Crystalline forms or salts of deuterated compounds

Abstract

The present disclosure relates to various crystalline forms of Compound 2 or salts of Compound 2, as well as pharmaceutical compositions, methods of making and methods of using the same. These crystalline forms are useful in the treatment of diseases and disorders modulated by PPARα and / or PPARγ agonists.

Description

[Technical Field]

[0001] The present disclosure relates generally to crystalline forms of Compound 2 or salts of Compound 2, pharmaceutical compositions containing these crystalline forms or salts, and methods of treatment by administering these crystalline forms or salts or said pharmaceutical compositions. [Background technology]

[0002] Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and are ligand-activated transcription factors that regulate gene expression. Various subtypes have been identified and cloned, including PPARα, PPARβ (also known as PPARδ), and PPARγ. PPARγ exists in at least two major isoforms. PPARγl is ubiquitously expressed in most tissues, while the longer isoform, PPARγ2, is found almost exclusively in adipocytes. In contrast, PPARα is primarily expressed in the liver, kidney, and heart. PPARs regulate various biological responses, including glucose and lipid homeostasis, cell differentiation, inflammatory responses, and cardiovascular events. Combining the lipid metabolism-regulating activity of PPARα and the insulin sensitivity-regulating activity of PPARγ to develop specific PPARα / γ dual agonists that control blood glucose levels and improve cardiovascular symptoms has significant implications for clinical drug development.

[0003] As a PPAR-α / γ dual agonist, aleglitazar possesses relatively balanced PPAR-α / γ activity. It can effectively improve fasting and postprandial blood glucose levels, insulin sensitivity, and blood lipid parameters. However, phase 3 clinical trials of aleglitazar demonstrated that while it effectively reduced blood glucose and blood lipid levels, it was associated with a certain risk of heart failure, resulting in no benefit for treating cardiovascular disease. Clinical trials also demonstrated adverse effects, such as increased risk of fractures, which are known to be caused by PPARγ activation (Lincoff AM, et al. JAMA. 2014;311(15):1515-1525). Therefore, the development of suitable selective PPAR-α / γ dual agonists that improve safety and patient benefits is necessary.

[0004] The present disclosure relates to aleglitazar, i.e., compound 2 [ka] By deuterating the compound, a novel dual agonist of PPARα and PPARγ is provided.

[0005] Compound 2 has different PPAR-α / γ selectivity than aleglitazar. Because compound 2 has stronger PPARα activity, it can demonstrate superior PPARα activity in in vitro transcription and in vivo lipid-lowering studies while maintaining a certain level of PPARγ activity. Therefore, it can achieve high therapeutic efficacy in regulating blood lipid and blood glucose levels while reducing side effects caused by PPARγ activity, such as weight gain and the risk of heart failure. Compared to aleglitazar, compound 2 has a more reasonable risk-benefit ratio for patients with metabolic syndrome, making it a promising candidate for clinical application.

[0006] Many compounds can exist in different crystalline forms, or polymorphs, which exhibit different physical, chemical, and spectroscopic properties. For some drugs, certain solid forms may be more bioavailable than others, or other forms may be more stable under manufacturing, storage, and biological conditions. To ensure the quality, safety, and efficacy of a drug during manufacturing, it is important to have one polymorph of a compound that exhibits certain desirable physical and chemical properties (including spectroscopic properties).

[0007] Thus, there is a strong need for one or more crystalline forms of Compound 2 or one or more salts of Compound 2 that provide an acceptable balance of these properties. Summary of the Invention

[0008] The present disclosure provides compounds 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 3 [ka] or salts of Compound 2, including certain anhydrous, hydrated, and solvated forms thereof, and solid forms, and pharmaceutical compositions thereof. Methods of using such compounds in the treatment of various diseases or conditions, such as diabetes, are also provided.

[0009] In one embodiment, the present disclosure provides crystalline Form B of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 8.16, 13.23, and 13.90 (±0.2 degrees 2θ).

[0010] In another aspect, the present disclosure provides crystalline Form C of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 5.06, 10.09, and 20.24 (±0.2 degrees 2θ).

[0011] In yet another aspect, the disclosure provides crystalline Form D of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 5.03, 12.98, 15.91, and 21.58 (±0.2 degrees 2θ).

[0012] In yet another aspect, the present disclosure provides crystalline Form E of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 10.12, 11.97, 13.73, and 18.89 (±0.2 degrees 2θ).

[0013] In yet another aspect, the present disclosure provides crystalline Form F of Compound 2, characterized by an XRPD pattern comprising one or two peaks at 15.50 and 21.23 (±0.2 degrees 2θ).

[0014] In yet another aspect, the present disclosure provides crystalline Form G of the maleate salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 9.67, 11.60, 12.90, and 14.43 (±0.2 degrees 2θ).

[0015] In another aspect, the present disclosure provides a salt of Compound 2 selected from the sodium, potassium, arginine, magnesium, or tromethamine salt of Compound 2.

[0016] In some embodiments, the present disclosure provides crystalline Form A of the sodium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 4.09, 4.62, and 14.21 (±0.2 degrees 2θ).

[0017] In some embodiments, the present disclosure provides crystalline Form C of the potassium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 12.91, 14.96, and 21.23 (±0.2 degrees 2θ).

[0018] In some embodiments, the present disclosure provides crystalline Form A of the arginine salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 12.93, 13.43, 18.21, and 19.49 (±0.2 degrees 2θ).

[0019] In some embodiments, the present disclosure provides crystalline Form A of the potassium salt of Compound 2, characterized by an XRPD pattern substantially as shown in the upper curve of Figure 19A.

[0020] In some embodiments, the present disclosure provides crystalline Form B of the potassium salt of Compound 2, characterized by an XRPD pattern substantially as shown in the lower curve of Figure 19A.

[0021] In some embodiments, the present disclosure provides crystalline Form A of the magnesium salt of Compound 2, characterized by an XRPD pattern substantially as shown in Figure 21A.

[0022] In some embodiments, the present disclosure provides crystalline Form A of the tromethamine salt of Compound 2, characterized by an XRPD pattern substantially as shown in Figure 22A.

[0023] In another aspect, the present disclosure provides a pharmaceutical composition comprising Compound 2 or a salt of Compound 2 and a pharmaceutically acceptable excipient, wherein Compound 2 or the salt of Compound 2 is a crystalline form of the present disclosure.

[0024] In yet another aspect, the present disclosure provides a method for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist in a subject, the method comprising administering to the subject an effective amount of a crystalline form of Compound 2 or a salt of Compound 2 described in the present disclosure, or a pharmaceutical composition described in the present disclosure.

[0025] In yet another aspect, the present disclosure provides use of a crystalline form of Compound 2 of the present disclosure or a salt of Compound 2, or a pharmaceutical composition described herein, in the manufacture of a medicament for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist.

[0026] In yet another aspect, the present disclosure provides a method for modulating PPARα and / or PPARγ in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of Compound 2 or a salt of Compound 2 described herein, or a pharmaceutical composition described herein. [Brief explanation of the drawings]

[0027] [Figure 1A] Figure 1A shows an XRPD overlay of the starting material (818159-01-A). [Figure 1B] FIG. 1B shows the TGA / DSC curve of the starting material (818159-01-A). [Figure 2A] Figure 2A shows an XRPD overlay of the starting material (818159-60-A). [Figure 2B] FIG. 2B shows the TGA / DSC curve of the starting material (818159-60-A). [Figure 3] FIG. 3 shows an XRPD overlay of the free acid crystalline form. [Figure 4A] FIG. 4A shows the XRPD patterns of free acid Form B (prepared from EtOAc, 818159-08-B, contains a small amount of Form E) before and after slurrying in CAN. [Figure 4B] FIG. 4B shows the TGA / DSC curve of free acid Form B (prepared from EtOAc, 818159-08-B, contains a small amount of Form E). [Figure 4C] FIG. 4C shows the H NMR spectrum of free acid form B (prepared from EtOAc, 818159-08-B, contains a small amount of form E). [Figure 4D] FIG. 4D shows the VT XRPD of free acid Form B (818159-08-B containing a small amount of Form E). [Figure 5A] FIG. 5A shows the XRPD pattern of free acid form B (818159-39-B). [Figure 5B] FIG. 5B shows the TGA / DSC curve of free acid form B (818159-39-B). [Figure 6A] FIG. 6A shows the XRPD pattern of the free acid form C (818159-30-B). [Figure 6B] FIG. 6B shows the TGA / DSC curve of the free acid form C (818159-30-B). [Figure 6C] FIG. 6C shows the H NMR spectrum of the free acid form C (818159-30-B). [Figure 7] FIG. 7 shows the XRPD pattern of free acid form D (818159-25-A11). [Figure 8] FIG. 8 shows an XRPD overlay of different batches of free acid form D. [Figure 9A] FIG. 9A shows the TGA / DSC curve of free acid form D (818159-36-B, containing a small amount of form E). [Figure 9B] FIG. 9B shows the 1H NMR spectrum of free acid form D (818159-36-B, containing a small amount of form E). [Figure 9C] FIG. 9C shows an XRPD overlay of free acid Form D (818159-36-B, containing a small amount of Form E) before and after storage at room temperature. [Figure 10] FIG. 10 shows an XRPD overlay of the reconstituted free acid form D. [Figure 11A] FIG. 11A shows the TGA / DSC curve of free acid form D (818159-68-B, containing a small amount of form E). [Figure 11B] FIG. 11B shows the 1H NMR spectrum of free acid form D (818159-68-B, containing a small amount of form E). [Figure 11C] FIG. 11C shows the VT-XRPD pattern of free acid Form D (818159-68-B, containing a small amount of Form E). [Figure 12] FIG. 12 shows the XRPD pattern of the free acid form E (818159-40-A2_30Jul). [Figure 13A] FIG. 13A shows an XRPD overlay of free acid Form E (818159-32-B, containing a small amount of Form B). [Figure 13B] FIG. 13B shows the TGA / DSC curve of free acid form E (818159-32-B, containing a small amount of form B). [Figure 13C] FIG. 13C shows the 1H NMR spectrum of the free acid form E (818159-32-B, containing a small amount of form B). [Figure 14A] FIG. 14A shows the XRPD pattern of the free acid form F (818159-37-B). [Figure 14B] FIG. 14B shows the TGA / DSC curve of the free acid form F (818159-37-B). [Figure 14C] FIG. 14C shows the 1H NMR spectrum of the free acid form F (818159-37-B). [Figure 14D] Figure 14D shows a VT-XRPD overlay of the free acid form F (818159-37-B). [Figure 15A] FIG. 15A shows the XRPD pattern of the free acid form G (818159-41-B). [Figure 15B] FIG. 15B shows the TGA / DSC curve of the free acid form G (818159-41-B). [Figure 15C] FIG. 15C shows the 1H NMR spectrum of the free acid form G (818159-41-B). [Figure 16A] FIG. 16A shows an XRPD overlay of the residual solids from a slurry competition of the anhydrous form (I / V). [Figure 16B] FIG. 16B shows an XRPD overlay of the residual solids from a slurry competition of the anhydrous form (II / V). [Figure 16C] FIG. 16C shows an XRPD overlay of the residual solids from a slurry competition of the anhydrous form (III / V). [Figure 16D] FIG. 16D shows an XRPD overlay of the residual solids from a slurry competition of the anhydrous form (IV / V). [Figure 16E] FIG. 16E shows an XRPD overlay of the residual solids from a slurry competition of the anhydrous form (V / V). [Figure 17A] FIG. 17A shows an XRPD overlay of residual solids from slurry competitions at different water activities (I / II). [Figure 17B] FIG. 17B shows an XRPD overlay of residual solids from slurry competitions at different water activities (II / II). [Figure 18A] FIG. 18A shows the XRPD pattern of Na salt form A (818159-03-B1). [Figure 18B]FIG. 18B shows the TGA / DSC curve of Na salt form A (818159-03-B1). [Figure 18C] FIG. 18C shows the H NMR spectrum of Na salt form A (818159-03-B1). [Figure 19A] FIG. 19A shows the XRPD pattern of K salt form A / B (818159-03-B2 / C2). [Figure 19B] FIG. 19B shows the TGA / DSC curve of K salt form A (818159-03-B2). [Figure 19C] FIG. 19C shows the H NMR spectrum of K salt form A (818159-03-B2). [Figure 20A] FIG. 20A shows the XRPD pattern of arginine salt form A (818159-03-B3). [Figure 20B] FIG. 20B shows the TGA / DSC curve of arginine salt form A (818159-03-B3). [Figure 20C] FIG. 20C shows the H NMR spectrum of arginine salt form A (818159-03-B3). [Figure 21A] FIG. 21A shows the XRPD pattern of Mg salt form A (818159-03-C5). [Figure 21B] FIG. 21B shows the TGA / DSC curve of Mg salt form A (818159-03-C5). [Figure 21C] FIG. 21C shows the H NMR spectrum of Mg salt form A (818159-03-C5). [Figure 22A] Figure 22A shows the XRPD pattern of Tris salt Form A (818159-03-B10). [Figure 22B] FIG. 22B shows the TGA / DSC curve of tris salt form A (818159-03-B10). [Figure 22C] FIG. 22C shows the H NMR spectrum of tris salt form A (818159-03-B10). [Figure 23] FIG. 23 shows an XRPD overlay of the reconstituted Na salt Form A. [Figure 24A] Figure 24A shows the XRPD pattern of Na salt form A (818159-09-B). [Figure 24B] FIG. 24B shows the TGA / DSC curve of the reconstituted Na salt form A (818159-09-B). [Figure 24C] FIG. 24C shows the 1H NMR spectrum of reconstituted Na salt form A (818159-09-B). [Figure 25] FIG. 25 shows an XRPD overlay of the reconstituted K salt form C. [Figure 26A] Figure 26A shows the XRPD pattern of K salt form C (818159-10-B). [Figure 26B] Figure 26B shows the TGA / DSC curve of the reconstituted K salt form C (818159-10-B). [Figure 26C] Figure 26C shows the H NMR spectrum of the reconstituted K salt form C (818159-10-B). [Figure 27] FIG. 27 shows an XRPD overlay of reconstituted arginine salt Form A. [Figure 28A] FIG. 28A shows the XRPD pattern of arginine salt form A (818159-11-B). [Figure 28B] FIG. 28B shows the TGA / DSC curve of reconstituted arginine salt form A (818159-11-B). [Figure 28C] FIG. 28C shows the 1H NMR spectrum of reconstituted arginine salt form A (818159-11-B). [Figure 29A] FIG. 29A shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in water. [Figure 29B] FIG. 29B shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in SGF. [Figure 29C] FIG. 29C shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in FaSSIF-V2. [Figure 29D]FIG. 29D shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in FeSSIF-V2. [Figure 29E] FIG. 29E shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in pH 1.2 buffer. [Figure 29F] FIG. 29F shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in pH 4.5 buffer. [Figure 29G] FIG. 29G shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid Form B in pH 6.8 buffer. [Figure 30A] FIG. 30A shows an XRPD overlay of the residual solids from the kinetic solubility starting with K salt Form C in water. [Figure 30B] FIG. 30B shows an XRPD overlay of the residual solids from the kinetic solubility starting with K salt Form C in SGF. [Figure 30C] FIG. 30C shows an XRPD overlay of the residual solids from the kinetic solubility starting with K salt Form C in pH 1.2 buffer. [Figure 30D] FIG. 30D shows an XRPD overlay of the residual solids from the kinetic solubility starting with K salt Form C in pH 4.5 buffer. [Figure 31A] FIG. 31A shows an XRPD overlay of residual solids from the kinetic solubility starting with arginine salt Form A in SGF. [Figure 31B] FIG. 31B shows an XRPD overlay of the residual solids from the kinetic solubility starting with arginine salt Form A in pH 1.2 buffer. [Figure 31C] FIG. 31C shows an XRPD overlay of the residual solids from the kinetic solubility starting with arginine salt Form A in pH 4.5 buffer. [Figure 31D] FIG. 31D shows the XRPD pattern of the residual solids from the kinetic solubility starting with arginine salt Form A in pH 6.8 buffer. [Figure 32A]FIG. 32A shows the XRPD pattern of the residual solid from the kinetic solubility starting with Na salt Form A in water. [Figure 32B] FIG. 32B shows an XRPD overlay of the residual solids from the kinetic solubility starting with Na salt Form A in SGF. [Figure 33] FIG. 33 shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid form E (818159-61-B, 24 hours). [Figure 34] FIG. 34 shows an XRPD overlay of the residual solids from the kinetic solubility starting with free acid form B (818159-71-B, 24 hours). [Figure 35] Figure 35 shows the kinetic solubility curves at 37°C. [Figure 36] FIG. 36 shows the kinetic solubility curves of free acid forms B and E. [Figure 37A] Figure 37A shows the DVS plot of free acid form B (818159-08-B). [Figure 37B] Figure 37B shows an XRPD overlay of free acid form B (818159-08-B) before and after DVS testing. [Figure 38A] Figure 38A shows the DVS plot of K salt form C (818159-10-B). [Figure 38B] Figure 38B shows an XRPD overlay of K salt form C (818159-10-B) before and after DVS testing. [Figure 39A] Figure 39A shows the DVS plot of arginine salt form A (818159-11-B). [Figure 39B] FIG. 39B shows an XRPD overlay of arginine salt Form A (818159-11-B) before and after DVS testing. [Figure 40A] Figure 40A shows the DVS plot of Na salt form A (818159-09-B). [Figure 40B] FIG. 40B shows an XRPD overlay of Na salt Form A (818159-09-B) before and after DVS testing. [Figure 41]Figure 41 shows an XRPD overlay of free acid form B (818159-08-B) before and after solid state stability evaluation. [Figure 42] Figure 42 shows an XRPD overlay of free acid form E (818159-61-B) before and after solid state stability evaluation. [Figure 43] FIG. 43 shows the DSC curve of free acid form E (821755-05-A / B) after 8 weeks of solid state stability evaluation. [Figure 44] Figure 44 shows an XRPD overlay of Na salt Form A (818159-09-B) before and after solid state stability evaluation. [Figure 45] Figure 45 shows an XRPD overlay of K salt form C (818159-10-B) before and after solid state stability evaluation. [Figure 46] Figure 46 shows the XRPD overlay of arginine salt Form A (818159-11-B) before and after solid state stability evaluation. [Figure 47] FIG. 47 shows the HPLC chromatograms of free acid form B (818159-08-B) before and after solid state stability evaluation. [Figure 48] FIG. 48 shows the HPLC chromatograms of free acid form E (818159-61-B) before and after solid state stability evaluation. [Figure 49] FIG. 49 shows the HPLC chromatograms of Na salt form A (818159-09-B) before and after solid state stability evaluation. [Figure 50] FIG. 50 shows the HPLC chromatograms of K salt form C (818159-10-B) before and after solid state stability evaluation. [Figure 51] FIG. 51 shows the HPLC chromatograms of arginine salt Form A (818159-11-B) before and after solid state stability evaluation. [Figure 52A] Figure 52A shows the changes in serum TG in each group. Data are presented as mean ± SD, and one-way ANOVA was performed using Prism GraphPad, n = 6. ****P<0.0001, ***P<0.001, **P<0.001, *P<0.05 vs. vehicle. [Figure 52B]Figure 52B shows the changes in serum NEFA in each group. Data are presented as mean ± SD and one-way ANOVA was performed using Prism GraphPad, n = 6. ****P < 0.0001 vs vehicle. [Figure 53A] FIG. 53A shows the change in weight gain of animals in each group compared to day 0. [Figure 53B] Figure 53B shows the change in the difference in weight gain between each group of animals and the vehicle group (*: weight gain of the treatment group minus the average weight gain of the vehicle group). [Figure 54] Figure 54 shows the effect of compounds on body weight change in db / db animals. Data are presented as mean ± SEM and analyzed by two-way ANOVA followed by Dunnett's test using Prism GraphPad, n=6-9. [Figure 55A] Figure 55A shows the effect of compounds on serum TG levels in db / db animals on day 6. Data are presented as mean ± SEM and analyzed by one-way ANOVA followed by Dunnett's test in Prism GraphPad, n = 6-9. **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. model. [Figure 55B] Figure 55B shows the effect of compounds on serum TG levels in db / db animals on day 12. Data are presented as mean ± SEM and analyzed by one-way ANOVA followed by Dunnett's test in Prism GraphPad, n=6-9. ****P<0.0001 vs. model. [Figure 56] Figure 56 shows the effect of compounds on random blood glucose in db / db animals. Data are presented as mean ± SEM, n = 6-9. [Figure 57A] Figure 57A shows the effect of compounds on oral glucose tolerance in db / db animals. Data are presented as mean ± SEM, n = 6-9. [Figure 57B]Figure 57B shows the effect of compounds on oral glucose tolerance in db / db animals. Data are presented as mean ± SEM and analyzed by one-way ANOVA followed by Dunnett's test using Prism GraphPad, n = 6-9. **P<0.01, ***P<0.001, ****P<0.0001 vs. model group. [Figure 58] Figure 58 shows the effect of Compound 2 on urinary albumin excretion. [Figure 59A] FIG. 59A shows the effect of Compound 2 on glomerular and tubular injury. [Figure 59B] FIG. 59B shows the effect of Compound 2 on glomerular and tubular injury. [Figure 59C] FIG. 59C shows the effect of Compound 2 on glomerular and tubular injury. [Figure 59D] FIG. 59D shows the effect of Compound 2 on glomerular and tubular injury. [Figure 60] FIG. 60 shows the effect of Compound 2 on ameliorating renal injury in a rat model of unilateral ureteral obstruction. DETAILED DESCRIPTION OF THE INVENTION

[0028] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. While the present disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all variations, modifications, and equivalents that may be included within the scope of the present disclosure, as defined by the claims. Those skilled in the art will recognize numerous methods and materials similar or equivalent to those described herein that could be used in practicing the present disclosure. The present disclosure is not limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials differs or contradicts the present application, including but not limited to defined terms, term usage, or described techniques, the present disclosure controls. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

[0029] It is understood that certain features of the present disclosure, which are for clarity described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are for brevity described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. It should be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0030] definition As used herein, the term "aleglitazar," also known as RG-1439 or RO-0728804, is a dual agonist of peroxisome proliferator-activated receptor α / γ (PPARα / γ) with insulin-sensitizing and blood glucose-lowering effects and favorable effects on lipid profiles. Its use in type 2 diabetes patients is being studied to reduce their risk of cardiovascular morbidity and mortality. "Aleglitazar" has the following structure: [ka]

[0031] As used herein, the term "compound 2," which is deuterated aleglitazar, refers to a compound having the following structure: [ka]

[0032] As used herein, the terms "crystal form" and "form" refer interchangeably to a crystalline structure (or polymorph) having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and / or dynamic vapor sorption (DVS). Thus, as used herein, the term "crystalline form [X] of Compound 2" refers to a unique crystalline form that can be identified and distinguished by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and / or dynamic vapor sorption (DVS). In some embodiments, the novel crystalline form is characterized by an X-ray powder diffraction pattern having one or more signals at one or more designated 2θ values ​​(°2θ).

[0033] As used herein, the term "solvate" refers to a crystalline form that contains one or more molecules of a compound of the present disclosure and one or more molecules of a solvent or solvent medium in a stoichiometric or non-stoichiometric amount that are incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate."

[0034] As used herein, the term "XRPD" refers to the analytical characterization method of X-ray powder diffraction. As used herein, the terms "X-ray powder diffractogram," "X-ray powder diffraction pattern," and "XRPD pattern" refer to an experimentally obtained pattern that plots signal position (abscissa) versus signal intensity (ordinate). For amorphous materials, the X-ray powder diffractogram may include one or more broad signals; for crystalline materials, the X-ray powder diffractogram may include one or more signals shown on the ordinate of the X-ray powder diffractogram, each identified by its angle value measured in degrees two-theta (°2θ).

[0035] As used herein, a "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be clearly visible to the naked eye, for example. Indeed, those skilled in the art will recognize that several art-recognized methods, such as the Rietveld method, are available and suitable for determining whether a signal is present in a pattern.

[0036] The repeatability of the measured angle values ​​is within ±0.2°2θ, i.e., the angle value can be the stated angle value +0.2°2θ, angle value −0.2°2θ, or any value between these endpoints (angle value +0.2°2θ and angle value −0.2°2θ). In some embodiments, the repeatability of the measured angle values ​​is within ±0.1°2θ.

[0037] The term "peak intensity" refers to the relative signal intensity within a given X-ray powder diffractogram. Factors that can affect relative signal or peak intensity include sample thickness and preferred orientation (e.g., crystalline grains are not randomly distributed).

[0038] As used herein, an X-ray powder diffractogram is "substantially similar to that in a [particular] diffractogram" if at least 90%, e.g., at least 95%, at least 98%, or at least 99% of the peaks in the two diffractograms overlap. In determining "substantially similar," one skilled in the art will understand that even for the same crystalline form, there may be variations in intensity and / or signal positions in an XRPD diffractogram. Thus, one skilled in the art will understand that signal maxima (in °2θ herein) in an XRPD diffractogram generally mean that the values ​​are identified to the reported value ± 0.2 degrees 2θ, an art-recognized difference. In some embodiments, signal differences are identified to the reported value ± 0.1 degrees 2θ.

[0039] As used herein, the terms "about" and "substantially" indicate that values ​​may vary with respect to features such as endotherms, endothermic peaks, exotherms, and baseline shifts. With respect to X-ray diffraction peak positions, "about" or "substantially" means that typical peak position and intensity variations are taken into account. For example, those skilled in the art will understand that peak positions (2θ) vary somewhat between instruments, typically by 0.2°. Occasionally, variations may exceed 0.2° due to differences in instrument calibration. Furthermore, those skilled in the art will understand that relative peak intensities vary not only between instruments, but also due to crystallinity, preferred orientation, the surface of the sample prepared, and other factors known to those skilled in the art, and should be viewed only as qualitative measurements. For DSC, observed temperature variations depend on the rate of temperature change, sample preparation technique, and the particular instrument employed. Thus, the endotherm / melting point values ​​reported herein in connection with DSC / TGA thermograms may vary by ±5°C (still considered characteristic of the particular crystalline form described herein). When used in the context of other characteristics, such as weight percent (wt %), reaction temperature, etc., the term "about" indicates a variance of ±5%.

[0040] As used herein, "amorphous" refers to a solid form of molecules, atoms, and / or ions that are not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns.

[0041] As used herein, "substantially pure," when used in reference to a form, means that the compound has a purity of greater than 90% by weight, based on the weight of the compound (including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, including greater than about 100% by weight of Compound 2). The remaining material comprises other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound 2 may be considered substantially pure as having a purity of greater than 90% by weight, as measured by means currently known and generally accepted in the art, where the remaining less than 10% by weight of the material comprises other forms of Compound 2 and / or reaction and / or processing impurities.

[0042] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound provided herein or a crystalline form thereof that is in a form suitable for administration to a subject.

[0043] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one or more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0044] As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition comprising a molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or modulating effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, the rate of administration, the therapeutic agent or combination of therapeutic agents selected for administration, and the discretion of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0045] As used herein, "subject" refers to humans and non-human animals. Examples of non-human animals include all vertebrates, for example, mammals such as non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, and cats, as well as non-mammals such as birds, amphibians, and reptiles. In preferred embodiments, the subject is a human. In some embodiments, the subject is an experimental animal or an animal suitable as a disease model.

[0046] Crystalline morphology The present disclosure relates to compound 2 [ka] or salts of Compound 2, and compounds containing them, methods of preparation for making pharmaceutical compositions, and various uses of the disclosed compounds.

[0047] Crystalline Form B of Compound 2 In one aspect, the disclosure relates to crystalline form B of Compound 2, characterized by an X-ray powder diffraction pattern (XRPD) comprising one or more peaks at 8.16, 13.23, and 13.90 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form B further comprises one or more peaks at 4.94, 11.83, 14.97, 18.54, and 26.24 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form B further comprises one or more peaks at 9.89, 19.74, and 20.92 (±0.2 degrees 2θ).

[0048] In some embodiments, crystalline form B is [Table A] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0049] In some embodiments, crystalline form B is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 5 A. In some embodiments, crystalline form B is characterized by an XRPD pattern substantially as shown in Figure 5A.

[0050] In some embodiments, crystalline Form B is characterized by a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 5B.

[0051] In some embodiments, crystalline form B is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with a peak temperature of about 151.1°C.

[0052] In some embodiments, crystalline form B is characterized by a DSC thermogram substantially as shown in Figure 5B.

[0053] In some embodiments, crystalline form B is anhydrous.

[0054] In some embodiments, crystalline form B is substantially pure. In other embodiments, crystalline form B has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0055] Crystalline Form C of Compound 2 In one aspect, the disclosure relates to crystalline form C of Compound 2, characterized by an XRPD pattern including one or more peaks at 5.06, 10.09, and 20.24 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form C further includes one or more peaks at 15.15, 16.18, and 16.75 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form C further includes one or more peaks at 7.99, 8.37, 11.71, 12.22, 12.87, 13.60, and 14.04 (±0.2 degrees 2θ).

[0056] In some embodiments, crystalline form C is [Table B] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0057] In some embodiments, crystalline form C is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 6A. In some embodiments, crystalline form C is characterized by an XRPD pattern substantially as shown in Figure 6A.

[0058] In some embodiments, crystalline form C is characterized by a TGA thermogram substantially as shown in Figure 6B.

[0059] In some embodiments, crystalline form C is characterized by a DSC thermogram with an endotherm having a peak temperature of about 149.0°C.

[0060] In some embodiments, crystalline form C is characterized by a DSC thermogram substantially as shown in Figure 6B.

[0061] In some embodiments, crystalline form C is anhydrous.

[0062] In some embodiments, crystalline form C is substantially pure. In other embodiments, crystalline form C has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0063] Crystalline Form D of Compound 2 In one aspect, the disclosure relates to crystalline form D of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 5.03, 12.98, 15.91, and 21.58 (±0.2 degrees two-theta). In some embodiments, the XRPD pattern of crystalline form D further comprises one or more peaks at 5.90, 9.21, 20.47, and 26.08 (±0.2 degrees two-theta). In some embodiments, the XRPD pattern of crystalline form D further comprises one or more peaks at 11.76, 15.04, 22.38, and 24.47 (±0.2 degrees two-theta).

[0064] In some embodiments, crystalline form D is [Table C] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0065] In some embodiments, crystalline form D is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 7. In some embodiments, crystalline form D is characterized by an XRPD pattern substantially as shown in Figure 7.

[0066] In some embodiments, crystalline form D is a hydrate.

[0067] In some embodiments, crystalline form D is a substantially pure form. In other embodiments, crystalline form D has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0068] Crystalline Form E of Compound 2 In one aspect, the disclosure relates to crystalline form E of Compound 2, characterized by an XRPD pattern including one or more peaks at 10.12, 11.97, 13.73, and 18.89 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form E further includes one or more peaks at 5.06, 8.14, 13.02, and 14.19 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form E further includes one or more peaks at 14.87, 21.30, 22.33, and 26.23 (±0.2 degrees 2θ).

[0069] In some embodiments, crystalline form E is [Table D] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0070] In some embodiments, crystalline form E is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 12. In some embodiments, crystalline form E is characterized by an XRPD pattern substantially as shown in Figure 12.

[0071] In some embodiments, crystalline form E is anhydrous.

[0072] In some embodiments, crystalline form E is a substantially pure form. In some embodiments, crystalline form E has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0073] Crystalline Form F of Compound 2 In one aspect, the disclosure relates to crystalline form F of Compound 2, characterized by an XRPD pattern comprising one or two peaks at 15.50 and 21.23 (±0.2 degrees two-theta). In some embodiments, the XRPD pattern of crystalline form F further comprises one or two peaks at 12.12 and 20.21 (±0.2 degrees two-theta).

[0074] In some embodiments, crystalline form F is [Table E] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0075] In some embodiments, crystalline form F is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 14A. In some embodiments, crystalline form F is characterized by an XRPD pattern substantially as shown in Figure 14A.

[0076] In some embodiments, crystalline form F is characterized by a TGA thermogram substantially as shown in Figure 14B.

[0077] In some embodiments, crystalline form F is characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with a peak temperature at about 111.2°C and / or about 149.8°C.

[0078] In some embodiments, crystalline form F is characterized by a DSC thermogram with an exotherm with a peak temperature of about 118.9°C.

[0079] In some embodiments, crystalline form F is characterized by a DSC thermogram substantially as shown in Figure 14B.

[0080] In some embodiments, crystalline form F is a hydrate.

[0081] In some embodiments, crystalline form F is substantially pure. In some embodiments, crystalline form F has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0082] Crystalline Form G of Compound 2 In one aspect, the disclosure relates to crystalline form G of Compound 2, characterized by an XRPD pattern including one or more peaks at 9.67, 11.60, 12.90, and 14.43 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form G further includes one or more peaks at 8.16, 13.69, 13.91, 16.15, 18.51, 18.93, and 20.47 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline form G further includes one or more peaks at 4.95, 11.83, 13.22, and 19.84 (±0.2 degrees 2θ).

[0083] In some embodiments, crystalline form G is [Table F] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0084] In some embodiments, crystalline form G is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 15 A. In some embodiments, crystalline form G is characterized by an XRPD pattern substantially as shown in Figure 15A.

[0085] In some embodiments, crystalline form G is characterized by a TGA thermogram substantially as shown in Figure 15B.

[0086] In some embodiments, crystalline form G is characterized by a DSC thermogram having an endotherm with a peak temperature at about 72.4°C and / or about 83.1°C.

[0087] In some embodiments, crystalline form G is characterized by a DSC thermogram substantially as shown in Figure 15B.

[0088] In some embodiments, crystalline form G is a DMSO solvate.

[0089] In some embodiments, crystalline form G is substantially pure. In some embodiments, crystalline form G has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0090] Salt of Compound 2 In another aspect, the present disclosure provides a salt of Compound 2 selected from the sodium, potassium, arginine, magnesium, or tromethamine salt of Compound 2.

[0091] Crystalline Form A of the sodium salt of Compound 2 In one aspect, the disclosure relates to crystalline Form A of the sodium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 4.09, 4.62, and 14.21 (±0.2 degrees two-theta). In some embodiments, the XRPD pattern of crystalline Form A of the sodium salt further comprises one or two peaks at 16.43 and 17.72 (±0.2 degrees two-theta).

[0092] In some embodiments, crystalline form A of the sodium salt is [Table G] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0093] In some embodiments, crystalline Form A of the sodium salt is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 24 A. In some embodiments, crystalline Form A of the sodium salt is characterized by an XRPD pattern substantially as shown in Figure 24A.

[0094] In some embodiments, crystalline Form A of the sodium salt is characterized by a TGA thermogram substantially as shown in Figure 24B.

[0095] In some embodiments, crystalline Form A of the sodium salt is characterized by a DSC thermogram having an endotherm with a peak temperature at about 163.5°C and / or about 204.0°C.

[0096] In some embodiments, crystalline Form A of the sodium salt is characterized by a DSC thermogram with an exotherm with a peak temperature of about 166.5°C.

[0097] In some embodiments, crystalline Form A of the sodium salt is characterized by a DSC thermogram substantially as shown in Figure 24B.

[0098] In some embodiments, crystalline Form A of the sodium salt is substantially pure. In some embodiments, crystalline Form A of the sodium salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0099] Crystalline Form C of the potassium salt of Compound 2 In one aspect, the disclosure relates to crystalline Form C of the potassium salt of Compound 2, characterized by an XRPD pattern including one or more peaks at 12.91, 14.96, and 21.23 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline Form C of the potassium salt further includes one or more peaks at 14.12, 20.68, 25.17, and 26.46 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline Form C of the potassium salt further includes one or more peaks at 3.92, 18.08, 22.48, 24.70, and 25.81 (±0.2 degrees 2θ).

[0100] In some embodiments, crystalline form C of the potassium salt is [Table H] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0101] In some embodiments, crystalline Form C of the potassium salt is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 26 A. In some embodiments, crystalline Form C of the potassium salt is characterized by an XRPD pattern substantially as shown in Figure 26A.

[0102] In some embodiments, crystalline Form C of the potassium salt is characterized by a TGA thermogram substantially as shown in Figure 26B.

[0103] In some embodiments, crystalline Form C of the potassium salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 108.1°C, about 140.2°C, and / or about 161.3°C.

[0104] In some embodiments, crystalline Form C of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 26B.

[0105] In some embodiments, crystalline Form C of the potassium salt is substantially pure. In some embodiments, crystalline Form C of the potassium salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0106] Crystalline Form A of the Arginine Salt of Compound 2 In one aspect, the disclosure relates to crystalline Form A of the arginine salt of Compound 2, characterized by an XRPD pattern including one or more peaks at 12.93, 13.43, 18.21, and 19.49 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline Form A of the arginine salt further includes one or more peaks at 10.91, 15.83, 19.14, 20.93, 21.15, and 22.02 (±0.2 degrees 2θ). In some embodiments, the XRPD pattern of crystalline Form A of the arginine salt further includes one or more peaks at 11.34, 19.84, 20.45, 25.63, and 26.15 (±0.2 degrees 2θ).

[0107] In some embodiments, the crystalline form A of the arginine salt is [Table I] The compound is characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

[0108] In some embodiments, crystalline Form A of the arginine salt is characterized by an XRPD pattern comprising one or more peaks as shown in Figure 28 A. In some embodiments, crystalline Form A of the arginine salt is characterized by an XRPD pattern substantially as shown in Figure 28A.

[0109] In some embodiments, crystalline Form A of the arginine salt is characterized by a TGA thermogram substantially as shown in Figure 28B.

[0110] In some embodiments, crystalline Form A of the arginine salt is characterized by a DSC thermogram having an endotherm with a peak temperature of about 195.2°C.

[0111] In some embodiments, crystalline Form A of the arginine salt is characterized by a DSC thermogram substantially as shown in Figure 28B.

[0112] In some embodiments, crystalline Form A of the arginine salt is substantially pure. In some embodiments, crystalline Form A of the arginine salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0113] Crystalline Form A of the potassium salt of Compound 2 In one aspect, the disclosure relates to crystalline Form A of the potassium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks as shown in the upper curve of Figure 19A. In some embodiments, crystalline Form A of the potassium salt is characterized by an XRPD pattern substantially as shown in the upper curve of Figure 19A.

[0114] In some embodiments, crystalline Form A of the potassium salt is characterized by a TGA thermogram substantially as shown in Figure 19B.

[0115] In some embodiments, crystalline Form A of the potassium salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 91.1°C, about 135.8°C, and / or about 147.7°C.

[0116] In some embodiments, crystalline Form A of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 19B.

[0117] In some embodiments, crystalline Form A of the potassium salt is substantially pure. In some embodiments, crystalline Form A of the potassium salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0118] Crystalline Form B of the potassium salt of Compound 2 In one aspect, the disclosure relates to crystalline Form B of the potassium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks as shown in the lower curve of Figure 19 A. In some embodiments, crystalline Form B of the potassium salt is characterized by an XRPD pattern substantially as shown in the lower curve of Figure 19A.

[0119] In some embodiments, crystalline Form B of the potassium salt is substantially pure. In some embodiments, crystalline Form B of the potassium salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0120] Crystalline Form A of the magnesium salt of Compound 2 In one aspect, the disclosure relates to crystalline Form A of the magnesium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks as shown in Figure 21 A. In some embodiments, crystalline Form A of the magnesium salt is characterized by an XRPD pattern substantially as shown in Figure 21 A.

[0121] In some embodiments, crystalline Form A of the magnesium salt is characterized by a TGA thermogram substantially as shown in Figure 21B.

[0122] In some embodiments, crystalline Form A of the magnesium salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 90.7°C, about 114.9°C, about 134.0°C, and / or about 154.2°C.

[0123] In some embodiments, crystalline Form A of the magnesium salt is characterized by a DSC thermogram substantially as shown in Figure 21B.

[0124] In some embodiments, crystalline Form A of the magnesium salt is substantially pure. In some embodiments, crystalline Form A of the magnesium salt has a purity of at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt%.

[0125] Crystalline Form A of the tromethamine salt of Compound 2 In one aspect, the disclosure relates to crystalline Form A of the tromethamine salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks as shown in Figure 22A. In some embodiments, crystalline Form A of the tromethamine salt is characterized by an XRPD pattern substantially as shown in Figure 22A.

[0126] In some embodiments, crystalline Form A of the tromethamine salt is characterized by a TGA thermogram substantially as shown in Figure 22B.

[0127] In some embodiments, crystalline Form A of the tromethamine salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 71.8°C, about 76.6°C, about 113.9°C, and / or about 213.1°C.

[0128] In some embodiments, crystalline Form A of the tromethamine salt is characterized by a DSC thermogram substantially as shown in Figure 22B.

[0129] In some embodiments, crystalline Form A of the tromethamine salt is substantially pure, ie, at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, at least 85 wt%, at least 86 wt%, at least 87 wt%, at least 88 wt%, at least 89 wt%, at least 90 wt%, at least 91 wt%, at least 92 wt%, at least 93 wt%, at least 94 wt%, at least 95 wt%, at least 96 wt%, at least 97 wt%, at least 98 wt%, or at least 99 wt% pure.

[0130] Synthesis of compound 2 Compound 2 can be synthesized by methods known to those skilled in the art, for example, according to the synthetic procedure described in Example 1.

[0131] Pharmaceutical Composition In yet another aspect, there is provided a pharmaceutical composition comprising Compound 2 or a salt of Compound 2, which is in a crystalline form selected from the group consisting of crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form A of the sodium salt, crystalline form C of the potassium salt, crystalline form A of the arginine salt, crystalline form A of the potassium salt, crystalline form B of the potassium salt, crystalline form A of the magnesium salt, and crystalline form A of the tromethamine salt of the present disclosure.

[0132] In another aspect, there is provided a pharmaceutical composition comprising Compound 2 or a salt of Compound 2, wherein the crystalline form is selected from the group consisting of crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form G, crystalline form A of the sodium salt, crystalline form C of the potassium salt, crystalline form A of the arginine salt, crystalline form A of the potassium salt, crystalline form B of the potassium salt, crystalline form A of the magnesium salt, and crystalline form A of the tromethamine salt of the present disclosure; and at least one pharmaceutically acceptable excipient.

[0133] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of Compound 2 is crystalline form B.

[0134] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of Compound 2 is crystalline form C.

[0135] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of Compound 2 is crystalline form D.

[0136] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of Compound 2 is crystalline form E.

[0137] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of Compound 2 is crystalline form F.

[0138] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline form G.

[0139] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form A of the sodium salt.

[0140] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form C of the potassium salt.

[0141] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form A of the arginine salt.

[0142] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form A of the potassium salt.

[0143] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form B of the potassium salt.

[0144] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form A of the magnesium salt.

[0145] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or 99.99% of the salt of Compound 2 is crystalline Form A of the tromethamine salt.

[0146] The specific excipients used in the pharmaceutical compositions provided herein are determined by the means and purpose for which the compounds of the present disclosure are applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe for administration to mammals, including humans. Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof.

[0147] In some embodiments, suitable excipients include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl paraben or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; gelatin; or immunoglobulins. It may include proteins such as globulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine, monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose, or sorbitol, salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or non-ionic surfactants such as TWEEN™ PLURONICS™ or polyethylene glycol (PEG).

[0148] In some embodiments, suitable excipients can include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to enhance the appearance of the drug (i.e., the compound of the present disclosure or a pharmaceutical composition thereof) or aid in the manufacture of the pharmaceutical product (i.e., a drug product). Active pharmaceutical ingredients can also be encapsulated in microcapsules, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions, prepared, for example, by coacervation techniques or interfacial polymerization. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). A "liposome" is a small vesicle composed of various types of lipids, phospholipids, and / or surfactant that is useful for delivery of drugs (e.g., compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of the liposome are usually arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0149] The pharmaceutical compositions provided herein may be in any form that allows for administration to a subject, not limited to humans, and may be formulated to be compatible with the intended route of administration.

[0150] Various routes are contemplated for the pharmaceutical compositions provided herein, and therefore, the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage form depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable solid dosage forms, while emulsions, syrups, elixirs, suspensions, and solutions may be acceptable liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable liquid dosage forms, and powders suitable for reconstitution with an appropriate solution may be acceptable solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams, and sprays can be acceptable dosage forms.

[0151] The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and varies depending on the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition containing the molecule or compound to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health, the nature and extent of the condition, the rate of administration, the therapeutic agent or combination of therapeutic agents selected for administration, and the discretion of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0152] In some embodiments, the effective dose of the compounds provided herein can range from about 0.5 μg / day to about 90 mg / day, 1 μg / day to about 50 mg / day, 2 μg / day to about 10 mg / day, 3 μg / day to about 1 mg / day, 5 μg / day to about 800 μg / day, 5 μg / day to about 600 μg / day, 5 μg / day to about 500 μg / day, 10 μg / day to about 500 μg / day, 12 μg / day to about 500 μg / day, 15 μg / day to about 500 μg / day, 20 μg / day to about 500 μg / day, or 25 μg / day to about 500 μg / day. In some embodiments, the effective dose of the compounds provided herein can range from about 25 μg / day to about 300 μg / day. In some embodiments, the effective amount of the compounds provided herein can range from about 50 μg / day to about 150 μg / day.

[0153] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for oral administration.

[0154] In certain embodiments, the pharmaceutical composition of the present disclosure is in the form of a tablet formulation. Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, lubricants such as magnesium stearate, stearic acid or talc, preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or may be coated using conventional coating agents and procedures well known in the art to regulate their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve their stability and / or appearance.

[0155] In certain embodiments, pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin, or olive oil.

[0156] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension containing the active ingredient, generally in finely divided form, together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia, a dispersing or wetting agent, such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol, such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a fatty acid and a partial ester derived from a hexitol anhydride, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate), antioxidant (for example, ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (for example, sucrose, saccharin or aspartame).

[0157] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of oily suspensions, generally containing the active ingredient suspended in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may further contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those mentioned above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant, such as ascorbic acid.

[0158] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oil-in-water emulsion.The oily phase can be vegetable oil such as olive oil or peanut oil, or mineral oil such as liquid paraffin, or any mixture thereof.Suitable emulsifiers can be, for example, naturally occurring gums such as gum acacia or gum tragacanth, naturally occurring phosphatides such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (for example, sorbitan monooleate), and condensation products of partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.Emulsions can also contain sweeteners, flavorings, and preservatives.

[0159] In certain embodiments, pharmaceutical compositions provided herein may be in the form of syrups and elixirs which may contain sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, demulcents, preservatives, flavoring and / or coloring agents.

[0160] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for injectable administration.

[0161] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension dissolved in a non-toxic, non-gastrointestinal-acceptable diluent or solvent, such as a solution in 1,3-butanediol, or prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils can be conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, can be employed. Additionally, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0162] In some embodiments, pharmaceutical compositions of the present disclosure may be in the form of a formulation for inhaled administration.

[0163] In certain embodiments, pharmaceutical compositions of the present disclosure may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the requirements of the particular compound, but typically include non-ionic surfactants (Tween, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols.

[0164] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for topical or transdermal administration.

[0165] In certain embodiments, the pharmaceutical compositions provided herein may generally be in the form of creams, ointments, gels and aqueous or oily solutions or suspensions, which may be obtained by formulating the active ingredient with conventional topically acceptable excipients, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0166] In certain embodiments, the pharmaceutical compositions provided herein can be formulated in the form of transdermal skin patches, which are well known to those of ordinary skill in the art.

[0167] In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this disclosure. Such excipients and carriers can be found, for example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991); "Remington: The Science and Practice of Pharmacy," Ed. University of the Sciences in Philadelphia, 21 st Edition, LWW (2005).

[0168] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending on the subject being treated and the particular mode of administration.

[0169] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated as short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations of the present disclosure can also be formulated for controlled release or slow release.

[0170] In yet another aspect, there are also provided veterinary compositions comprising one or more molecules or compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and a veterinary carrier. The veterinary carrier is a substance useful for the purpose of administering the composition, and may be an otherwise inert or solid, liquid, or gaseous substance that is acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0171] Pharmaceutical or veterinary compositions may be packaged in a variety of ways depending on the method used to administer the drug. For example, an article for distribution may include a container into which the composition is placed in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampule bottles, plastic bags, metal tubes, and the like. The container may also include a tamper-evident assembly to prevent indiscreet access to the contents of the package. In addition, the container is labeled with a label describing the contents of the container. The label may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier for injection, e.g., water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

[0172] In yet another aspect, pharmaceutical compositions are also provided that include one or more compounds of the present disclosure, or pharmaceutically acceptable salts thereof, as a first active ingredient, and a second active ingredient.

[0173] For pharmaceutical compositions containing a second active agent, the effective amount of the second active agent is about 20% to 100% of the dose typically employed in a monotherapy regimen using that agent alone. Preferably, the effective amount is about 70% to 100% of the typical monotherapy dose. Typical monotherapy doses for these second active agents are well known in the art. See, for example, Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which is incorporated herein by reference in its entirety.

[0174] Some second active agents are expected to act synergistically with the compounds provided herein, allowing the effective dose of the second active agent and / or the compounds provided herein to be reduced from the dose required for monotherapy. This has the advantage of minimizing toxic side effects of either the second active agent or the compounds provided herein, synergistically improving efficacy, improving ease of administration or use, and / or reducing the overall cost of compound preparation or formulation.

[0175] In some embodiments, the second active agent may include (1) a cholesterol absorption inhibitor, (2) an HMG-CoA reductase inhibitor, (3) a bile acid sequestrant, (4) nicotinyl alcohol, nicotinic acid or a salt thereof, (5) a phenolic antioxidant, (6) an ACAT inhibitor, and (7) a CTEP inhibitor.

[0176] Treatment of Disease In another aspect, the present disclosure provides a crystalline form of Compound 2 or a salt of Compound 2 of the present disclosure, or a pharmaceutical composition of the present disclosure, for use in a method for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist.

[0177] In another aspect, the present disclosure provides a method for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist in a subject, the method comprising administering an effective amount of a crystalline form of Compound 2 or a salt of Compound 2 of the present disclosure, or a pharmaceutical composition of the present disclosure.

[0178] In another aspect, the present disclosure provides use of a crystalline form of Compound 2 or a salt of Compound 2 of the present disclosure, or a pharmaceutical composition of the present disclosure, in the manufacture of a medicament for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist.

[0179] As used herein, the term "treat," "treating," or "treatment" is intended to include ameliorating, preventing, alleviating, or eliminating a disorder, or alleviating, preventing, or eliminating one or more of the symptoms associated with the disorder, and / or preventing, alleviating, or eradicating the cause of the disorder itself, i.e., preventing serious clinical symptoms from developing in a mammal that may be predisposed to the disease but has not yet experienced or displayed symptoms of the disease. This may include improving a subject's ability to perform activities of daily living, household chores, financial management, and / or occupational tasks, or reducing the level of care required by the subject. Treatment may include at least a 20%, 30%, 50%, 80%, 90%, or 100% improvement in symptoms. The symptoms associated with a particular disorder will depend on the specific type of the particular disorder.

[0180] As used herein, the terms "prevention" or "prophylactic" are intended to have their ordinary meaning and include primary prevention, in which the onset of a disease is prevented, and secondary prevention, in which a disease has already occurred and the patient is protected, either temporarily or permanently, from recurrence or worsening of the disease or the development of new symptoms associated with the disease.

[0181] As used herein, the term "disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

[0182] In some embodiments, the disease is diabetes, non-insulin dependent diabetes mellitus, hypertension, dyslipidemia, arteriosclerotic disease, metabolic syndrome, or diabetic nephropathy.

[0183] In some embodiments, the disease is non-insulin dependent diabetes mellitus or diabetic nephropathy.

[0184] In some embodiments, the disease is diabetic nephropathy.

[0185] As used herein, the term "diabetes" refers to a disease in which a patient's ability to control blood glucose levels is impaired due to a partial loss of the ability to respond appropriately to the action of insulin.

[0186] As used herein, the term "non-insulin-dependent diabetes mellitus" also refers to type 2 diabetes (T2D), which accounts for 80-90% of diabetes patients in developed countries. While the pancreatic islets of Langerhans still produce insulin, target organs, primarily muscle, liver, and adipose tissue, exhibit a strong resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. However, in the later stages of the disease, pancreatic exhaustion leads to decreased insulin secretion.

[0187] As used herein, the term "atherosclerotic disease," also known as arteriosclerotic vascular disease or ASVD, is a specific form of arteriosclerosis in which the arterial wall thickens as a result of invasion and accumulation of white blood cells (foam cells) and proliferation of smooth muscle cells, producing atheromatous (fibrofatty) plaques.

[0188] As used herein, the term "metabolic syndrome" refers to a group of co-occurring conditions that increase the risk of heart disease, stroke, and type 2 diabetes. These conditions include high blood pressure, high blood sugar, excess fat around the waist, and abnormal cholesterol or triglyceride levels.

[0189] As used herein, the term "diabetic nephropathy" refers to kidney disease caused by diabetes, which is the leading cause of kidney failure. Approximately one-third of diabetic patients develop diabetic nephropathy. Early-stage diabetic nephropathy often has no symptoms. As kidney function deteriorates, symptoms may include swelling of the hands, feet, and face, trouble sleeping or focusing, loss of appetite, nausea, weakness, itching (end-stage renal disease) and extreme dry skin, drowsiness (end-stage renal disease), abnormal heart rhythms due to increased potassium in the blood, and muscle cramps.

[0190] In some embodiments, the condition is renal trauma. In some embodiments, the renal trauma is induced by ureteral obstruction. In some embodiments, the renal trauma is induced by unilateral ureteral obstruction.

[0191] As used herein, the term "PPARα / γ dual agonist" refers to a compound that exhibits both significant PPARα and PPARγ agonism. In some embodiments, the PPARα / γ dual agonist exhibits significant PPARα and / or PPARγ agonism, wherein the half-maximal effective concentration (EC ) of hPPARγ activation is greater than or equal to 1000 fold. 50 ) and EC of hPPARα activation 50 is less than 30-fold, 25-fold, 20-fold, 15-fold, 10-fold, 5-fold, or 3-fold. In some embodiments, the dual PPARα / γ agonist exhibits significant PPARα and / or PPARγ agonism, wherein the half-maximal effective concentration (EC) of hPPARγ activation is 50 ) and EC of hPPARα activation 50 The difference is 30-fold, 25-fold, 20-fold, 15-fold, 10-fold, 5-fold, or more than 3-fold.

[0192] In certain embodiments, the dual PPARα and PPARγ agonist is Compound 2 provided herein or a crystalline form thereof.

[0193] In another aspect, the present disclosure provides a method for modulating PPARα and / or PPARγ in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of Compound 2 or a salt of Compound 2 of the present disclosure, or a pharmaceutical composition of the present disclosure. [Example]

[0194] The following examples are included for illustrative purposes. However, it is understood that these examples do not limit the disclosure and are intended only to suggest a method of practicing the disclosure. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare many other compounds of the disclosure, and alternative methods for preparing compounds of the disclosure are considered to be within the scope of the disclosure. For example, compounds not exemplified according to the disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as appropriate protection of interfering groups, utilizing other suitable reagents and components known in the art other than those described, and / or routinely modifying reaction conditions. Alternatively, it will be recognized that other reactions disclosed herein or known in the art can be applied to prepare other compounds of the disclosure.

[0195] [Example 1] Synthesis of Compound 2 [ka] To a suspension of LiAlD4 (1.9 g, 45.4 mmol) in THF (40 mL) was added methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (7.0 g, 30.3 mmol) in THF (60 mL) at 0 °C under N2. The reaction was stirred at 0 °C for 2 h and then quenched with water (3 mL). The resulting solid was removed by filtration. The filter cake was washed with EtOAc (500 mL) and DCM / MeOH (10 / 1, 500 mL). The filtrate was concentrated in vacuo to give 2-(5-methyl-2-phenyloxazol-4-yl)ethane-1,1-d2-1-ol (5.0 g, 80.6% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.05-7.87 (m, 1H), 7.50-7.33 (m, 2H), 2.71 (s, 2H), 2.34 (s, 3H). LC-MS (ESI + ): m / z = 206.2 ([M+H] + ).

[0196] To a solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethane-1,1-d2-1-ol (5.0 g, 24.4 mmol) in DCM (100 mL) was added Et3N (5.4 g, 53.7 mmol). The reaction mixture was cooled to 0 °C, and MsCl (5.6 g, 48.8 mmol) was added under N2. The reaction was stirred at 0 °C for 2 h and then poured into water. 1 N HCl (40 mL) was added, and the mixture was extracted with DCM (100 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc = 20:1 to 10:1) to give 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (5.0 g, 72.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.97 (dd, J = 7.4, 2.2 Hz, 2H), 7.53-7.34 (m, 3H), 3.04-2.90 (m, 5H), 2.36 (s, 3H). LC-MS (ESI + ): m / z = 284.0 ([M+H] + ).

[0197] To a solution of 4-hydroxybenzo[b]thiophene-7-carbaldehyde (3.2 g, 17.7 mmol) in DMF (30 mL) was added K2CO3 (2.9 g, 21.2 mmol). The reaction mixture was heated at 85 °C under N2. 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (5.0 g, 17.7 mmol) in DMF (15 mL) was added dropwise at this temperature. The reaction was stirred at 85 °C for 5 h, then cooled to room temperature and poured into water and extracted with EtOAc (300 mL × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with petroleum ether / EtOAc=5 / 1 to give 4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-carbaldehyde (5.7 g, 88.2% yield) as a brown solid. 1 H NMR (300 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.00-7.86 (m, 2H), 7.82 (d, J = 5.5 Hz, 1H), 7.62-7.38 (m, 4H), 7.23 (d, J = 8.1 Hz, 1H), 3.06 (s, 2H), 2.40 (s, 3H). LC-MS (ESI + ): m / z = 366.0 ([M+H] + ).

[0198] To a solution of methyl 2-methoxyacetate (5.9 g, 57.2 mmol) in THF (40 mL) was added TiCl (10.8 g, 57.2 mmol) at 0 °C under argon. The yellow solution was stirred at 0 °C for 15 min, and DIEA (7.9 g, 61.6 mmol) was added. The black solution was stirred for an additional 15 min, and 4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d)benzo[b]thiophene-7-carbaldehyde (4.0 g, 11.0 mmol) in DCM (60 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h and allowed to warm to room temperature overnight. It was then cooled to 0 °C, quenched with water, and extracted with DCM (200 mL × 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to give crude methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (7.7 g), which was used directly in the next step without further purification. LC-MS (ESI + ): m / z = 470.2 ([M+H] + ).

[0199] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)propanoate (7.7 g, crude) in DMF (40 mL) was added concentrated H2SO4 (10 mL) dropwise at ambient temperature. The reaction was stirred overnight at 100 °C, then diluted with EtOH (40 mL) and stirred at 0 °C for 1 h. The solid was filtered and washed with EtOH (10 mL) and water (50 mL). The wet cake was dried to give methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (2.3 g, 46.4% yield over two steps) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 7.6, 1.8 Hz, 2H), 7.53-7.37 (m, 4H), 7.34 (d, J = 5.5 Hz, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.08 (s, 2H), 2.40 (s, 3H). LC-MS (ESI + ): m / z = 452.2 ([M+H] + ).

[0200] To a solution of methyl (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylate (2.3 g, 5.1 mmol) in MeOH (50 mL) was added KOH (1.7 g, 30.6 mmol) in HO (5 mL) at room temperature. The reaction was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with HO (50 mL), and adjusted to pH = 3 with 6 N HCl. The mixture was cooled to 0 °C, and the solid was filtered. The filter cake was suspended in EtOH (40 mL) at 80 °C for 1 h, cooled to 0 °C, and stirred for 1 h. The solid was filtered and dried to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (1.5 g, 68.2% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ: 8.09 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 7.6, 1.9 Hz, 2H), 7.49 (d, J = 5.5 Hz, 1H), 7.48-7.39 (m, 3H), 7.35 (t, J = 2.7 Hz, 2H), 6.87 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H), 3.10 (s, 2H), 2.41 (s, 3H). LC-MS (ESI + ): m / z = 438.2 ([M+H] + ).

[0201] A 300 mL stainless steel autoclave was charged with (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophen-7-yl)acrylic acid (1.5 g, 3.4 mmol), (S)-phenylethylamine (82 mg, 0.68 mmol), MeOH (18 mL), THF (12 mL), and Ir-cat([(S)-DTBSIPHOX)Ir(COD)]BArF, 9.3 mg, 0.001 equiv.). The autoclave was sealed and the hydrogenation reaction was stirred at 70 °C under 30 bar of hydrogen for 16 h. LCMS indicated approximately half of the starting material remained; Ir-cat (10.3 mg) was added, and the reaction was stirred for an additional day. The autoclave was opened, and the yellowish solution was rotary evaporated to dryness (45 °C). The crude product was dissolved in EtOAc (150 mL) and washed with 1N HCl (40 mL × 2). The organic layer was dried over NaSO, filtered, and evaporated to dryness. The crude product was dissolved in isopropyl acetate under reflux and cooled to 0 °C to initiate crystallization. The formed crystals were filtered off, washed with isopropyl acetate (50 mL), and dried to give a yellow solid (920 mg), which was further purified by preparative HPLC (CHCN and 0.1% FA in water) to give compound 2 (518 mg, 34.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ: 7.99 (dd, J = 6.4, 2.4 Hz, 2H), 7.48 (d, J = 5.6 Hz, 1H), 7.43 - 7.41 (m, 3H), 7.32 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.20 (dd, J = 7.9, 4.7 Hz, 1H), 3.39-3.28 (m, 4H), 3.23-3.18 (m, 1H), 3.05 (s, 2H), 2.40 (s, 3H). LC-MS (ESI + ): m / z = 440.2 ([M+H] + ).

[0202] Chiral HPLC (Chiralpak AD-3 4.6mm*250mm 3μm, 90% hexane / 9.99% EtOH / 0.01% TFA, 210nm): 99.57% ee.

[0203] Example 2: Preparation of crystalline form of Compound 2 2.1 Abbreviations for solvents used The following abbreviations are used in the examples: [Table 1]

[0204] 2.2 Characterization of Starting Materials A total of two patches of AP-303 (i.e., Compound 2) free acid (batch number 01321040801) were procured and subsequently characterized by XRPD, TGA, and DSC. The results are summarized in Table 2. After further comparison, the first batch of free acid material (818159-01-A) was a mixture of free acid forms C and E. The second batch of free acid material (818159-60-A) was a mixture of free acid forms B / C / E. The XRPD patterns are shown in Figures 1A and 2A, respectively.

[0205] As shown in Figure 1B, for the first batch of free acid material, the TGA results showed a 0.9% weight loss up to 100°C, and the DSC results showed two endothermic peaks at 148.9 and 151.7°C (peak temperatures). As shown in Figure 2B, for the second batch of free acid material, the TGA results showed a 3.9% weight loss up to 100°C, and the DSC results showed three endothermic peaks at 73.5, 149.0, and 151.6°C (peak temperatures). [Table 2]

[0206] The approximate solubility of AP-303 (818159-01-A) was determined in 14 single solvents at room temperature (25 ± 3 °C). Approximately 2 mg of sample was added to a 3-mL glass vial. The corresponding solvent was added stepwise (50 μL → 50 μL → 100 μL → 200 μL → 600 μL → 1000 μL) to the vial until the solid was visibly dissolved or a total volume of 2 mL was reached. The approximate solubility range was calculated based on the sample mass, solvent volume, and observation results. The results, summarized in Table 3, were used as a guide for solvent selection in polymorph screening. [Table 3]

[0207] 2.3 Polymorphism screening experiments Polymorph screening was performed using the free acid (818159-01-A) as the starting material under 100 experimental conditions. Ten methods were used, including antisolvent addition / reverse antisolvent addition, room temperature slurry, 50°C slurry, solid vapor diffusion, liquid vapor diffusion, slow evaporation, slow cooling, temperature cycling, polymer-induced crystallization, and humidity-induced crystallization. The results of the polymorph screening are summarized in Table 4. As shown in Figure 3, six free acid forms, i.e., free acid forms B to G, were obtained from the XRPD results. [Table 4]

[0208] 2.3.1 Slow cooling Slow cooling experiments were performed with six solvent systems. Approximately 20 mg of starting material (818159-01-A) was dissolved in 1.0 mL of solvent or solvent mixture at 50°C and filtered through a 0.45 μm PTFE membrane into a new vial. The filtrate was slowly cooled from 50°C to 5°C at a rate of 0.05°C / min. The resulting solid was stored isothermally at 5°C or -20°C before isolation for XRPD analysis. If no solid was observed, slow evaporation was performed. The results, summarized in Table 5, showed free acid Form E / F, Form E+C, Form B+ peaks (unidentified peaks except for Form B), and low crystallinity. [Table 5]

[0209] 2.3.2 Liquid vapor diffusion Liquid vapor diffusion experiments were performed under six conditions. Approximately 20 mg of starting material (818159-01-A) was dissolved in 0.2–0.8 mL of solvent to obtain a clear solution in a 3-mL vial, which was then filtered through a 0.45 μm PTFE membrane into a new vial. The filtrate was transferred to a 3-mL vial, which was then placed in a 20-mL vial containing 3 mL of volatile solvent. The 20-mL vial was capped, sealed, and stored at room temperature to allow sufficient time for the organic vapor to react with the solution. If the sample was still clear, slow evaporation was performed at room temperature. The precipitate was isolated for XRPD analysis. According to the results summarized in Table 6, free acid form F, forms B+E, low crystallinity, and amorphous were obtained. [Table 6]

[0210] 2.3.3 Antisolvent addition Antisolvent addition experiments were performed under 12 conditions. Approximately 20 mg of starting material (818159-01-A) was dissolved in 0.4–1.0 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and then 0.2 mL of antisolvent was added stepwise until a precipitate appeared or the total amount of antisolvent reached 5 mL. The clear solution was transferred and stirred at 5°C or -20°C to induce precipitation. If the sample was still clear, slow evaporation was performed at room temperature. The resulting precipitate was isolated for XRPD analysis. According to the results in Table 7, free acid forms C / E / F / G, C+E, B+C+E, amorphous, and low crystallinity were observed. [Table 7]

[0211] 2.3.4 Reverse antisolvent addition Reverse antisolvent addition experiments were performed under eight conditions. Approximately 20 mg of starting material (818159-01-A) was dissolved in 0.4 to 1.0 mL of solvent to obtain a clear solution. The solution was added to the antisolvent. The clear solution was transferred and stirred at 5°C or -20°C to induce precipitation. If the sample was still clear, slow evaporation was performed at room temperature. The resulting precipitate was isolated for XRPD analysis. According to the results in Table 8, free acid forms C / E / F, B+E, amorphous, and low crystallinity were observed. [Table 8]

[0212] 2.3.5 Slow evaporation Slow evaporation experiments were performed with five solvent systems. Approximately 20 mg of starting material (818159-01-A) was dissolved in 0.6–3.0 mL of solvent or solvent mixture and filtered through a 0.45 μm PTFE membrane into a new vial. The filtrate was slowly evaporated at room temperature, and the resulting solid was isolated for XRPD analysis. The results, summarized in Table 9, showed peaks for free acid Form C / F, Form B+E, and Form E+. [Table 9]

[0213] 2.3.6 Slurrying at 50°C Slurry conversion experiments were performed in 17 solvent systems at 50° C. Approximately 20 mg of starting material (818159-01-A) was suspended in 0.5 mL of solvent at 50° C. for 2 days. The remaining solid was isolated for XRPD analysis. According to the results summarized in Table 10, free acid Form E, Form B+E, Form E+C, and Form E+ peaks were obtained. [Table 10]

[0214] 2.3.7 Temperature Cycling Temperature cycling experiments were performed under nine conditions each. Approximately 20 mg of starting material (818159-01-A) was suspended in 0.5 mL of solvent. The suspension was then magnetically stirred from 50°C to 5°C at a heating / cooling rate of 0.1°C / min for two cycles. The remaining solid was isolated for XRPD analysis. According to the results summarized in Table 11, the free acid forms B+E were obtained. [Table 11]

[0215] 2.3.8 Solid Vapor Diffusion Solid vapor diffusion experiments were performed with eight different solvent systems. Approximately 20 mg of starting material (818159-01-A) was weighed into a 3-mL vial and placed in a 20-mL vial containing 3.0 mL of volatile solvent. The 20-mL vial was capped, sealed, and stored at room temperature for 10 days to allow interaction of the solvent vapor with the sample. The solid was examined by XRPD. Results, summarized in Table 12, showed peaks for free acid Form E+B, Form C+E, Form C+E+B, and Form F+. [Table 12]

[0216] 2.3.9 Humidity-induced crystallization Humidity-induced crystallization experiments were performed under five conditions. Approximately 20 mg of starting material (818159-01-A) was weighed into a 3-mL vial and placed in a 20-mL vial containing 2 mL of saturated aqueous inorganic salt solution. The 20-mL vial was capped, sealed, and stored at room temperature for 9 days to allow water vapor to interact with the sample. The solid was examined by XRPD. According to the results summarized in Table 13, free acid forms C+E+B were obtained. [Table 13]

[0217] 2.3.10 Polymer-induced crystallization Polymer-induced crystallization experiments were conducted on two sets of polymer mixtures in different solvent systems. Approximately 20 mg of starting material (818159-01-A) was dissolved in 0.4 to 2.0 mL of solvent in a 3-mL glass vial. Approximately 2 mg of the polymer mixture was added to the 3-mL glass vial. All solutions and suspensions were filtered through a 0.45 μm PTFE membrane. The resulting solutions were evaporated at room temperature with the vials sealed with Parafilm® for slow evaporation. The solids were isolated for XRPD analysis. According to the results summarized in Table 14, free acid Form E / F and Form B+E were obtained. [Table 14]

[0218] 2.3.11 Slurrying at Room Temperature Slurry conversion experiments were performed in 17 solvent systems at room temperature. Approximately 20 mg of starting material (818159-01-A) was suspended in 0.5 mL of solvent. The sample was stirred at room temperature for 7 days. The remaining solid was isolated for XRPD analysis. According to the results summarized in Table 15, free acid Forms B / D / E and Form B+E were obtained. [Table 15]

[0219] Example 3: Characterization of the crystalline form of Compound 2 General method X-ray powder diffraction (XRPD) A PANalytical X'pert3 X-ray powder diffractometer was used for XRPD analysis. Samples were spread in the center of a zero-background Si holder. The XRPD parameters used are listed in Table 16. [Table 16]

[0220] Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA data were collected on a TA Q5000 TGA from TA Instruments, and DSC was performed on a TA 2500 DSC from TA Instruments. Detailed parameters used are listed in Table 17. [Table 17]

[0221] Dynamic Vapor Sorption (DVS) DVS was measured by SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. Parameters for the DVS test are listed in Table 18. [Table 18]

[0222] solution 1 H NMR Solution proton NMR was collected on a Bruker 400M NMR spectrometer in DMSO-d6 or MeOD.

[0223] HPLC / IC An Agilent 1260 HPLC with a DAD / VWD detector was utilized and the detailed chromatographic conditions for the HPLC analysis are listed in Table 19. The IC method for counterion content measurement is listed in Table 20 below. [Table 19] [Table 20]

[0224] 3.1 Crystalline Form B of Compound 2 Free acid form B (818159-08-B) was obtained by slurrying starting material (818159-01-A) in EtOAc, as shown in Figure 4A. As shown in Figure 4B, the TGA results showed a weight loss of 1.5% up to 100°C, and the DSC results showed two endothermic peaks at 81.3°C (peak temperature) and 151.1°C (onset temperature). 1 No residual EtOAc was detected based on the 1 H NMR results (FIG. 4C).

[0225] Free acid Form B (818159-39-B) was purified by slurrying free acid Form B (818159-08-B) in ACN at room temperature, as shown in XRPD in Figure 5A and Table 21. As shown in Figure 5B, the TGA results showed a weight loss of 1.9% up to 100°C, and the DSC results showed two endothermic peaks at 84.7°C (peak temperature) and 150.4°C (onset temperature).

[0226] To investigate the origin of the forms, variable temperature XRPD (VT XRPD) experiments were performed on free acid form B (818159-08-B), as shown in Figure 4D. The VT XRPD results indicated: 1) no form change was observed after N bleeding at 30 °C; 2) conversion to free acid form E occurred after heating to 100 °C under N protection; 3) partial reconversion to free acid form B occurred after cooling to 30 °C under N protection; and 4) complete reconversion to free acid form B after storage at room temperature for 2 days. Based on the VT XRPD results, free acid forms B and E are presumed to be anhydrous. The endothermic peak at 84.7 °C (peak temperature) is presumed to be associated with a form transition, and the endothermic peak at 150.4 °C (onset temperature) is consistent with form E. [Table 21]

[0227] 3.2 Crystalline Form C of Compound 2 The free acid form C (818159-30-B) was obtained by slow evaporation in DCM. XRPD and TGA / DSC are shown in Figure 6A and Table 22, and Figure 6B, respectively. The TGA results showed a weight loss of 2.8% up to 100°C, and the DSC results showed one endothermic peak at 147.6°C (onset temperature), which was estimated to be the melting point. 1 H NMR results (Figure 6C) showed no detectable residual DCM. Given the low TGA weight loss and pure DSC, it is speculated that the free acid form C is an anhydride. [Table 22]

[0228] 3.3 Crystalline Form D of Compound 2 Free acid form D (818159-25-A11) was obtained by slurrying starting material (818159-01-A) in DCM / cyclohexane (2:1, v / v) at room temperature. XRPD results are shown in Figure 7 and Table 23. Free acid form D (818159-36-B) was reprepared by the same method as for characterization. XRPD and TGA / DSC results are shown in Figure 8 and Figure 9A. TGA results showed a weight loss of 2.9% up to 100°C, and DSC results (Figure 9A) showed one endothermic peak at 150.7°C (one temperature) and one exothermic peak at 92.8°C (peak temperature). 1 According to the H NMR results (Figure 9B), the molar ratio of cyclohexane to API was 0.05 (0.9 wt%). As shown in Figure 9C, it converted to free acid form E after 1 month of storage at room temperature. Based on the characterization results, free acid form D is presumed to be a hygroscopic free acid anhydride or hydrate (theoretical weight loss for a monohydrate is 2.1%).

[0229] Free acid Form D (818159-68-B) was reconstituted by the same method for form identification. As shown in Figure 10, the reconstituted free acid Form D was a mixture of Form D and a small amount of Form E. TGA results (Figure 11A) showed a 5.0% weight loss up to 100°C, and DSC results (Figure 11A) showed one endothermic peak at 50.4°C (one temperature) and one exothermic peak at 95.5°C (peak temperature). 1According to the H NMR results (Figure 11B), the molar ratio of cyclohexane to API was 0.09 (1.8 wt%). VT XRPD was performed to investigate the origin of the form. As shown in Figure 11C, 1) a peak shift was observed after N bleeding at 30 °C, 2) conversion to free acid form E was observed after heating to 100 °C under N protection, and 3) no form change was observed after cooling to 30 °C under N protection. Combining the characterization and VT results, it is inferred to be a hydrate. Combined with the VT XRPD results, the exothermic peak at 95.5 °C (peak temperature) is inferred to be associated with a form transition, and the endothermic peak at 150.4 °C (peak temperature) is consistent with form E. [Table 23]

[0230] 3.4 Crystalline Form E of Compound 2 Little free acid Form E was observed in the 50°C slurry experiment. Meanwhile, pure free acid Form E (818159-40-A2_30Jul) was obtained by a slurry competition experiment in MIBK at 50°C. The XRPD is shown in Figure 12 and Table 24. As shown in Figure 13A, free acid Form E (818159-32-B) was prepared by slurrying the starting material in IPA at 50°C. After further comparison, a small amount of Form B was observed in free acid Form E (818159-32-B). The TGA result (Figure 13B) showed a weight loss of 2.8% up to 100°C, and the DSC result (Figure 13B) showed one endothermic peak at 151.1°C (onset temperature), which was estimated to be the melting point. 1 No residual IPA was observed according to the H NMR results (Figure 13C), and given the low TGA weight loss and pure DSC, it is assumed to be anhydrous. [Table 24]

[0231] 3.5 Crystalline Form F of Compound 2 As shown in Figure 14A and Table 25, free acid form F (818159-37-B) was obtained by evaporation in THF / HO (4:1, v / v) at room temperature. Free acid form F was also observed in the residual solids from kinetic solubility starting from different salts. TGA results (Figure 14B) showed a weight loss of 3.9% up to 100°C, and DSC results (Figure 14B) showed four endothermic peaks at 44.8°C, 77.1°C, 111.2°C, and 149.8°C (peak temperatures) and one exothermic peak at 118.9°C (peak temperature). 1 According to the H NMR results (Figure 14C), no residual THF was observed. VT XRPD was performed to investigate the origin of the form. As shown in Figure 14D, 1) no change in form was observed after N bleeding at 30 °C, 2) conversion to free acid form E was observed after heating to 130 °C under N protection, and 3) no change in form was observed after cooling to 30 °C under N protection. Based on the characterization and preparation conditions, it is inferred to be a hydrate. The endothermic peak before 100 °C is inferred to be a hydrate, and the exothermic peak at 118.9 °C (peak temperature) is inferred to be a form transition. The endothermic peak at 149.8 °C (peak temperature) is consistent with form E. [Table 25]

[0232] 3.6 Crystalline Form G of Compound 2 The free acid form G (818159-41-B) was obtained by evaporation in DMSO / MTBE at room temperature. The XRPD and TGA / DSC results are shown in Figure 15A and Table 26, and Figure 15B, respectively. The TGA results showed a 36.7% weight loss up to 150°C, and the DSC results showed two endothermic peaks at 72.4°C and 83.1°C (peak temperatures). Using CD3OD as the solvent, 1H NMR (FIG. 15C) was examined, and the results indicated that the DMSO / free acid molar ratio was 1.7 (23.0 wt%). To further investigate the origin of the form, a heating experiment was performed. Melting was observed after heating to 110°C and then cooling to room temperature. Based on the characterization and heating experiment results, it is speculated that free acid form G is a DMSO solvate. The endothermic peak is speculated to be a desolvation peak. [Table 26]

[0233] [Example 4] Test of mutual conversion relationship 4.1 Anhydrous Slurry Competition To investigate the interconversion relationship between free anhydride forms B, C, and E, slurry competition experiments were performed in IPA, ACN, and n-heptane at room temperature and 50°C. Approximately equal masses of the corresponding mixtures of forms were added to pre-saturated solutions and stirred at the corresponding temperatures. The residual solids were extracted for XRPD analysis. The results are summarized in Table 27, and the XRPD results are shown in Figures 16A-16E. Based on the results, form B was obtained in all solvents tested at room temperature, and form E was observed in IPA and n-heptane at 50°C. Meanwhile, possibly due to a solvent effect, form B was observed in CAN at both room temperature and 50°C. To further investigate the transition temperatures of forms B and E, slurry competition experiments were performed in MIBK and IPAc at 40°C and 50°C. Form B (major) was obtained at 40°C, and form E (major) was obtained at 50°C. In the next experiment (these experiments were performed before Form D was identified), Form D material was added to IPA at 50° C., IPAc at 40 and 50° C. The results showed that Form B was observed at 40° C., and a mixture of Forms B and E was observed at 50° C.

[0234] In particular, Forms B and E are enantiotropic, with Form B being the cold stable form. The transition temperature between Forms B and E is 40-50°C. [Table 27]

[0235] 4.2 Slurry competition between anhydrous and hydrated To investigate the interconversion relationship between the free acid anhydride Form B and the hydrate Forms D / F, slurry competitions were performed in IPA / water at room temperature with different water activities. The procedure involved adding approximately equal masses of a mixture of Forms B / D / F to a pre-saturated solution and stirring at room temperature. The residual solid was extracted for XRPD analysis. The results are summarized in Table 28, and the XRPD results are shown in Figures 17A and 17B. Based on the results, free acid Form B was obtained under all test conditions. [Table 28]

[0236] Example 5: Salt screening and characterization 5.1 Salt screening Starting with free acid form A (818159-01-A), 30 salt screening experiments were performed using 10 bases and 3 solvent systems according to their pKa (acidic, 3.36) and approximate solubility. Approximately 20 mg of the free acid and an equimolar amount of base were added to 0.5 mL of solvent at room temperature. The solid was centrifuged for XRPD. A total of six salt hits were observed, with the results summarized in Table 29. All hits were analyzed by TGA, DSC, and NMR. 1 Characterized by 1 H NMR or HPLC / IC and the results are summarized in Table 30. [Table 29] [Table 30]

[0237] 5.1.1 Na Salt Form A Na salt Form A (818159-03-B1) was prepared by slurrying free acid Form A (818159-01-A) and NaOH in a 1:1 molar ratio (base / acid) in EtOAc at room temperature for 3 days, followed by centrifugation and vacuum drying at 50°C. The XRPD and TGA / DSC results are shown in Figures 18A and 18B. The TGA results showed a 4.5% weight loss up to 220°C, and the DSC results showed three endothermic peaks at 155.7, 201.8°C (onset temperatures), and 288.7°C (peak temperature) and one exothermic peak at 166.3°C (peak temperature). 1 H NMR (FIG. 18C) showed that the EtOAc / free acid molar ratio was 0.19 (0.8 wt%). HPLC / IC showed that the base / acid molar ratio was 1.1.

[0238] 5.1.2 K-salt Forms A / B As shown in Figure 19A, K-salt Form A / B (818159-03-B2 / C2) was prepared by slurrying free acid Form A (818159-01-A) and KOH in a 1:1 molar ratio (base / acid) in EtOAc and acetone / HO at room temperature for 3 days, followed by centrifugation and vacuum drying at 50°C. For K-salt Form A, the TGA / DSC results are shown in Figure 19B. The TGA results showed a 3.6% weight loss up to 150°C, and the DSC results showed three endothermic peaks at 91.1, 135.8, and 147.7°C (peak temperatures). 1 H NMR (FIG. 19C) results showed no EtOAc was observed. HPLC / IC indicated that the base / acid molar ratio of K salt form A was 1.1. Due to limited material, no characterization of K salt form B was performed.

[0239] 5.1.3 Arginine Salt Form A Arginine salt Form A (818159-03-B3) was prepared by slurrying free acid Form A (818159-01-A) and arginine in a 1:1 molar ratio (base / acid) in EtOAc at room temperature for 3 days, followed by centrifugation and vacuum drying at 50° C. The XRPD and TGA / DSC results are shown in Figures 20A and 20B. The TGA results showed a weight loss of 4.0% up to 180° C., and the DSC results showed one endothermic peak at 186.9° C. (onset temperature). 1 H NMR (Figure 20C) results showed that the molar ratio of arginine / free acid was 1.0 and the molar ratio of EtOAc / free acid was 0.12 (2.3 wt%).

[0240] 5.1.4 Mg Salt Form A Mg salt Form A (818159-03-C5) was prepared by slurrying free acid Form A (818159-01-A) and MgOH in a 1:1 molar ratio (base / acid) in acetone at room temperature for 3 days, followed by centrifugation and vacuum drying at 50°C. The XRPD and TGA / DSC results are shown in Figures 21A and 21B. The TGA results showed a weight loss of 6.9% up to 150°C, and the DSC results showed four endothermic peaks at 90.7, 114.9, 134.0, and 154.2°C (peak temperatures). 1 H NMR (FIG. 21C) showed that the acetone / free acid molar ratio was 0.01 (0.2 wt%). HPLC / IC showed that the base / acid molar ratio was 0.8.

[0241] 5.1.5 Tris Salt Form A Tris salt Form A (818159-03-B10) was prepared by slurrying free acid Form A (818159-01-A) and Tris in a 1:1 molar ratio (base / acid) in EtOAc at room temperature for 3 days, followed by centrifugation and vacuum drying at 50° C. The XRPD and TGA / DSC results are shown in Figures 22A and 22B. The TGA results showed a weight loss of 6.5% up to 150° C., and the DSC results showed four endothermic peaks at 71.8, 76.6, 113.9, and 213.1° C. (peak temperatures). 1H NMR (Figure 22C) results showed that the molar ratio of Tris / API was 1.0 and the molar ratio of EtOAc / API was 0.26 (4.9 wt%).

[0242] 5.2 Salt Lead Reconstitution Based on the characterization results, it is assumed that arginine salt Form A is an anhydrate, while the other salts are hydrates or solvates. Considering the safety of the salt coformers and the dehydration temperature, Na salt Form A, K salt Form A, and arginine salt Form A are selected as lead salts for reformulation and evaluation. A new K salt (K salt Form C) was obtained during reformulation, and the other salts were successfully reformulated. The detailed preparation procedures and characterization results are summarized in Table 31 and Table 32. [Table 31] [Table 32]

[0243] 5.2.1 Na Salt Form A Na salt Form A (818159-09-B) was reconstituted, as shown in Figure 24A, Figure 23, and Table 33 for the XRPD results. A new form was observed in the wet sample and converted to Na salt Form A. TGA / DSC results are shown in Figure 24B. TGA results showed a 6.2% weight loss up to 220°C, and DSC results showed two endothermic peaks at 157.4°C (onset temperature) and 204.0°C (peak temperature) and one exothermic peak at 166.5°C (peak temperature). 1 H NMR (Figure 24C) showed that the EtOAc / free acid molar ratio was 0.31 (5.8 wt%). HPLC / IC showed that the base / acid molar ratio was 0.9. [Table 33]

[0244] 5.2.2 K-salt form C As shown in Figure 26A, Figure 25, and Table 34, a new K salt, classified as K salt form C (818159-10-B), was observed during the preparation. The TGA / DSC results are shown in Figure 26B. The TGA results showed a 5.5% weight loss up to 200°C, and the DSC results showed three endothermic peaks at 108.1, 140.2, and 161.3°C (peak temperatures). 1 H NMR (Figure 26C) showed no detectable EtOAc, and HPLC / IC showed a base / acid molar ratio of 0.9. [Table 34]

[0245] 5.2.3 Arginine Salt Form A Arginine salt Form A (818159-11-B) was reconstituted as shown in Figure 28A, Figure 27, and Table 35. The TGA results (Figure 28B) showed a weight loss of 1.3% up to 150°C, and the DSC results (Figure 28B) showed one endothermic peak at 194.0°C (onset temperature). 1 1 H NMR (Figure 28C) results showed an arginine / free acid molar ratio of 1.0, and no EtOAc was detected. [Table 35]

[0246] [Example 6] Evaluation Based on the salt screening and characterization results, Na salt Form A, K salt Form C, and arginine salt Form A were selected to evaluate kinetic solubility, hygroscopicity, solid state stability, etc., using free acid Form B as a control.

[0247] 6.1 Kinetic solubility evaluation Kinetic solubility profiles were measured at 37°C with a solid loading of ~2 mg / mL (calculated as the free acid) in water, SGF, FaSSIF-V2, FeSSIF-V2, and four pH buffers (pH 1.2, 4.5, 6.8, and 8.0 buffers). Na salt Form A was measured in water, SGF, FaSSIF-V2, and FeSSIF-V2 alone. Specifically, the salt solids were suspended in the medium, and the suspensions were agitated in a rotary incubator. Samples were taken at 2 and 24 hours, respectively. The supernatant was extracted by centrifugation before filtering through a 0.45 μm PTFE membrane and used for solubility and pH measurements. The residual solids were collected for XRPD characterization (Figures 29-32). The results are summarized in Table 36, and the kinetic solubility profiles are shown in Figure 35. The results showed that 1) Na salt Form A, K salt Form C, and arginine salt Form A showed comparable solubilities in water and three biorelevant media, with improved solubility compared to free acid Form B; 2) K salt Form C and arginine salt Form A showed comparable solubilities in pH 4.5 and 6.8 buffers, with improved solubility compared to free acid Form B; and 3) no conformational change was observed after solubility testing of free acid Form B, while conformational change to free acid Form F or amorphous occurred after solubility testing of Na salt Form A, K salt Form C, and arginine salt Form A. [Table 36]

[0248] Based on the characterization of the different free acid forms and the slurry competition results, free acid Forms B and E are anhydrous and enantiotropic, with Form B being the cold-stable form. The transition temperature between Forms B and E is 40-50°C. To assess the difference in solubility, solubility studies were performed at 37°C with a solid loading of ~2 mg / mL in water, SGF, FaSSIF-V2, FeSSIF-V2, and two pH buffers (pH 1.2, 4.5, 6.8, and 8.0 buffers). Specifically, salt solids were suspended in the media, and the suspensions were agitated in a rotary incubator. Samples were taken at 2 and 24 hours, respectively. The supernatant was extracted by centrifugation before filtering through a 0.45 μm PTFE membrane and used for solubility and pH measurements. The residual solids were collected for XRPD characterization (Figures 33 and 34). The results are summarized in Table 37, and the kinetic solubility profile is shown in Figure 36. The results showed that 1) free acid forms B and E exhibited comparable solubility in water and at pH 8.0 (nearly clear), 2) free acid form E exhibited slightly higher solubility than form B in other media, and 3) no form changes were observed after the solubility test. [Table 37]

[0249] 6.2 Moisture absorption evaluation To examine the solid-state morphology stability as a function of humidity (0% RH, 50% RH, and 60% RH), DVS isotherm plots of free acid Form B, Na salt Form A, K salt Form C, and arginine salt Form A were collected at 25°C. The DVS plots and XRPDs after DVS testing are shown in Figures 37-40. Free acid Form B and arginine salt Form A exhibited water absorption rates of 0.07% and 0.5%, respectively, up to 80% RH, indicating that free acid Form B is non-hygroscopic and arginine salt Form A is slightly hygroscopic. No morphology changes were observed for free acid Form B and arginine salt Form A. After DVS testing, water absorption and morphology changes of 5.5% and 12.0% up to 80% RH were observed for Na salt Form A and K salt Form C.

[0250] 6.3 Solid-state stability assessment To understand the solid-state stability, the physicochemical stability of free acid Form B (Table 39) / E (Table 40), Na salt Form A (Table 41), K salt Form C (Table 42), and arginine salt Form A (Table 43) was evaluated at 60°C / closed and 40°C / 75% RH / open for 2, 4, and 8 weeks. The results are summarized in Table 38. XRPD results are shown in Figures 41, 42, 44, 45, and 46. Form E samples after solid-state stability were tested by DSC (Figure 43), and no significant differences were observed. HPLC results are shown in Figures 47-51. No loss in morphology or purity was observed for free acid Form B / E and arginine salt Form A. No loss in purity was observed for K salt Form C after storage under the test conditions, but a change in morphology was observed. Na salt Form A showed a slight loss in purity and a change in morphology after 8 weeks of storage at 60°C. [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43]

[0251] [Example 7] Evaluation of PPARα / PPARγ activity of Compound 2 using a luciferase reporter system HEK293T cells were cultured according to the ATCC culture guide. Experiments were performed when the cells were in exponential growth phase. A total of 6 × 10 6Cells were seeded into 60 mm cell culture dishes and cultured overnight at 37°C and 5% CO2. The transfection reagent Lipofectamine® 3000 was mixed with the plasmid combination (a mixture of pGL4.35[luc2P / 9XGAL4 UAS / Hygro], pBIND-RXRα, and pBIND-PPPARα or a mixture of pGL4.35[luc2P / 9XGAL4 UAS / Hygro], pBIND-RXRα, and pBIND-PPPARγ) and then added to the dishes. After 5 hours of incubation at 37°C and 5% CO2, the cells were trypsinized, seeded into 384-well assay plates, and subsequently incubated overnight with a range of concentrations of test compounds at 37°C and 5% CO2. The next day, the cells were lysed, and luciferase was activated using the Steady-Glo™ Luciferase Assay System. The luminescence signal from the luciferase assay was measured by Envision HTS / 2105. Because peroxisome proliferator-activated transcription regulates luciferase expression, the agonist activity of test compounds can be determined by luminescence intensity. EC2 of PPARα / γ agonist potency of test compounds 50 The values ​​were calculated using Graphpad 8.0, and the results are shown in Table 44. The selectivity of the compounds for PPARα or PPARγ was evaluated by the PPARγ EC 50 / PPARα EC 50 It is expressed as: [Table 44]

[0252] [Example 8] Effect of Compound 2 on a high-cholesterol diet-induced hyperlipidemia rat model 8.1 Experimental materials Thirty 6- to 8-week-old male Sprague-Dawley rats, source: SPF (Beijing) Biotechnology Co., Ltd., animal certificate number: 110324201104469613.

[0253] 8.2 Experimental Method 8.2.1 An animal model of hyperlipidemia was induced in SD rats using a high cholesterol diet (ASHF4).

[0254] 8.2.2 Male SD rats were fed a high-cholesterol diet (ASHF4, Dyet, China) for 14 days. On the day before the start of treatment (day 0), the animals were divided into five groups based on body weight and serum indices and continued to receive the high-cholesterol diet. The treatment groups received oral administration of the compound or vehicle while continuing to receive the high-cholesterol diet for a total of one week. The animals were weighed daily before treatment, and the compound was administered between 9:00 and 9:30 AM based on the body weight of the day. The specific groupings and administration regimens are shown in Table 45. [Table 45]

[0255] formulation Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 5 g of sodium carboxymethylcellulose was added to 900 ml of ddH2O and stirred until completely dissolved, then filled with 1000 ml of ddH2O. 2. Working solution for 0.6 mg / kg dose: 0.12 mg / ml working solution. 12 mg of compound was added to 100 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended. 3. Working solution for 0.2 mg / kg dose: 0.04 mg / ml working solution. 30 ml of 0.12 mg / ml compound solution was mixed with 60 ml of 0.5% sodium carboxymethylcellulose and then vortexed until well suspended.

[0256] 8.2.3 At the end of the day before treatment and on the final day of the experiment, animal blood was collected and serum was separated for serum lipid index analysis.

[0257] 8.2.4 Serum indices of triglycerides (TG) and free fatty acids (NEFA) were determined by an automated blood biochemistry analyzer.

[0258] 8.3 Results Serum lipid analysis showed that after 7 days of treatment (day 8), both aleglitazar and Compound 2 could significantly reduce serum TG and NEFA levels at both 0.2 mg / kg and 0.6 mg / kg dose levels compared with the vehicle group. Animal serum TG and NEFA are shown in Figures 52A and 52B, and the values ​​are shown in Tables 46 and 47, respectively. No clinical abnormalities were observed during the experiment. For comparison purposes, t-test statistical analysis was performed on the results of each compound at a dose of 0.2 mg / kg using the GraphPad 8.0 software package. At the dose level of 0.2 mg / kg, Compound 2 could significantly reduce TG and NEFA (P<0.05) compared with aleglitazar. [Table 46] [Table 47]

[0259] [Example 9] Effect of repeated oral administration for 7 days on the body weight of ICR mice 9.1 Experimental animals Fifty 6-8 week old male ICR mice. Source: Laboratory Animal Business Department, Shanghai Institute of Planned Parenthood Research.

[0260] 9.2 Method After 3 days of acclimation, the ICR mice were divided into groups based on their body weight. The day of grouping was designated as day 0. After grouping, the mice were orally administered with vehicle or compound once daily for 7 consecutive days. The doses and groupings are shown in Table 48. The body weights of the animals were measured and recorded daily. [Table 48]

[0261] formulation Formulations were prepared twice weekly. 1. Vehicle: 0.5% carboxymethylcellulose sodium. 2.5 g of carboxymethylcellulose sodium was weighed and mixed with 500 ml of ddH2O until completely dissolved. 2. Working solution for 1 mg / kg dosing: 0.1 mg / ml working solution. 3 mg of compound was added to 30 ml of 0.5% carboxymethylcellulose sodium, then vortexed until well suspended. 3. Working solution for 0.2 mg / kg dosing: 0.02 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 24 ml of 0.5% carboxymethylcellulose sodium, then vortexed until well suspended.

[0262] 9.3 Results The effects of the compounds on body weight change in ICR mice are shown in Table 49 and Figure 53A. Animal weight gradually increased over time during the experiment. The average daily weight gain of the aleglitazar group at doses of 0.2 mg / kg (days 4 and 5) and 1 mg / kg (day 6) was significantly higher than that of the vehicle group. Compared with the vehicle group, the average daily weight gain of the Compound 2 group at the low dose of 0.2 mg / kg was not significantly different throughout the study. The average daily weight gain of the Compound 2 group at the high dose of 1 mg / kg (days 4 and 5) was significantly higher than that of the vehicle group. Complete data are shown in Table 49. For comparison purposes, the net weight gain of treatment was calculated by subtracting the average weight gain of the vehicle group from the average weight gain of each treatment group, and is shown in Figure 53B. [Table 49]

[0263] [Example 10] Pharmacodynamics test of Compound 2 in db / db type 2 diabetes model 10.1 Experimental materials [Table J]

[0264] 10.2 Experimental Method 10.2.1 Experimental Grouping Six wild-type mice were used as the control group (group 1). Before the start of treatment, 45 Db / db mice were uniformly divided into five groups based on body weight, serum triglyceride (TG) level, and random blood glucose level.

[0265] 10.2.2 Formulations Formulations were prepared twice weekly. 1. Vehicle: 0.5% carboxymethylcellulose sodium. 2.5 g of carboxymethylcellulose sodium was weighed and mixed with 500 ml of ddH2O until completely dissolved. 2. Working solution for 1 mg / kg dose: 0.1 mg / ml working solution. 3 mg of compound was added to 0 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended. 3. Working solution for 0.2 mg / kg dose: 0.02 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 24 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended. 4. Working solution for 0.05 mg / kg dose: 0.005 mg / ml working solution. 6 ml of 0.02 mg / ml compound solution was mixed with 18 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended.

[0266] 10.2.3 Administration Animals were orally administered according to grouping: vehicle (Group 2), aleglitazar at a dose level of 0.2 mg / kg (Group 3), and Compound 2 at dose levels of either 0.05 mg / kg (Group 4), 0.2 mg / kg (Group 5), or 1 mg / kg (Group 6). All animals were weighed daily before each administration and treated daily for 14 consecutive days.

[0267] 10.2.4 Study results will include daily body weights throughout the entire study, pre-dose serum TG levels on study days 6 and 12, pre-dose random blood glucose levels on study days 7 and 14, and results from an oral glucose tolerance test (OGTT) performed on study day 14.

[0268] 10.3 Data Analysis All data were imported into an Excel file and presented as mean ± SEM. Data were statistically analyzed by one-way or two-way ANOVA using Graphpad Prism 7.0 software, with P < 0.05 as the criterion for significance.

[0269] 10.4 Experimental Results Both aleglitazar and all two compound groups significantly reduced lipid, free fatty acid and blood glucose levels and significantly increased body weight compared to the vehicle group.

[0270] 10.4.1 Animal weight The body weight changes of db / db model animals treated with aleglitazar and different doses of Compound 2 are shown in Figure 54. As shown in Figure 54, the body weights of animals in the aleglitazar (0.2 mg / kg) dose group and Compound 2 dose groups (0.05 mg / kg, 0.2 mg / kg, 1 mg / kg) gradually increased over time during the experiment, and the mean daily body weights (from day 10 to day 15) were significantly higher than those of the vehicle group.

[0271] 10.4.2 Animal Blood Chemistry Indicators The blood biochemistry index TG of the animals was measured on days 6 and 12, and the results are shown in Figures 55A and 55B. As shown in Figures 55A and 55B, the serum TG levels of the groups treated with aleglitazar or different doses of Compound 2 were significantly lower than that of the vehicle group on days 6 and 12, with the greatest effect observed in Group 6 (Compound 2, 1 mg / kg).

[0272] 10.4.3 Random Blood Glucose The effects of aleglitazar and different doses of Compound 2 on random blood glucose levels in db / db model animals during the experimental period are shown in Figure 56. Compared with the vehicle group, the random blood glucose levels of animals treated with aleglitazar or different doses of Compound 2 were reduced on day 7. This reduction reached statistical significance in Group 3 (aleglitazar, 0.2 mg / kg) and Group 6 (Compound 2, 1 mg / kg), but not in Groups 4 and 5 (Compound 2, 0.05 mg / kg and 0.2 mg / kg). On day 14, compared with day 7, a more pronounced hypoglycemic effect was observed in Group 6 (Compound 2, 1 mg / kg) than in Group 2 (vehicle), while Groups 3 and 5 (aleglitazar, 0.2 mg / kg and Compound 2, 0.2 mg / kg) showed similar effects. Meanwhile, this effect in Group 3 (Compound 2, 0.05 mg / kg) had not yet reached statistical significance. Therefore, Compound 2 had a slightly lower hypoglycemic effect than aleglitazar (Table 50). [Table 50]

[0273] 10.4.4 Animal glucose tolerance tests At the end of the experiment, oral glucose tolerance tests were performed on the db / db animals treated with different compounds. The blood glucose levels and area under the blood glucose time curve at each time point within 120 minutes after the test are shown in Figures 57A and 57B. Compared with the vehicle group, the blood glucose levels of both aleglitazar and Compound 2 at different doses were significantly reduced at each time point. Among them, the AUC of the test product aleglitazar (0.2 mg / kg, P<0.001) and Compound 2 (0.2 mg / kg, P<0.01 & 1 mg / kg, P<0.0001) were significantly reduced. 0-120min was significantly lower than that of the vehicle group. In addition, the AUC 0-120min was higher, indicating lower PPARγ activity. Furthermore, the results for Group 4 (Compound 2, 0.05 mg / kg) showed a trend toward a decrease at all time points compared to the vehicle group, but did not reach statistical significance. [Table 51]

[0274] 10.5 Discussion In the present disclosure, the inventors have obtained a novel compound, namely, Compound 2, with higher α / γ activity.

[0275] In vitro transcriptional activity experiments showed that compounds activate the PPARα and PPARγ pathways in EC 50 was at the nanomolar level, indicating that Compound 2 had high in vitro biological activity. Compared with aleglitazar, Compound 2 exhibited stronger PPARα agonist activity and weaker PPARγ agonist potency.

[0276] According to the hyperlipidemia rat model experiment, compound 2 can effectively and significantly reduce the blood lipid level of animals.In addition, compound 2 at low dose level has a higher blood lipid lowering effect than aleglitazar at the corresponding concentration.Therefore, the results show that compound 2 has a higher PPARα activity at low dose level, which leads to a higher blood lipid lowering effect.

[0277] In ICR mouse body weight experiments, after treatment with low doses of Compound 2, the body weight of the animals was comparable to that of the control group, with no significant change. In contrast, aleglitazar at the same dose level caused a significant increase in body weight. Since weight gain is a well-known side effect of PPARγ, this indicated that at low doses, Compound 2 had lower PPARγ activity than aleglitazar.

[0278] In a study using db / db mice, Compound 2 effectively reduced blood glucose and triglyceride levels in type 2 diabetic mice. This indicated that Compound 2 exerted an in vivo biological effect of PPARγ regulating blood glucose. Furthermore, at the same dose level, Compound 2 achieved a similar hypoglycemic effect to aleglitazar. Therefore, the agonistic effect of Compound 2 on the PPARγ pathway is sufficient to regulate glucose homeostasis.

[0279] [Example 11] Pharmacodynamic model of diabetic nephropathy 11.1 Experimental Method 11.1.1 Animals Five-week-old wild-type and db / db:BLKS male mice were purchased from Jiangsu GemPharmatech, Co., Ltd. The animals were housed in a 12-hour light / dark cycle in a SPF environment. The temperature was maintained at 22–26°C and the humidity at 40–60%. Mice had free access to food and water. At 6 weeks of age, db / db mice were anesthetized with 2.5% isopentane and underwent uninephrectomy to remove the right kidney. Buprenorphine was administered postoperatively.

[0280] 11.1.2 Procedure Two weeks after surgery, db / db mice were randomly divided into five groups. Wild-type mice were used as controls. Five groups were included in the study: Group 1 (a control group of six animals receiving vehicle), Group 2 (a vehicle group of 10 animals receiving vehicle), Group 3 (a low-compound group of 10 animals receiving 0.1 mg / kg of Compound 2), Group 4 (a medium-compound group of 10 animals receiving 0.3 mg / kg of Compound 2), and Group 5 (a high-compound group of 10 animals receiving 1 mg / kg of Compound 2). The compounds were orally administered once daily for 10 weeks.

[0281] 11.1.3 Formulations Formulations were prepared twice weekly. 1. Vehicle: 0.5% carboxymethylcellulose sodium. 2.5 g of carboxymethylcellulose sodium was weighed and mixed with 500 ml of ddH2O until completely dissolved. 2. Working solution for 1 mg / kg dose: 0.2 mg / ml working solution. 6 mg of compound was added to 30 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended. 3. Working solution for 0.3 mg / kg dose: 0.06 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 14 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended. 4. Working solution for 0.1 mg / kg dose: 0.02 mg / ml working solution. 2 ml of 0.2 mg / ml compound solution was mixed with 18 ml of 0.5% carboxymethylcellulose sodium and then vortexed until well suspended.

[0282] At 5 and 9 weeks after compound administration, mice were placed in metabolic cages for urine collection. Albumin levels were measured for 24-hour albumin excretion calculations. At 10 weeks after treatment, animals were sacrificed and kidneys were removed. Kidneys were fixed in 10% neutral buffered formalin and then paraffin-embedded for histopathological analysis. Glomerular sclerosis was assessed by evaluating the glomerular basement membrane, mesangial expansion, nodular sclerosis, and glomerular sclerosis. Severity was graded as follows: 0: normal; 1: glomerular basement membrane thickening: isolated glomerular basement membrane thickening with only mild, nonspecific changes by light microscopy; 2: mild (IIa) or severe (IIb) mesangial expansion: mild or severe mesangial expansion in more than 50% of glomeruli but without nodular or global glomerular sclerosis; 3: nodular sclerosis: at least one glomerulus with nodular increases in the mesangial matrix; 4: advanced diabetic glomerulosclerosis: global glomerular sclerosis rate >50% with other clinical or pathological evidence that the sclerosis is due to diabetic nephropathy. Renal tubular damage was scored as follows: 0: no obvious lesions; 1: up to 25% tubular lesions; 2: 25%-50% tubular lesions; 3: 50%-75% tubular lesions; and grade 4: >75% tubular lesions.

[0283] 11.1.4 Data were expressed as mean + SEM. Statistical analysis was performed using Graphpad 8.0 software. Differences in values ​​were analyzed by one-way ANOVA. Differences in histopathological scores were analyzed by Kruskal-Wallis nonparametric test. All values ​​were compared with Group 2.

[0284] 11.2 Results 1. 24-hour urinary albumin. In vehicle-treated unilaterally nephrectomized db / db mice, 24-hour urinary albumin increased more than 10-fold compared to controls. Compound 2 significantly reduced 24-hour urinary albumin at 5 and 9 weeks after compound administration. Compound 2 treatment achieved a greater than 50% reduction in urinary albumin (Figure 58). 2. Glomerulosclerosis. As shown in Figure 59A, control animals had normal glomerular appearance and glomerular volume. However, mesangial expansion, glomerular basement membrane thickening, and nodular sclerosis were observed in vehicle-treated db / db animals. Compound 2 inhibited glomerular injury and ameliorated glomerular hypertrophy. After administration of a high dose of Compound 2, both the histopathological score and glomerular volume of the animals were statistically significantly reduced (Figures 59B and 59C). 3. Renal tubular injury. Histopathological analysis revealed that control animals had normal tubular structure, whereas vehicle-treated animals developed tubular dilatation, basement membrane thickening / tubular atrophy, and tubular casts. Compound 2 at all dose levels ameliorated tubular damage to some extent (Figure 59D).

[0285] Example 12: Effect of Compound 2 on ameliorating renal injury in a rat model of unilateral ureteral obstruction 12.1 Experimental Method 12.1.1 Male SD rats weighing 240–260 g were housed in a SPF environment with a 12-hour light / dark cycle. The temperature was maintained at 20–26°C and the humidity at 40–60%. The rats were fed a standard diet and had free access to food and water.

[0286] 12.1.2 Formulations Formulations were prepared twice weekly. 1. Vehicle: 0.5% carboxymethylcellulose sodium was prepared as described in 17.1.3. 2. 0.2 mg / ml solution of Compound 2 or Aleglitazar. 6 mg of compound was added to 30 ml of 0.5% carboxymethylcellulose sodium, then vortexed until well suspended. 3. 0.02 mg / ml solution of Compound 2 or Aleglitazar for a 0.2 mg / kg dose. 2 ml of the 0.2 mg / ml solution was mixed with 18 ml of 0.5% carboxymethylcellulose sodium, then vortexed until well suspended.

[0287] 12.1.3 Procedure After acclimatization, the animals were randomly assigned to the following groups: a control group of 8 animals receiving 10 ml / kg of vehicle; a model group of 10 rats receiving 10 ml / kg of vehicle; a reference group of 10 animals receiving 0.2 mg / kg of aleglitazar; and a compound group of 10 animals receiving 0.2 mg / kg of Compound 2. Vehicle or compound was administered orally daily. On the second day of compound treatment, unilateral ureteral obstruction was performed. Animals in the model, reference, and compound groups underwent urethral ligation under isoflurane anesthesia 1 hour after compound administration. The left ureter was exposed through a laparotomy, and urethral obstruction was achieved by two-point ligation using 4-0 sutures. The ureter was transected between the two ligation points. Animals in the control group underwent the same surgical treatment except for ligation and transsection. Following surgery, animals in each group received vehicle or compound continuously for 12 more days, for a total of 14 days of treatment.

[0288] After 14 days of compound treatment, rats were sacrificed. The obstructed kidneys were weighed and collected for histological examination. Tissue samples were fixed in formalin and then embedded in paraffin. The embedded tissues were sectioned and stained with hematoxylin and eosin and Masson's trichrome to evaluate renal structure and fibrosis. Focal lesions included infarction, tubular dilatation, tubular obstruction, and necrosis, each of which was assigned a score of 0 to 4 as a percentage of the lesion area in the biopsy (score 0: none, 1: <25%, 2: 25%-50%, 3: 50%-75%, 4: >75%). The severity of renal injury was assessed by the total lesion score. Renal fibrosis was graded from 0 to 4 based on the percentage of Masson's trichrome stained area (score 0: none, 1: <25%, 2: 25%–50%, 3: 50%–75%, 4: >75%).

[0289] 12.1.4 Data were expressed as mean + SEM. Multiple comparisons were analyzed by the Kruskal-Wallis nonparametric test. Dunn's test was used to compare differences between model groups. A P value of <0.05 was considered statistically significant.

[0290] 12.1.5 Results Compared with the vehicle-administered model group, Compound 2 at 0.2 mg / kg significantly improved the total score, which consisted of focal renal lesions including infarction, tubular dilatation, tubular obstruction, fibrosis, and necrosis (Figure 60). Meanwhile, the reference compound, aleglitazar, did not achieve a statistically significant improvement in the total score at the same dose of 0.2 mg / kg. Therefore, Compound 2 is superior to aleglitazar in preventing and alleviating renal injury due to unilateral ureteral obstruction.

[0291] The foregoing description is considered as merely illustrative of the principles of the present disclosure. Moreover, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the specific constructions and processes described above. Accordingly, all suitable modifications and equivalents may be deemed to be included within the scope of the present invention as defined by the following claims.

Claims

1. Crystalline form B of compound 2, 【Chemistry 1】 Crystalline form B, characterized by an X-ray powder diffraction pattern (XRPD) containing one or more peaks at 8.16, 13.23, and 13.90 (±0.2° 2θ).

2. 2. The crystalline form B of claim 1, wherein the XRPD pattern further comprises one or more peaks at 4.94, 11.83, 14.97, 18.54, and 26.24 (±0.2 degrees 2θ).

3. 3. The crystalline form B of claim 1 or 2, wherein the XRPD pattern further comprises one or more peaks at 9.89, 19.74, and 20.92 (±0.2 degrees 2θ). 【Request Item 4】 【Table 1】 4. The crystalline form B of any one of claims 1 to 3, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

5. Crystalline form B according to any one of claims 1 to 4, characterized by an XRPD pattern substantially as shown in Figure 5A.

6. 6. Crystalline form B according to any one of claims 1 to 5, characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with a peak temperature of about 151.1°C.

7. 7. Crystalline form B of claim 6, characterized by a DSC thermogram substantially as shown in Figure 5B.

8. The crystalline form B of any one of claims 1 to 7, wherein the crystalline form B is anhydrous.

9. Crystalline Form C of Compound 2, characterized by an XRPD pattern containing one or more peaks at 5.06, 10.09, and 20.24 (±0.2° 2θ).

10. 10. The crystalline form C of claim 9, wherein the XRPD pattern further comprises one or more peaks at 15.15, 16.18, and 16.75 (±0.2 degrees 2θ).

11. 11. The crystalline form C of claim 9 or 10, wherein the XRPD pattern further comprises one or more peaks at 7.99, 8.37, 11.71, 12.22, 12.87, 13.60, and 14.04 (±0.2 degrees 2θ). 【Request Item 12】 【Table 2】 12. The crystalline form C of any one of claims 9 to 11, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

13. 13. Crystalline form C according to any one of claims 9 to 12, characterized by an XRPD pattern substantially as shown in Figure 6A.

14. 14. Crystalline form C according to any one of claims 9 to 13, characterized by a DSC thermogram having an endotherm with a peak temperature of about 149.0°C.

15. 15. Crystalline form C of claim 14 characterized by a DSC thermogram substantially as shown in Figure 6B.

16. 16. The crystalline form C of any one of claims 9 to 15, wherein the crystalline form C is anhydrous.

17. Crystalline Form D of Compound 2, characterized by an XRPD pattern containing one or more peaks at 5.03, 12.98, 15.91, and 21.58 (±0.2° 2θ).

18. 18. The crystalline form D of claim 17, wherein the XRPD pattern further comprises one or more peaks at 5.90, 9.21, 20.47, and 26.08 (±0.2 degrees 2θ).

19. 19. The crystalline form D of claim 17 or 18, wherein the XRPD pattern further comprises one or more peaks at 11.76, 15.04, 22.38, and 24.47 (±0.2 degrees 2θ). 【Request Item 20】 【Table 3】 20. The crystalline form D of any one of claims 17 to 19, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

21. Crystalline form D according to any one of claims 17 to 20, characterized by an XRPD pattern substantially as shown in Figure 7.

22. 22. The crystalline form D of any one of claims 17 to 21, wherein the crystalline form D is a hydrate.

23. Crystalline Form E of Compound 2, characterized by an XRPD pattern containing one or more peaks at 10.12, 11.97, 13.73, and 18.89 (±0.2° 2θ).

24. 24. The crystalline form E of claim 23, wherein the XRPD pattern further comprises one or more peaks at 5.06, 8.14, 13.02, and 14.19 (±0.2 degrees 2θ).

25. 25. The crystalline form E of claim 23 or 24, wherein the XRPD pattern further comprises one or more peaks at 14.87, 21.30, 22.33, and 26.23 (±0.2 degrees 2θ). 【Request Item 26】 【Table 4】 26. The crystalline form E of any one of claims 23 to 25, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

27. 27. Crystalline form E according to any one of claims 23 to 26, characterized by an XRPD pattern substantially as shown in Figure 12.

28. 28. The crystalline form E of any one of claims 23 to 27, wherein the crystalline form E is anhydrous.

29. Crystalline Form F of Compound 2, characterized by an XRPD pattern containing one or two peaks at 15.50 and 21.23 (±0.2° 2θ).

30. 30. The crystalline form F of claim 29, wherein the XRPD pattern further comprises one or two peaks at 12.12 and 20.21 (±0.2 degrees 2θ). 【Request Item 31】 【Table 5】 31. The crystalline form F of claim 29 or 30, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

32. 32. Crystalline form F according to any one of claims 29 to 31, characterized by an XRPD pattern substantially as shown in Figure 14A.

33. 33. Crystalline form F according to any one of claims 29 to 32, characterized by a DSC thermogram having an endotherm with a peak temperature at about 111.2°C and / or about 149.8°C.

34. 34. Crystalline form F of any one of claims 29 to 33, characterized by a DSC thermogram having an exotherm with a peak temperature of about 118.9°C.

35. 35. Crystalline form F of claim 34, characterized by a DSC thermogram substantially as shown in Figure 14B.

36. 36. The crystalline form F of any one of claims 29 to 35, wherein the crystalline form F is a hydrate.

37. Crystalline Form G of Compound 2, characterized by an XRPD pattern containing one or more peaks at 9.67, 11.60, 12.90, and 14.43 (±0.2° 2θ).

38. 38. The crystalline form G of claim 37, wherein the XRPD pattern further comprises one or more peaks at 8.16, 13.69, 13.91, 16.15, 18.51, 18.93, and 20.47 (±0.2 degrees 2θ).

39. 39. The crystalline form G of claim 37 or 38, wherein the XRPD pattern further comprises one or more peaks at 4.95, 11.83, 13.22, and 19.

84. (±0.2 degrees 2θ). 【Request Item 40】 【Table 6】 40. The crystalline form G of any one of claims 37 to 39, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

41. 41. Crystalline form G according to any one of claims 37 to 40, characterized by an XRPD pattern substantially as shown in Figure 15A.

42. 42. Crystalline form G according to any one of claims 37 to 41, characterized by a DSC thermogram having an endotherm with a peak temperature at about 72.4°C and / or about 83.1°C.

43. 43. Crystalline form G of claim 42, characterized by a DSC thermogram substantially as shown in Figure 15B.

44. 44. The crystalline form G of any one of claims 37 to 43, wherein the crystalline form G is a DMSO solvate.

45. A salt of Compound 2, 【Chemistry 2】 A salt of Compound 2 selected from the sodium salt, potassium salt, arginine salt, magnesium salt, or tromethamine salt of Compound 2.

46. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form A of the sodium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 4.09, 4.62, and 14.21 (±0.2° 2θ).

47. 47. The salt of Compound 2 of claim 46, wherein the XRPD pattern further comprises one or two peaks at 16.43 and 17.72 (±0.2° 2θ).

48. The crystalline form A of the sodium salt is Table 7 48. The salt of compound 2 of claim 46 or 47, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

49. 49. The salt of Compound 2 of any one of claims 46-48, wherein crystalline Form A of the sodium salt is characterized by an XRPD pattern substantially as shown in Figure 24A.

50. 50. The salt of Compound 2 of any one of claims 46-49, wherein crystalline Form A of the sodium salt is characterized by a DSC thermogram having an endotherm with a peak temperature at about 163.5°C and / or about 204.0°C.

51. 51. The salt of Compound 2 of any one of claims 46-50, wherein crystalline Form A of the sodium salt is characterized by a DSC thermogram having an exotherm with a peak temperature of about 166.5°C.

52. 52. The salt of Compound 2 of claim 51, wherein crystalline Form A of the sodium salt is characterized by a DSC thermogram substantially as shown in Figure 24B.

53. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form C of the potassium salt of Compound 2, characterized by an XRPD pattern comprising one or more peaks at 12.91, 14.96, and 21.23 (±0.2° 2θ).

54. 54. The salt of Compound 2 of claim 53, wherein the XRPD pattern further comprises one or more peaks at 14.12, 20.68, 25.17, and 26.46 (±0.2° 2θ).

55. 55. The salt of Compound 2 of claim 53 or 54, wherein the XRPD pattern further comprises one or more peaks at 3.92, 18.08, 22.48, 24.70, and 25.81 (±0.2° 2θ).

56. Crystalline Form C of the potassium salt is Table 8 56. The salt of compound 2 of any one of claims 53 to 55, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

57. 57. The salt of Compound 2 according to any one of claims 53 to 56, wherein crystalline Form C of the potassium salt is characterized by an XRPD pattern substantially as shown in Figure 26A.

58. 58. The salt of Compound 2 of any one of claims 53-57, wherein crystalline Form C of the potassium salt is characterized by a DSC thermogram having an endotherm with a peak temperature at about 108.1°C, about 140.2°C, and / or about 161.3°C.

59. 59. The salt of Compound 2 of claim 58, wherein crystalline Form C of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 26B.

60. 46. ​​The salt of Compound 2 of claim 45, wherein the salt of Compound 2 is crystalline Form A of the arginine salt of Compound 2 characterized by an XRPD pattern including one or more peaks at 12.93, 13.43, 18.21, and 19.49 (±0.2° 2θ).

61. 61. The salt of Compound 2 of claim 60, wherein the XRPD pattern further comprises one or more peaks at 10.91, 15.83, 19.14, 20.93, 21.15, and 22.02 (±0.2° 2θ).

62. 62. The salt of Compound 2 of claim 60 or 61, wherein the XRPD pattern further comprises one or more peaks at 11.34, 19.84, 20.45, 25.63, and 26.15 (±0.2° 2θ).

63. The crystalline form A of the arginine salt is Table 9 63. The salt of compound 2 of any one of claims 60 to 62, characterized by an XRPD pattern comprising one or more peaks selected from the group consisting of:

64. 64. The salt of Compound 2 according to any one of claims 60 to 63, wherein crystalline Form A of the arginine salt is characterized by an XRPD pattern substantially as shown in Figure 28A.

65. 65. The salt of Compound 2 of any one of claims 60-64, wherein crystalline Form A of the arginine salt is characterized by a DSC thermogram having an endotherm with a peak temperature of about 195.2°C.

66. 66. The salt of Compound 2 of claim 65, wherein crystalline Form A of the arginine salt is characterized by a DSC thermogram substantially as shown in Figure 28B.

67. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form A of the potassium salt of Compound 2 characterized by an XRPD pattern substantially as shown in the upper curve of Figure 19A.

68. 68. The salt of Compound 2 of claim 67, wherein crystalline Form A of the potassium salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 91.1°C, about 135.8°C, and / or about 147.7°C.

69. 69. The salt of Compound 2 of claim 68, wherein crystalline Form A of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 19B.

70. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form B of the potassium salt of Compound 2 characterized by an XRPD pattern substantially as shown in the lower curve of Figure 19A.

71. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form A of the magnesium salt of Compound 2 characterized by an XRPD pattern substantially as shown in Figure 21A.

72. 72. The salt of Compound 2 of claim 71, wherein crystalline Form A of the magnesium salt is characterized by a DSC thermogram having an endotherm with peak temperatures at about 90.7°C, about 114.9°C, about 134.0°C, and / or about 154.2°C.

73. 73. The salt of Compound 2 of claim 72, wherein crystalline Form A of the magnesium salt is characterized by a DSC thermogram substantially as shown in Figure 21B.

74. 46. ​​The salt of Compound 2 according to claim 45, wherein the salt of Compound 2 is crystalline Form A of the tromethamine salt of Compound 2 characterized by an XRPD pattern substantially as shown in Figure 22A.

75. 75. The salt of Compound 2 of claim 74, wherein crystalline Form A of the tromethamine salt is characterized by a DSC thermogram having endotherms with peak temperatures at about 71.8°C, about 76.6°C, about 113.9°C, and / or about 213.1°C.

76. 76. The salt of Compound 2 of claim 75, wherein crystalline Form A of the tromethamine salt is characterized by a DSC thermogram substantially as shown in Figure 22B.

77. The crystalline form of any one of claims 1 to 44 and the salt of any one of claims 45 to 76 in substantially pure form.

78. 78. The crystalline form or salt of claim 77, wherein the crystalline form or salt has a purity of at least 90 wt%.

79. 1. A pharmaceutical composition comprising compound 2 and a pharmaceutically acceptable excipient, wherein compound 2 is in a crystalline form selected from the group consisting of crystalline form B of any one of claims 1 to 8, crystalline form C of any one of claims 9 to 16, crystalline form D of any one of claims 17 to 22, crystalline form E of any one of claims 23 to 28, crystalline form F of any one of claims 29 to 36, and crystalline form G of any one of claims 37 to 44.

80. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form B.

81. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form C.

82. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form D.

83. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form E.

84. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form F.

85. 80. The pharmaceutical composition of claim 79, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is crystalline form G.

86. 77. A pharmaceutical composition comprising the salt of compound 2 according to any one of claims 45 to 76 and a pharmaceutically acceptable excipient.

87. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline form A of the sodium salt.

88. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline form C of the potassium salt.

89. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline Form A of the arginine salt.

90. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline Form A of the potassium salt.

91. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline form B of the potassium salt.

92. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline form A of the magnesium salt.

93. 87. The pharmaceutical composition of claim 86, wherein at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of the salt of Compound 2 is crystalline Form A of the tromethamine salt.

94. A crystalline form of compound 2 or a salt of compound 2 according to any one of claims 1 to 78 or a pharmaceutical composition according to any one of claims 79 to 93 for use in a method for the treatment and / or prevention of diseases which are modulated by PPARα and / or PPARγ agonists.

95. 94. A method for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist in a subject, the method comprising administering to the subject an effective amount of a crystalline form of compound 2 or a salt of compound 2 according to any one of claims 1 to 78 or a pharmaceutical composition according to any one of claims 79 to 93.

96. Use of a crystalline form of compound 2 or a salt of compound 2 according to any one of claims 1 to 78 or a pharmaceutical composition according to any one of claims 79 to 93 in the manufacture of a medicament for the treatment and / or prevention of diseases which are modulated by PPARα and / or PPARγ agonists.

97. 97. The use and / or method according to any one of claims 94 to 96, wherein the disease is diabetes, non-insulin dependent diabetes mellitus, hypertension, dyslipidemia, arteriosclerotic disease, metabolic syndrome, or diabetic nephropathy.

98. 97. The use and / or method according to any one of claims 94 to 96, wherein the disease is a kidney disorder.

99. 99. The use and / or method of claim 98, wherein the renal damage is induced by ureteral obstruction.

100. 99. The use and / or method of claim 98, wherein the renal damage is induced by unilateral ureteral obstruction.

101. 94. A method for modulating PPARα and / or PPARγ in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form of compound 2 or a salt of compound 2 according to any one of claims 1 to 78, or a pharmaceutical composition according to any one of claims 79 to 93.

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