190] *Relative intensities can vary depending on crystal size and morphology.

[0191] In one aspect, the crystalline form of Compound I is characterized by an endothermic peak beginning at about 171 °C as determined by DSC. In one aspect, the crystalline form of Compound I is characterized by a DSC curve substantially as shown in Figure 15A In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in Figure 15B In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in

[0192] ​In an aspect, the crystalline form of Compound I is Form E.

[0193] F. Crystalline Form F

[0194] In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, and 16.8 ± 0.2 degrees two-theta. In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, 16.8 ± 0.2, and 17.9 ± 0.2 degrees two-theta.

[0195] In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 16 In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in

[0196] In an aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, expressed in degrees two-theta and relative intensity, in Table 8:

[0197] Table 8

[0198]

[0199]

[0200] *Relative intensities can vary depending on crystal size and morphology.

[0201] In an aspect, the crystalline form of Compound I is Form F.

[0202] G. Crystalline Form G

[0203] In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, and 21.9 ± 0.2 degrees two-theta. In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, and 22.4 ± 0.2 degrees two-theta.

[0204] In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 17 In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in

[0205] In an aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, expressed in degrees two-theta and relative intensity, in Table 9:

[0206] Table 9

[0207]

[0208]

[0209] *Relative intensities can vary depending on crystal size and morphology.

[0210] In an aspect, the crystalline form of Compound I is Form G.

[0211] H. Crystalline Form H

[0212] In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, and 8.5 ± 0.2 degrees two-theta. In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, 8.5 ± 0.2, and 15.9 ± 0.2 degrees two-theta.

[0213] In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 18

[0214] In an aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, in terms of degrees two-theta and relative intensity, in Table 10:

[0215] Table 10

[0216]

[0217]

[0218] *Relative intensities can vary depending on crystal size and morphology.

[0219] In an aspect, the crystalline form of Compound I is Form H.

[0220] I. Crystalline Form I

[0221] In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees two-theta. In an aspect, the disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0222] In an aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in Figure 19

[0223] In an aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, in terms of degrees two-theta and relative intensity, in Table 11:​​

[0224] Table 11

[0225]

[0226] *Relative intensities can vary depending on crystal size and morphology.

[0227] In one aspect, the crystalline form of Compound I is Form I.

[0228] J. Crystalline Form J

[0229] In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees two-theta. In one aspect, the present disclosure relates to a crystalline form of Compound I characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 12.7 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0230] In one aspect, the crystalline form of Compound I is characterized by an XRPD pattern substantially as shown in FIG. 5. Figure 20

[0231] In one aspect, the crystalline form of Compound I is characterized by an endothermic peak beginning at about 164 °C as determined by DSC. In one aspect, the crystalline form of Compound I is characterized by a DSC curve substantially as shown in FIG. 6. Figure 21A Figure 21B In one aspect, the crystalline form of Compound I is characterized by a TGA curve substantially as shown in FIG. 7.

[0232] In one aspect, the crystalline form of Compound I is characterized by the following XRPD pattern, expressed in degrees two-theta and relative intensity, in Table 12:

[0233] Table 12

[0234]

[0235]

[0236] *Relative intensities can vary depending on crystal size and morphology.

[0237] In one aspect, the crystalline form of Compound I is Form J.

[0238] ​​In some aspects, any of the crystalline forms discussed above are substantially free of other polymorphic forms. In some aspects, the crystalline form has a polymorphic purity of at least about 80%. In some aspects, the crystalline form has a polymorphic purity of at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0239] In one aspect, the crystalline form of Compound I is selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. In one aspect, the crystalline form of Compound I is Form A.

[0240] In one aspect, the crystalline form of Compound I is a mixture of two or more forms selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. In another aspect, the crystalline form of Compound I is a mixture of two or more forms selected from Form A, Form B, and Form C. In another aspect, the crystalline form of Compound I is a mixture of Form A and Form B, wherein Form B is the major form and Form A is the minor form.

[0241] In some aspects, the disclosure provides a method of preparing a crystalline form of Compound I, wherein the crystalline form is selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. One or more methods of preparing Forms A-J are provided in the Experimental Section herein.

[0242] III. Pharmaceutical Compositions

[0243] The disclosure relates to a pharmaceutical composition comprising a crystalline form of any one of Forms A-J of Compound I and a pharmaceutically acceptable carrier, diluent, or excipient, or a mixture thereof.

[0244] In one aspect, the pharmaceutical composition comprises a crystalline form of any one of Forms A-J of Compound I.

[0245] The pharmaceutical composition comprising a crystalline form of any one of Forms A-J of Compound I can be in a form suitable for oral use, for example as a tablet, troche, lozenge, dispersible powder or granule, or hard or soft capsule. The composition intended for oral use can be prepared according to any known method, and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

[0246] In some aspects, the pharmaceutical composition can be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, and infusion techniques), rectal, intranasal, local, or transdermal (e.g., by use of a patch) routes.

[0247] In one aspect, the pharmaceutical composition comprises about 100 mg to about 1500 mg, about 100 mg to about 1400 mg, about 100 mg to about 1300 mg, about 100 mg to about 1200 mg, about 100 mg to about 1100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg of a crystalline form of any of Forms A-J of Compound I disclosed herein. In one aspect, the pharmaceutical composition comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg of a crystalline form of any of Forms A-J of Compound I disclosed herein.

[0248] In some aspects, the pharmaceutical composition is an oral tablet. In some aspects, the oral tablet comprises about 0.1 mg to 2000 mg of a crystalline form of any of Forms A-J of 2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid. In some aspects, the oral tablet comprises about 1 mg to about 2000 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 1 mg to about 1000 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 100 mg to about 800 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 50 mg to about 400 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 100 mg to about 400 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 100 mg to about 300 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 500 mg to about 1000 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises 800 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises 400 mg of a crystalline form of any of Forms A-J of Compound I. In some aspects, the oral tablet comprises 300 mg of a crystalline form of any of Forms A-J of Compound I.In some aspects, the oral tablet comprises about 200 mg of the crystalline form of any one of Forms A-J of Compound I.

[0249] IV. Methods of Treatment

[0250] In some aspects, the present disclosure relates to a method of treating a type of diabetes, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition discussed above. The method can comprise administering a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of any one of Forms A-J of Compound I. In some aspects, the type of diabetes is Type 1 diabetes. In some aspects, the type of diabetes is Type 2 diabetes. In some aspects, the type of diabetes is one or both of Type 1 diabetes and Type 2 diabetes.

[0251] In some aspects, the patient is being treated with insulin therapy. In some aspects, the insulin therapy is continuous insulin infusion. In some aspects, the insulin therapy is continuous subcutaneous insulin infusion. In some aspects, the insulin therapy is multiple daily administration of insulin.

[0252] In another aspect, the present disclosure provides a method for treating a glucokinase deficiency-mediated condition or disease, or a condition that benefits from an increase in glucokinase activity, comprising administering to a subject in need thereof a compound or pharmaceutical composition of the present disclosure.

[0253] In another aspect, the present disclosure provides a method for treating a metabolic disorder, for lowering blood glucose, for treating hyperglycemia, for treating hypoglycemia, for treating impaired glucose tolerance (IGT), for treating Syndrome X, for treating impaired fasting glucose (IFG), for delaying the progression of impaired glucose tolerance (IGT) to Type 2 diabetes, for delaying the progression of non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for regulating appetite, for treating obesity, for regulating feeding behavior, or for enhancing the secretion of enteroincretins from the gut, comprising administering to a subject in need of such treatment a compound or pharmaceutical composition of the present disclosure.

[0254] In another aspect, the present disclosure provides a method for preserving beta cell mass and function, comprising administering to a subject in need of such treatment a compound or pharmaceutical composition of the present disclosure.

[0255] In another aspect, the present disclosure provides a method of preserving and / or increasing beta cell mass and function in a subject undergoing pancreatic islet transplantation, comprising administering to a subject in need of such treatment a compound or pharmaceutical composition of the present disclosure.

[0256] In another aspect, the present disclosure provides a method of improving liver function and / or survival in a subject undergoing liver transplantation, comprising administering to a subject in need of such treatment a compound or pharmaceutical composition of the present disclosure. In a further aspect, the administration occurs before, during, or after transplantation, or any combination thereof.

[0257] In another aspect, the present disclosure provides a method of preventing diabetic ketoacidosis or reducing the occurrence of diabetic ketoacidosis events in a subject, comprising administering to a subject in need of such treatment a compound or pharmaceutical composition of the present disclosure.

[0258] Depending on the condition, disorder, or disease to be treated and the condition of the subject, the pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, or intra-arterial (e.g., via catheter), ICV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, and / or topical (e.g., transdermal or local) routes of administration, and can be formulated either singly or in mixtures of suitable dosage units with pharmaceutically acceptable vehicles, carriers, diluents, excipients, or mixtures thereof appropriate for each route of administration. In one aspect, the pharmaceutical composition is administered orally.

[0259] For oral administration, the pharmaceutical compositions provided herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions (e.g., aqueous or oily suspensions), wafer, sprinkle, elixir, syrup, bolus, electuary, or paste. In one aspect, the pharmaceutical composition is administered as a tablet.

[0260] The dosage can be in the form of one, two, three, four, five, six, or more divided doses administered at appropriate intervals of time through the day. The dosage or divided dose can be administered in the form of dosage units containing from about 1 mg to about 2000 mg, from about 10 mg to about 2000 mg, from about 100 mg to about 1500 mg, from about 200 mg to about 1500 mg, from about 200 mg to about 1500 mg, from about 300 mg to about 1500 mg, from about 400 mg to about 1500 mg, from about 500 mg to about 1500 mg, from about 500 mg to about 1000 mg, or from about 500 mg to about 800 mg of the crystalline form of any of Forms A-J per dosage unit. For example, the dosage or divided dose can be administered in the form of dosage units containing about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg of the crystalline form of any of Forms A-J disclosed herein per dosage unit.

[0261] In some aspects, the patient is administered about 0.1 mg to about 2000 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 1 mg to about 2000 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 100 mg to about 800 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 50 mg to about 400 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 100 mg to about 400 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 100 mg to about 300 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 500 mg to about 1000 mg of the crystalline form of any of Forms A-J of Compound I per day. In some aspects, the patient is administered about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 500 mg, about 550 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg of the crystalline form of any of Forms A-J of Compound I once per day. In some aspects, the patient is administered about 800 mg of the crystalline form of any of Forms A-J of Compound I once per day. In some aspects, the patient is administered about 400 mg of the crystalline form of any of Forms A-J of Compound I once per day. In some aspects, the patient is administered about 300 mg of the crystalline form of any of Forms A-J of Compound I once per day. In some aspects, the patient is administered about 200 mg of the crystalline form of any of Forms A-J of Compound I once per day. In some aspects, the patient is administered about 100 mg of the crystalline form of any of Forms A-J of Compound I once per day.

[0262] The present application provides, among other things, the following embodiments:

[0263] 1. A crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid of formula (I)

[0264]

[0265] said crystalline form is selected from:

[0266] a) a crystalline form characterized by an XRPD pattern having peaks at 16.9±0.2, 17.4±0.2 and 20.1±0.2 degrees 2-theta;

[0267] b) a crystalline form characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2 and 17.8±0.2 degrees 2-theta;

[0268] c) a crystalline form characterized by an XRPD pattern having peaks at 4.3±0.2, 17.4±0.2 and 21.6±0.2 degrees 2-theta;

[0269] d) a crystalline form characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2 and 26.4±0.2 degrees 2-theta;

[0270] e) a crystalline form characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2 and 18.9±0.2 degrees 2-theta;

[0271] f) a crystalline form characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2 and 16.8±0.2 degrees 2-theta;

[0272] g) a crystalline form characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2 and 21.9±0.2 degrees 2-theta;

[0273] h) a crystalline form characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2 and 8.5±0.2 degrees 2-theta;

[0274] i) a crystalline form characterized by an XRPD pattern having peaks at 5.0±0.2, 16.8±0.2 and 18.8±0.2 degrees 2-theta; and

[0275] j) a crystalline form characterized by an XRPD pattern having peaks at 5.9±0.2, 17.4±0.2 and 18.8±0.2 degrees 2-theta.

[0276] 2. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees two-theta.

[0277] 3. The crystalline form of embodiment 2, wherein the crystalline form is characterized by an XRPD pattern having peaks at 8.7 ± 0.2, 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees two-theta.

[0278] 4. The crystalline form of embodiment 2 or embodiment 3, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 1 .

[0279] 5. The crystalline form of any one of embodiments 2 to 4, wherein the crystalline form is characterized by an endothermic peak starting at about 160 °C as determined by DSC.

[0280] 6. The crystalline form of any one of embodiments 2 to 5, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 2A .

[0281] 7. The crystalline form of any one of embodiments 2 to 6, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 2B .

[0282] 8. The crystalline form of any one of embodiments 2 to 7, wherein the crystalline form is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, and 1313.2 ± 2.0 cm -1 .

[0283] 9. The crystalline form of any one of embodiments 2 to 8, wherein the crystalline form is characterized by an IR pattern having peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, 1238.7 ± 2.0, and 1313.2 ± 2.0 cm -1 .

[0284] 10. The crystalline form of any one of embodiments 2 to 9, wherein the crystalline form is characterized by an IR pattern substantially as shown in Figure 3 .

[0285] 11. The crystalline form of any one of embodiments 2 to 10, wherein the crystalline form is characterized by a C solid-state NMR substantially as shown in Figure 4 . 13 .

[0286] 12. The crystalline form of any one of embodiments 2-11, wherein the crystalline form is anhydrous.

[0287] 13. The crystalline form of any one of embodiments 2-12, wherein the crystalline form has a unit cell indexed in the simple monoclinic system.

[0288] 14. The crystalline form of any one of embodiments 2-13, wherein the crystalline form has a unit cell with an a value of about a b value of about and a c value of about

[0289] 15. The crystalline form of any one of embodiments 2-14, wherein the crystalline form has a unit cell with a volume of about

[0290] 16. The crystalline form of any one of embodiments 2-15, wherein the crystalline form is Form A.

[0291] 17. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, and 17.8 ± 0.2 degrees two-theta.

[0292] 18. The crystalline form of embodiment 17, wherein the crystalline form is characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, 17.8 ± 0.2, and 21.1 ± 0.2 degrees two-theta.

[0293] 19. The crystalline form of embodiment 17 or embodiment 18, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 5

[0294] 20. The crystalline form of any one of embodiments 17-19, wherein the crystalline form is characterized by an endothermic peak beginning at about 166 °C as determined by DSC.

[0295] 21. The crystalline form of any one of embodiments 17-20, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 6A

[0296] 22. The crystalline form of any one of embodiments 17-21, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 6B

[0297] ​​​​​23. The crystalline form of any one of embodiments 17-22, wherein the crystalline form is characterized by an IR pattern having peaks at 1310.1 ± 2.0, 1514.4 ± 2.0, and 1661.3 ± 2.0 cm -1

[0298] 24. The crystalline form of any one of embodiments 17-23, wherein the crystalline form is characterized by an IR pattern having peaks at 1097.3 ± 2.0, 1310.1 ± 2.0, 1541.4 ± 2.0, and 1661.3 ± 2.0 cm -1

[0299] 25. The crystalline form of any one of embodiments 17-24, wherein the crystalline form is characterized by an IR pattern substantially as shown in Figure 7

[0300] 26. The crystalline form of any one of embodiments 17-25, wherein the crystalline form is characterized by a C solid state NMR substantially as shown in Figure 8 13

[0301] 27. The crystalline form of any one of embodiments 17-26, wherein the crystalline form is anhydrous.

[0302] 28. The crystalline form of any one of embodiments 17-27, wherein the crystalline form has a unit cell indexed in the simple monoclinic system.

[0303] 29. The crystalline form of any one of embodiments 17-28, wherein the crystalline form has a unit cell with an a value of about a b value of about and a c value of about

[0304] 30. The crystalline form of any one of embodiments 17-29, wherein the crystalline form has a unit cell with a volume of about

[0305] 31. The crystalline form of any one of embodiments 17-30, wherein the crystalline form is Form B.

[0306] 32. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees 2-theta.

[0307] ​​​​​​​33. The crystalline form of embodiment 32, wherein the crystalline form is characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 8.0 ± 0.2, 17.4 ± 0.2, and about 21.6 ± 0.2 degrees two-theta.

[0308] 34. The crystalline form of embodiment 32 or embodiment 33, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 9

[0309] 35. The crystalline form of any one of embodiments 32 to 34, wherein the crystalline form is characterized by an endothermic peak beginning at about 149 °C as determined by DSC.

[0310] 36. The crystalline form of any one of embodiments 32 to 35, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 10A

[0311] 37. The crystalline form of any one of embodiments 32 to 36, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 10B

[0312] 38. The crystalline form of any one of embodiments 32 to 37, wherein the crystalline form is a dichloromethane solvate.

[0313] 39. The crystalline form of any one of embodiments 32 to 38, wherein the crystalline form has a unit cell indexed in the simple monoclinic system.

[0314] 40. The crystalline form of any one of embodiments 32 to 39, wherein the crystalline form has a unit cell with an a value of about a b value of about and a c value of about

[0315] 41. The crystalline form of any one of embodiments 32 to 40, wherein the crystalline form has a unit cell with a volume of about

[0316] 42. The crystalline form of any one of embodiments 32 to 41, wherein the crystalline form is Form C.

[0317] 43. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, and 26.4 ± 0.2 degrees two-theta.

[0318] ​​​​​44. The crystalline form of embodiment 43, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, 18.2 ± 0.2, and 26.4 ± 0.2 degrees two-theta.

[0319] 45. The crystalline form of embodiment 43 or embodiment 44, which is characterized by an XRPD pattern substantially as shown in Figure 11

[0320] 46. The crystalline form of any one of embodiments 43 to 45, wherein the crystalline form is characterized by an endothermic peak beginning at about 147 °C as determined by DSC.

[0321] 47. The crystalline form of any one of embodiments 43 to 46, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 12A

[0322] 48. The crystalline form of any one of embodiments 43 to 47, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 12B

[0323] 49. The crystalline form of any one of embodiments 43 to 48, wherein the crystalline form is characterized by a Figure 13 13 C solid state NMR substantially as shown in

[0324] 50. The crystalline form of any one of embodiments 43 to 49, wherein the crystalline form is anhydrous.

[0325] 51. The crystalline form of any one of embodiments 43 to 50, wherein the crystalline form is Form D.

[0326] 52. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, and 18.9 ± 0.2 degrees two-theta.

[0327] 53. The crystalline form of embodiment 52, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 20.7 ± 0.2 degrees two-theta.

[0328] 54. The crystalline form of embodiment 52 or embodiment 53, which is characterized by an XRPD pattern substantially as shown in Figure 14

[0329] ​​​​​55. The crystalline form of any one of embodiments 52-54, wherein the crystalline form is characterized by an endothermic peak beginning at about 171 °C as determined by DSC.

[0330] 56. The crystalline form of any one of embodiments 52-55, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 15A

[0331] 57. The crystalline form of any one of embodiments 52-56, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 15B

[0332] 58. The crystalline form of any one of embodiments 52-57, wherein the crystalline form is anhydrous.

[0333] 59. The crystalline form of any one of embodiments 52-58, wherein the crystalline form is Form E.

[0334] 60. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, and 16.8 ± 0.2 degrees 2-theta.

[0335] 61. The crystalline form of embodiment 60, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, 16.8 ± 0.2, and 17.9 ± 0.2 degrees 2-theta.

[0336] 62. The crystalline form of embodiment 60 or embodiment 61, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 16

[0337] 63. The crystalline form of any one of embodiments 60-62, wherein the crystalline form is a solvate.

[0338] 64. The crystalline form of any one of embodiments 60-63, wherein the crystalline form is Form F.

[0339] 65. The crystalline form of embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, and 21.9 ± 0.2 degrees 2-theta.

[0340] 66. The crystalline form of embodiment 65, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, and 22.4 ± 0.2 degrees 2-theta.​​​

[0341] 67. The crystalline form of either Embodiment 65 or Embodiment 66, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 17

[0342] 68. The crystalline form of any one of Embodiments 65-67, wherein the crystalline form is a solvate.

[0343] 69. The crystalline form of any one of Embodiments 65-68, wherein the crystalline form is Form G.

[0344] 70. The crystalline form of Embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, and 8.5 ± 0.2 degrees two-theta.

[0345] 71. The crystalline form of Embodiment 70, wherein the crystalline form is characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, 8.5 ± 0.2, and 15.9 ± 0.2 degrees two-theta.

[0346] 72. The crystalline form of either Embodiment 70 or Embodiment 71, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 18

[0347] 73. The crystalline form of any one of Embodiments 70-72, wherein the crystalline form is a solvate.

[0348] 74. The crystalline form of any one of Embodiments 70-73, wherein the crystalline form is Form H.

[0349] 75. The crystalline form of Embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0350] 76. The crystalline form of Embodiment 75, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0351] 77. The crystalline form of either Embodiment 75 or Embodiment 76, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 19

[0352] ​​​78. The crystalline form of any one of Embodiments 75-77, wherein the crystalline form is a solvate.

[0353] 79. The crystalline form of any one of Embodiments 75-78, wherein the crystalline form is Form I.

[0354] 80. The crystalline form of Embodiment 1, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0355] 81. The crystalline form of Embodiment 80, wherein the crystalline form is characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 12.7 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees two-theta.

[0356] 82. The crystalline form of Embodiment 80 or Embodiment 81, wherein the crystalline form is characterized by an XRPD pattern substantially as shown in Figure 20 .

[0357] 83. The crystalline form of any one of Embodiments 80-82, wherein the crystalline form is characterized by an endothermic peak beginning at about 164 °C as determined by DSC.

[0358] 84. The crystalline form of any one of Embodiments 80-83, wherein the crystalline form is characterized by a DSC curve substantially as shown in Figure 21A .

[0359] 85. The crystalline form of any one of Embodiments 80-84, wherein the crystalline form is characterized by a TGA curve substantially as shown in Figure 21B .

[0360] 86. The crystalline form of any one of Embodiments 80-85, wherein the crystalline form is Form J.

[0361] 87. The crystalline form of any one of Embodiments 1-86, wherein the crystalline form is substantially free of other polymorphic forms.

[0362] 88. The crystalline form of any one of Embodiments 1-86, wherein the crystalline form has a polymorphic purity of at least about 80%.

[0363] 89. The crystalline form of any one of Embodiments 1-86, wherein the crystalline form has a polymorphic purity of at least about 90%.

[0364] 90. The crystalline form according to any one of embodiments 1 to 86, wherein the crystalline form has a polymorphic purity of at least about 95%.

[0365] 91. The crystalline form according to any one of embodiments 1 to 86, wherein the crystalline form has a polymorphic purity of at least about 99%.

[0366] 92. A pharmaceutical composition comprising a crystalline form according to any one of embodiments 1 to 91 and a pharmaceutically acceptable carrier, diluent, or excipient, or a mixture thereof.

[0367] 93. A method of treating a type of diabetes, wherein the method comprises administering to a patient in need thereof a pharmaceutical composition according to embodiment 92.

[0368] 94. The method according to embodiment 93, wherein the type of diabetes is Type 1 diabetes.

[0369] 95. The method according to embodiment 93, wherein the type of diabetes is Type 2 diabetes.

[0370] 96. The method according to any one of embodiments 93 to 95, wherein the pharmaceutical composition is administered orally.

[0371] 97. The method according to any one of embodiments 93 to 96, wherein the pharmaceutical composition is administered as a tablet.

[0372] 98. The method according to any one of embodiments 93 to 97, wherein the patient is administered up to about 2000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid once a day.

[0373] 99. The method according to any one of embodiments 93 to 97, wherein the patient is administered about 100 mg to about 1500 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid once a day.

[0374] 100. The method according to any one of embodiments 93 to 97, wherein the patient is administered about 500 mg to about 1000 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid once a day.

[0375] 101. The method of any one of embodiments 93 to 97, wherein the patient is administered about 800 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}- acetic acid once a day.

[0376] 102. The method of any one of embodiments 93 to 97, wherein the patient is administered less than 800 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}- acetic acid once a day.

[0377] 103. The method of any one of embodiments 93 to 97, wherein the patient is administered about 500 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}- acetic acid once a day.

[0378] 104. The method of any one of embodiments 93 to 97, wherein the patient is administered about 300 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}- acetic acid once a day.

[0379] 105. The method of any one of embodiments 93 to 97, wherein the patient is administered about 100 mg of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}- acetic acid once a day.

[0380] EXAMPLE

[0381] A. Abbreviations and Acronyms

[0382]

[0383]

[0384]

[0385] B. Experimental Methods

[0386] Example 1: Screening of stable forms and hydrates via homogenate grinding experiments

[0387] Homogenate grinding experiments were targeted at stable forms, including stable solvates and hydrates.

[0388] Homogenate grinding experiments were performed by stirring solid Compound I in the indicated solvents and solvent mixtures at various temperatures for 7 days (high temperature) or 14-18 days (ambient and below ambient temperatures). The experimental conditions and summary of results are detailed in Table 13.

[0389] Table 13

[0390]

[0391]

[0392]

[0393] * Temperature is an approximation.

[0394] Example 2: Polymorph screening

[0395] Unless otherwise stated, the solid of Compound I was used as the starting material. The material produced in the study was used for selected experiments.

[0396] Method a: evaporation experiments

[0397] At ambient or elevated temperature, a solution of the starting material was allowed to partially evaporate or evaporate to dryness from an open vial for fast evaporation (FE) or from a vial covered with aluminium foil with a pinhole for slow evaporation (SE). Prior to evaporation, the solution was filtered at ambient or elevated temperature with a 0.2 pm nylon filter.

[0398] Method b: cooling experiments

[0399] Using a hot plate for heating, a solution of the starting material was prepared in the specified solvent at elevated temperature. These were hot filtered through a 0.2 pm nylon filter into a warm receiving vial. The vial was quickly transferred to a bath below ambient temperature (typically dry ice / acetone) for a sudden cooling (CC), removed from the elevated temperature for a fast cooling (FC), or the heating was turned off to allow slow cooling (SC). If solids precipitated, they were separated by vacuum filtration. If the solution remained clear, the sample was stored below ambient, or further crystallization techniques were applied.

[0400] Method c: homogenization experiments

[0401] The solid was suspended in the specified solvent. The suspension was then agitated at ambient or a set temperature. After a given amount of time, the solid was separated.

[0402] Method d: solvent / anti-solvent precipitation

[0403] A solution of the starting material was prepared at ambient or elevated temperature and filtered using a 0.2 pm nylon filter. They were then mixed with the appropriate anti-solvent at elevated temperature. If no solids were observed, the sample was cooled to ambient or below ambient temperature, or other crystallization techniques were applied.

[0404] Polymorph screening was performed using various solvent-based techniques including evaporation, cooling, slurry, solvent / anti-solvent addition, and combinations of these techniques. The detailed experimental conditions, observations, and XRPD results are summarized in Table 14.

[0405] Table 14

[0406]

[0407]

[0408]

[0409]

[0410]

[0411] * Time and temperature are approximate.

[0412] Example 3: Preparation of Selected Materials

[0413] Table 15 summarizes the preparation conditions for the selected materials.

[0414] Table 15

[0415]

[0416] * Time and temperature are approximate.

[0417] Table 16 summarizes the drying conditions for the selected materials

[0418] Table 16

[0419]

[0420] * Time and temperature are approximate.

[0421] Example 4: Competitive Slurry Experiments

[0422] To identify the thermodynamically most stable anhydrous form of Form A, Form D, Form B, and Form E, competitive slurries were performed in acetone at 2-8 °C, ambient temperature, and 45 °C.

[0423] Under each condition, similar amounts of solids from the four forms / materials were slurried in pre-saturated solutions at the temperature condition being tested for 7 days; the solids were then isolated and analyzed by XRPD wet. The detailed experimental conditions and XRPD results are summarized in Table 17.

[0424] Table 17

[0425]

[0426]

[0427] *: The solution was pre-saturated with Form A under each condition.

[0428] **: Time and temperature are approximate.

[0429] X-ray powder diffraction (XRPD)

[0430] XRPD patterns were collected using a PANalytical X’Pert PRO MPD or Empyrean diffractometer with an incident beam of Cu radiation generated using an Optix long-fine focus source. An elliptical gradient multilayer mirror was used to focus the Cu Ka X-ray radiation through the sample and onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the position of the observed Si(l l l) peak was consistent with the NIST certified position. The sample of the sample was sandwiched between 3 pm thick films and analyzed in transmission geometry. A beam blocker, short anti-scatter extension, and anti-scatter blade were used to minimize background arising from air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. The diffractogram was collected using a scanning position sensitive detector (X’Celerator) at a distance of 240 mm from the sample and data acquisition software v.5.5.

[0431] Thermogravimetric analysis and differential scanning calorimetry combined analysis (TGA / DSC)

[0432] TGA / DSC combined analysis was performed using a Mettler Toledo TGA / DSC3+ analyzer. Temperature and enthalpy calibration was performed using indium, tin, and zinc, followed by verification using indium. Equilibration was verified with calcium oxalate. The sample was placed in an aluminum pan. The pan was hermetically sealed, pierced, and then inserted into the TG furnace. An aluminum pan configured for weighing of the sample pan was placed on the reference platform. The furnace was heated under nitrogen.

[0433] Dynamic vapor sorption (DVS)

[0434] Moisture sorption / desorption data were collected on a Surface Measurement Systems DVS Intrinsic instrument. Samples were not dried prior to analysis. For batches received as-is, sorption and desorption data were collected at 10% RH increments over the range of 5% to 95% RH. The equilibration criterion used for analysis was a weight change of less than 0.0100% in 5 minutes, with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the sample.

[0435] Hot stage microscopy (HSM)

[0436] A SPOT RTM microscope equipped with a SPOT InsightTM Thermomicroscopy was performed on a Linkam hot stage (FTIR 600) on a Leica DM LP microscope for color digital cameras. Temperature calibration was performed using USP melting point standards. The sample was placed on a coverslip and a second coverslip was placed on top of the sample. Each sample was visually observed using a 20x objective, 0.40 NA, and crossed polarizers and a first order red compensator as the hot stage was heated. Images were captured using SPOT software (v. 4.5.9).

[0437] Polarized light microscopy (PLM)

[0438] PLM was performed using a Leica DM LP microscope equipped with a Spot Insight color camera. Crossed polarized light was used with a first order red compensator. Various objectives were used to view the samples. The samples were suspended in mineral oil or a dispersant chosen for the method. Images were acquired at ambient temperature using Spot Advanced software (v. 4.5.9). Micron bars were inserted into the images as a reference for size. Particle size was measured using an ocular reticle scale calibrated with a NIST traceable stage micrometer.

[0439] Proton solution nuclear magnetic resonance spectroscopy 1 H NMR)

[0440] Solution NMR spectra were obtained using DMSO-d6 using a Bruker AVANCE 600 MHz spectrometer.

[0441] Carbon-13 solid state nuclear magnetic resonance spectroscopy 13 C Solid State NMR)

[0442] 13 C Solid State Cross-Polarization Magic-Angle Spinning (CP / MAS) NMR spectra were obtained on an Agilent DD2-400 spectrometer (Larmor frequencies: 13 C = 100.549 MHz, 1 H = 399.812 MHz) at ambient temperature. The samples were packed into 4 mm PENCIL type zirconia rotors and spun at 12 kHz in a magic angle. During acquisition time, high power 1 H decoupling was used with a 2.6 μ8 (90°) pulse. 1H pulse width, 5 ms, tilt amplitude cross-polarization contact time, 30 ms, acquisition time, 10 seconds, spectral width of 45 kHz with 2678 data points, and 1600 scans co-added. The free induction decay (FID) was processed using Agilent VnmrJ 3.2A software with 65536 points and an exponential line broadening factor of 10 Hz to improve the signal-to-noise. The first three data points of the FID were inverse predicted using the VNMR linear prediction algorithm to produce a flat baseline. The chemical shift of the spectral peaks was externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm.

[0443] Infrared spectroscopy (IR)

[0444] IR spectra were obtained using a Nicolet 6700 Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid / far-IR source, potassium bromide (KBr) beamsplitter, and deuterated tris-glycine sulfate (DTGS) detector. Wavelength verification was performed using NIST SRM 1921b (polystyrene). An attenuated total reflectance (ATR) accessory (Thunderdome TM , Thermo Spectra-Tech) equipped with a germanium (Ge) crystal was used for data acquisition. The spectra represent 256 scans co-added collected at a spectral resolution of 4 cm -1 -1. A background data set was obtained with a clean Ge crystal. Log 1 / R (R = reflectance) spectra were obtained by taking the ratio of these two data sets relative to each other.

[0445] XRPD indexing

[0446] In this study, high resolution XRPD patterns of Compound I were indexed using X’pert High Score Plus 2.2a (2.2.1). Indexing and structure refinement were computational studies. The agreement between the allowed peak positions and the observed peaks marked with a red bar represents a consistent cell determination. Successful indexing of the pattern indicates that the sample is primarily composed of a single crystalline phase. The space group consistent with the assigned extinction symbol, cell parameters, and derived quantities were tabulated below each figure, showing the tentative indexing solution. To confirm the tentative indexing solution, the molecular packing motif within the crystallographic unit cell must be determined. No attempt at molecular packing was made.

[0447] Conclusion

[0448] A variety of crystalline materials of Compound I, including Forms A-J, were observed in this study.

[0449] Form A, Form B, Form D, and Form E are anhydrous materials of Compound I. Among them, Form A is likely to be the most stable form in the range of 2-8 °C to 45 °C based on results from competitive homogenization.

[0450] Form C is likely to be a DCM solvate which desolvates to Form D. Form F is also a solvated material and converts to Form D upon drying.

[0451] Form I likely represents a family of isomeric solvates. Upon drying, it converts to Form E or a solid similar to Form E.

[0452] Forms G and H are disordered crystalline materials and are likely solvates. They become disordered upon drying.

[0453] While the application has been described in connection with specific aspects thereof, it will be understood that it is capable of further modification and we intend to encompass any variations, uses, or alterations of the application generally following, without departing from the spirit or ambit of the aspects of the application and including such deviations from the disclosed embodiments that come within the known or customary practice within the art to which the application pertains and can be applied to the essential features set forth above and within the scope of the claims.

Claims

1. A crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]- thiazol-5-ylsulfanyl}-acetic acid of formula (I) characterized by an XRPD pattern having peaks at 8.7±0.2, 16.9±0.2, 17.4±0.2 and 20.1±0.2 degrees 2-theta, measured by using Cu K alpha radiation, which is crystalline Form A having a polymorphic purity of at least 95% or at least 99%; wherein the crystalline form of formula (I) does not comprise: i. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 11.0±0.2, 11.6±0.2, 17.8±0.2 and 21.1±0.2 degrees 2-theta, which is crystalline Form B; ii. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 4.3±0.2, 8.0±0.2, 17.4±0.2 and 21.6±0.2 degrees 2-theta, which is crystalline Form C; iii. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 5.3±0.2, 8.7±0.2, 18.2±0.2 and 26.4±0.2 degrees 2-theta, which is crystalline Form D; iv. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 5.8±0.2, 17.9±0.2, 18.9±0.2 and 20.7±0.2 degrees 2-theta, which is crystalline Form E; v. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 3.8±0.2, 9.5±0.2, 16.8±0.2 and 17.9±0.2 degrees 2-theta, which is crystalline Form F; vi. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 3.4±0.2, 21.2±0.2, 21.9±0.2 and 22.4±0.2 degrees 2-theta, which is crystalline Form G; vii. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 3.8±0.2, 5.3±0.2, 8.5±0.2 and 15.9±0.2 degrees 2-theta, which is crystalline Form H; viii. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 5.0±0.2, 15.9±0.2, 16.8±0.2 and 18.8±0.2 degrees 2-theta, which is crystalline Form I; and ix. a crystalline form of formula (I) characterized by an XRPD pattern having peaks at 5.9±0.2, 12.7±0.2, 17.4±0.2 and 18.8±0.2 degrees 2-theta, which is crystalline Form J.

2. The crystalline form according to claim 1, wherein the crystalline form is characterized by an endothermic peak starting at 160°C as determined by DSC.

4. The crystalline form according to claim 3, wherein the crystalline form is anhydrous.

3. The crystalline form of claim 1 or 2, wherein the crystalline form is characterized by an IR pattern with peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, 1238.7 ± 2.0, and 1313.2 ± 2.0 cm -1 . ​ 5. The crystalline form of claim 4, wherein the crystalline form has a unit cell indexed to a simple monoclinic crystal system; wherein the crystalline form has a unit cell with a value of b value of and a c value of . wherein said crystalline form has a unit cell with a volume of about 1,200 A3. The crystal form described therein does not include a crystal form of formula (I) that has a unit cell indexed as a simple monoclinic system and has an a value of b is a value And the value of c is The unit cell, and having a volume of The unit cell; and wherein the crystalline form does not include a crystalline form of Formula (I) having a unit cell with a value of a b value of and a value of c of the unit cell, and a unit cell with a volume of .

6. A pharmaceutical composition comprising a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid of Formula (I); and a pharmaceutically acceptable carrier, diluent or excipient or mixture thereof; wherein the pharmaceutical composition is an oral tablet; and wherein the oral tablet comprises 400 mg of the crystalline form; wherein the crystalline form of Formula (I): is characterized by an XRPD pattern having peaks at 8.7 ± 0.2, 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees 2-theta, as measured using Cu Ka radiation, which is crystalline Form A having a polymorphic purity of at least 95% or at least 99%; wherein the crystalline form of Formula (I) does not comprise: i. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, 17.8 ± 0.2, and 21.1 ± 0.2 degrees 2-theta, which is crystalline Form B; ii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 8.0 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees 2-theta, which is crystalline Form C; iii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, 18.2 ± 0.2, and 26.4 ± 0.2 degrees 2-theta, which is crystalline Form D; iv. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 20.7 ± 0.2 degrees 2-theta, which is crystalline Form E; v. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, 16.8 ± 0.2, and 17.9 ± 0.2 degrees 2-theta, which is crystalline Form F; vi. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, and 22.4 ± 0.2 degrees 2-theta, which is crystalline Form G; vii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, 8.5 ± 0.2, and 15.9 ± 0.2 degrees 2-theta, which is crystalline Form H; viii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees 2-theta, which is crystalline Form I; and ix. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 12.7 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees 2-theta, which is crystalline Form J.

7. The pharmaceutical composition of claim 6, wherein the crystalline form is characterized by an endothermic peak beginning at 160 °C as determined by DSC.

8. The pharmaceutical composition according to claim 6 or 7, wherein the crystalline form is characterized by an IR pattern with peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, 1238.7 ± 2.0 and 1313.2 ± 2.0 cm -1 1.

9. The pharmaceutical composition of claim 8, wherein the crystalline form is anhydrous.

10. The pharmaceutical composition of claim 9, wherein the crystalline form has a unit cell indexed in the simple monoclinic system; wherein the crystalline form has a unit cell with a value of b value of and a c value of . wherein the crystalline form has a unit cell with a volume of about 1, 2, 3, 4, 5, 6, 7, wherein said crystalline form does not comprise a crystalline form of Formula (I) having a unit cell with an index of simple monoclinic crystal system, with a value of a of b value of and a value of c of a unit cell with a volume of ; and wherein the crystalline form does not include a crystalline form of Formula (I) having a unit cell with a value of b value of and a value of and a unit cell with a volume of .

11. Use of a crystalline form of {2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)- ureido]-thiazol-5-ylsulfanyl} -acetic acid of Formula (I) in combination with insulin therapy in the manufacture of a medicament for the treatment of a type of diabetes, wherein the type of diabetes is Type 1 diabetes or Type 2 diabetes; wherein the medicament is formulated for oral administration of the crystalline form of Formula (I); and the medicament is formulated as a capsule or a tablet; wherein the dosage form for a single administration comprises 800 mg of the crystalline form of Formula (I); wherein the insulin therapy is formulated for administration by continuous subcutaneous insulin infusion or by multiple daily dosing of insulin; wherein the crystalline form of Formula (I): is characterized by an XRPD pattern having peaks at 8.7 ± 0.2, 16.9 ± 0.2, 17.4 ± 0.2, and 20.1 ± 0.2 degrees 2-theta, as measured using Cu K alpha radiation, which is crystalline Form A having a polymorphic purity of at least 95% or at least 99%; wherein the crystalline form of Formula (I) does not comprise: i. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 11.0 ± 0.2, 11.6 ± 0.2, 17.8 ± 0.2, and 21.1 ± 0.2 degrees 2-theta, which is crystalline Form B; ii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 4.3 ± 0.2, 8.0 ± 0.2, 17.4 ± 0.2, and 21.6 ± 0.2 degrees 2-theta, which is crystalline Form C; iii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.3 ± 0.2, 8.7 ± 0.2, 18.2 ± 0.2, and 26.4 ± 0.2 degrees 2-theta, which is crystalline Form D; iv. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.8 ± 0.2, 17.9 ± 0.2, 18.9 ± 0.2, and 20.7 ± 0.2 degrees 2-theta, which is crystalline Form E; v. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 9.5 ± 0.2, 16.8 ± 0.2, and 17.9 ± 0.2 degrees 2-theta, which is crystalline Form F; vi. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.4 ± 0.2, 21.2 ± 0.2, 21.9 ± 0.2, and 22.4 ± 0.2 degrees 2-theta, which is crystalline Form G; vii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 3.8 ± 0.2, 5.3 ± 0.2, 8.5 ± 0.2, and 15.9 ± 0.2 degrees 2-theta, which is crystalline Form H; viii. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.0 ± 0.2, 15.9 ± 0.2, 16.8 ± 0.2, and 18.8 ± 0.2 degrees 2-theta, which is crystalline Form I; and ix. a crystalline form of Formula (I) characterized by an XRPD pattern having peaks at 5.9 ± 0.2, 12.7 ± 0.2, 17.4 ± 0.2, and 18.8 ± 0.2 degrees 2-theta, which is crystalline Form J.

12. The use of claim 11, wherein the type of diabetes is Type 1 diabetes.

13. The use of claim 11, wherein the type of diabetes is Type 2 diabetes.

14. The use of any one of claims 11-13, wherein the crystalline form is characterized by an endothermic peak beginning at 160 °C as determined by DSC.

15. The use according to any one of claims 11-13, wherein the crystalline form is characterized by an IR pattern with peaks at 1099.7 ± 2.0, 1158.0 ± 2.0, 1238.7 ± 2.0 and 1313.2 ± 2.0 cm -1 1.

16. The use of any one of claims 11-13, wherein the crystalline form is anhydrous.

17. The use of any one of claims 11-13, wherein the crystalline form has a unit cell indexed in the simple monoclinic system. wherein the crystalline form has a unit cell with a value of b value of and a c value of . wherein the crystalline form has a unit cell with a volume of about 1, 2, 3, 4, 5, 6, 7, The crystal form described therein does not include a crystal form of formula (I) that has a unit cell indexed as a simple monoclinic system and has an a value of b is a value And the value of c is The unit cell, and having a volume of The unit cell; and The crystalline form described herein does not include a crystalline form of formula (I) that has a value of a. b is a value And the value of c is The unit cell, and having a volume of The unit cell.

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