Crystal form or salt of deuterated compound

Abstract

The present disclosure relates to various crystalline forms of Compound 2 or a salt of Compound 2, as well as pharmaceutical compositions, preparation methods, and methods of use thereof. These crystalline forms can be used to treat diseases and conditions modulated by PPARα and / or PPARγ agonists.

Description

Technical Field

[0001] The present disclosure generally relates to crystalline forms of Compound 2 or a salt of Compound 2, as well as pharmaceutical compositions comprising these crystalline forms or salts and methods of treatment by administering these crystalline forms or salts or pharmaceutical compositions. Background Art

[0002] Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear hormone receptor superfamily, which is a ligand-activated transcription factor that regulates gene expression. Its various subtypes have been identified and cloned. These subtypes include PPARα, PPARβ (also known as PPARδ) and PPARγ. There are at least two major PPARγ isotypes. Although PPARγl is commonly expressed in most tissues, the longer isoform PPARγ2 is almost exclusively found in adipocytes. In contrast, PPARα is mainly expressed in the liver, kidney and heart. PPAR regulates various body responses, including glucose homeostasis and lipid homeostasis, cell differentiation, inflammatory response and cardiovascular events. The lipid metabolism regulating activity of PPARα is combined with the insulin sensitivity regulating activity of PPARγ to develop specific PPAR-α / γ dual agonists, to control blood sugar and improve cardiovascular symptoms, which is of great significance for clinical drug development.

[0003] As a PPAR-α / γ dual agonist, aleglitazar has a relatively balanced PPAR-α / γ activity. Aleglitazar can effectively improve fasting and postprandial blood glucose levels, insulin sensitivity and blood lipid parameters. However, the results of the Phase 3 clinical trial of aleglitazar show that although aleglitazar can effectively reduce blood glucose and blood lipid levels, it also brings a certain degree of heart failure risk, so aleglitazar does not produce corresponding cardiovascular benefits. At the same time, adverse reactions such as fracture risk have also been found in clinical trials, and it is known that these adverse reactions are caused by PPARγ activation (Lincoff AM et al., "Journal of the American Medical Association (JAMA.)" 2014; 311 (15): 1515-1525). Therefore, it is necessary to develop suitable selective PPAR-α / γ dual agonists to improve safety and benefit patients.

[0004] The present disclosure provides a novel PPARα and PPARγ dual agonist by deuterated aleglitazar (i.e., compound 2):

[0005]

[0006] Compound 2 has a PPAR-α / γ selectivity different from that of Aleglitazar. Compound 2 has stronger PPARα activity, and therefore can show better PPARα activity in in vitro transcription and in vivo lipid reduction, while maintaining a certain degree of PPARγ activity. Therefore, it still has a good therapeutic effect in regulating blood lipid and blood glucose levels, and at the same time can reduce the side effects caused by PPARγ activity, such as weight gain and the risk of heart failure. Compared with Aleglitazar, Compound 2 may have a more reasonable risk-benefit ratio for patients with metabolic syndrome and has good prospects for clinical application.

[0007] Many compounds can exist in different crystal forms or polymorphs that exhibit different physical, chemical, and spectral properties. In the case of certain drugs, certain solid forms may be more bioavailable than other forms, while other forms may be more stable under manufacturing, storage, and biological conditions. In order to ensure the quality, safety, and efficacy of a drug during manufacturing, it is important to have polymorphs of a compound that exhibit certain desired physical and chemical (including spectral) properties.

[0008] Therefore, there is a strong need for one or more crystalline forms of Compound 2 or a salt of Compound 2 that have an acceptable balance of these properties. Summary of the invention

[0009] The present disclosure provides a crystalline form of Compound 2 or a salt of Compound 2:

[0010]

[0011] The invention also provides methods of using such compounds to treat various diseases or conditions such as diabetes.

[0012] In one aspect, the present disclosure provides Form B of Compound 2, characterized in that its XRPD pattern comprises one or more peaks at 8.16, 13.23 and 13.90 (±0.2° 2θ).

[0013] In another aspect, the present disclosure provides Form C of Compound 2, characterized in that its XRPD pattern comprises one or more peaks at 5.06, 10.09 and 20.24 (±0.2° 2θ).

[0014] In a further aspect, the present disclosure provides Form D of Compound 2, characterized in that its XRPD pattern comprises one or more peaks at 5.03, 12.98, 15.91 and 21.58 (±0.2° 2θ).

[0015] In a further aspect, the present disclosure provides Form E of Compound 2, characterized in that its XRPD pattern comprises one or more peaks at 10.12, 11.97, 13.73 and 18.89 (±0.2° 2θ).

[0016] In a further aspect, the present disclosure provides Form F of Compound 2, characterized in that its XRPD pattern comprises one or two peaks at 15.50 and 21.23 (±0.2° 2θ).

[0017] In a further aspect, the present disclosure provides Form G of the maleate salt of Compound 2, characterized in that its XRPD pattern comprises one or more peaks at 9.67, 11.60, 12.90 and 14.43 (±0.2° 2θ).

[0018] In another aspect, the present disclosure provides a salt of Compound 2, wherein the salt of Compound 2 is selected from a sodium salt, a potassium salt, an arginine salt, a magnesium salt or a tromethamine salt of Compound 2.

[0019] In some embodiments, the present disclosure provides Form A of the sodium salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 4.09, 4.62, and 14.21 (±0.2° 2θ).

[0020] In some embodiments, the present disclosure provides Form C of the potassium salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 12.91, 14.96, and 21.23 (±0.2° 2θ).

[0021] In some embodiments, the present disclosure provides Form A of the arginine salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 12.93, 13.43, 18.21, and 19.49 (±0.2° 2θ).

[0022] In some embodiments, the present disclosure provides Form A of the potassium salt of Compound 2, characterized in that it is substantially as follows Fig.19A The XRPD pattern shown in the upper curve.

[0023] In some embodiments, the present disclosure provides Form B of the potassium salt of Compound 2, characterized in that it is substantially as follows Fig.19A The XRPD pattern shown in the lower curve.

[0024] In some embodiments, the present disclosure provides Form A of the magnesium salt of Compound 2, characterized in that it is substantially as follows Fig.21A XRPD pattern shown.

[0025] In some embodiments, the present disclosure provides a crystalline Form A of the tromethamine salt of Compound 2, characterized in that it is substantially as follows Fig.22A XRPD pattern shown.

[0026] 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 a salt of Compound 2 is in the crystalline form of the present disclosure.

[0027] 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 to the subject an effective amount of a crystalline form of Compound 2 or a salt of Compound 2 or a pharmaceutical composition of the present disclosure.

[0028] In another aspect, the present disclosure provides use of a crystalline form of Compound 2 or a salt of Compound 2 or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease modulated by a PPARα and / or PPARγ agonist.

[0029] In another aspect, the present disclosure provides a method of modulating PPARα and / or PPARγ in a subject in need thereof, the method comprising administering to the subject an effective amount of Compound 2 or a crystalline form of a salt of Compound 2 or a pharmaceutical composition of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1A An XRPD overlay of the starting material (818159-01-A) is shown. Figure 1B The TGA / DSC curve of the starting material (818159-01-A) is shown.

[0031] Figure 2A An XRPD overlay of the starting material (818159-60-A) is shown. Figure 2B The TGA / DSC curve of the starting material (818159-60-A) is shown.

[0032] Figure 3 An XRPD overlay of the free acid crystalline form is shown.

[0033] Figure 4A Shown are XRPD patterns of the free acid Form B (prepared from EtOAc, 818159-08-B, with a small amount of Form E) before and after slurrying in ACN. Figure 4B The TGA / DSC curve of the free acid Form B (prepared from EtOAc, 818159-08-B, with a small amount of Form E) is shown. Figure 4CThe free acid Form B (prepared from EtOAc, 818159-08-B, with a small amount of Form E) is shown. 1 H NMR spectrum. Figure 4D VT XRPD of the free acid Form B (818159-08-B has a small amount of Form E) is shown.

[0034] Figure 5A The XRPD pattern of the free acid Form B (818159-39-B) is shown. Figure 5B The TGA / DSC curve of the free acid Form B (818159-39-B) is shown.

[0035] Fig. 6A The XRPD pattern of the free acid Form C (818159-30-B) is shown. Figure 6B The TGA / DSC curve of the free acid Form C (818159-30-B) is shown. Figure 6C The free acid form C (818159-30-B) is shown 1 H NMR spectrum.

[0036] Figure 7 The XRPD pattern of the free acid Form D (818159-25-A11) is shown.

[0037] Figure 8 An XRPD overlay of different batches of free acid Form D is shown.

[0038] Fig.9A The TGA / DSC curve of the free acid Form D (818159-36-B with a small amount of Form E) is shown. Fig. 9B The free acid form D (818159-36-B, with a small amount of form E) is shown. 1 H NMR spectrum. Fig. 9C Shown are XRPD overlays of the free acid Form D (818159-36-B with a small amount of Form E) before and after storage at room temperature.

[0039] Fig.10 An XRPD overlay of the re-prepared free acid Form D is shown.

[0040] Fig.11A The TGA / DSC curve of the free acid Form D (818159-68-B with a small amount of Form E) is shown. Fig. 11B The free acid form D (818159-68-B, with a small amount of form E) is shown. 1 H NMR spectrum. Fig. 11C The VT-XRPD pattern of the free acid Form D (818159-68-B with a small amount of Form E) is shown.

[0041] Fig.12 The XRPD pattern of the free acid Form E (818159-40-A2_July 30) is shown.

[0042] Fig.13A An XRPD overlay of the free acid Form E (818159-32-B with a small amount of Form B) is shown. Fig. 13B The TGA / DSC curve of the free acid Form E (818159-32-B with a small amount of Form B) is shown. Fig. 13C The free acid form E (818159-32-B with a small amount of form B) is shown. 1 H NMR spectrum.

[0043] Fig.14A The XRPD pattern of the free acid Form F (818159-37-B) is shown. Fig. 14B The TGA / DSC curve of the free acid Form F (818159-37-B) is shown. Fig. 14C The free acid form F (818159-37-B) is shown 1 H NMR spectrum. Fig.14D Shown is a VT-XRPD overlay of the free acid Form F (818159-37-B).

[0044] Fig.15A The XRPD pattern of the free acid Form G (818159-41-B) is shown. Fig. 15B The TGA / DSC curve of the free acid Form G (818159-41-B) is shown. Fig. 15C The free acid form G (818159-41-B) is shown 1 H NMR spectrum.

[0045] Fig.16A Shown is an XRPD overlay of the residual solid resulting from the anhydrate form (I / V) slurry competition. Fig. 16B Shown is an XRPD overlay of the residual solid resulting from the suspension competition of the anhydrate form (II / V). Fig. 16C Shown is an XRPD overlay of the residual solid resulting from the suspension competition of the anhydrate form (III / V). Fig.16D Shown is an XRPD overlay of the residual solid resulting from the suspension competition of the anhydrate form (IV / V). Fig.16E Shown is an XRPD overlay of the residual solid resulting from the suspension competition of the anhydrate form (V / V).

[0046] Fig.17AShown are XRPD overlays of residual solids resulting from suspension competition at different water activities (I / II). Fig. 17B Shown are XRPD overlays of residual solids resulting from suspension competition at different water activities (II / II).

[0047] Fig.18A The XRPD pattern of Na salt Form A (818159-03-B1) is shown. Fig.18B The TGA / DSC curve of Na salt Form A (818159-03-B1) is shown. Fig.18C The Na salt form A (818159-03-B1) is shown 1 H NMR spectrum.

[0048] Fig.19A The XRPD pattern of K salt Form A / B (818159-03-B2 / C2) is shown. Fig.19B The TGA / DSC curve of K salt Form A (818159-03-B2) is shown. Fig.19C K salt form A (818159-03-B2) is shown 1 H NMR spectrum.

[0049] Fig. 20A The XRPD pattern of arginine salt Form A (818159-03-B3) is shown. Fig. 20B The TGA / DSC curve of arginine salt Form A (818159-03-B3) is shown. Fig. 20C Arginine salt form A (818159-03-B3) is shown. 1 HNMR spectrum.

[0050] Fig.21A The XRPD pattern of Mg salt Form A (818159-03-C5) is shown. Fig. 21B The TGA / DSC curve of Mg salt Form A (818159-03-C5) is shown. Fig. 21C The Mg salt form A (818159-03-C5) is shown 1 H NMR spectrum.

[0051] Fig.22A The XRPD pattern of tromethamine (tris) salt Form A (818159-03-B10) is shown. Fig. 22B The TGA / DSC curve of tris salt Form A (818159-03-B10) is shown. Fig. 22C The tris salt form A (818159-03-B10) is shown 1 H NMR spectrum.

[0052] Fig.23 An XRPD overlay of the re-prepared Na salt Form A is shown.

[0053] Fig.24A The XRPD pattern of Na salt Form A (818159-09-B) is shown. Fig. 24B Shown is the TGA / DSC curve of the re-prepared Na salt Form A (818159-09-B). Fig.24C The re-prepared Na salt form A (818159-09-B) is shown. 1 H NMR spectrum.

[0054] Fig.25 An XRPD overlay of the re-prepared K salt Form C is shown.

[0055] Fig.26A The XRPD pattern of K salt Form C (818159-10-B) is shown. Fig.26B Shown is the TGA / DSC curve of the re-prepared K salt Form C (818159-10-B). Fig.26C The re-prepared K salt form C (818159-10-B) is shown 1 HNMR spectrum.

[0056] Fig. 27 An XRPD overlay of the re-prepared arginine salt Form A is shown.

[0057] Fig.28A The XRPD pattern of arginine salt Form A (818159-11-B) is shown. Fig.28B Shown is the TGA / DSC curve of the re-prepared arginine salt Form A (818159-11-B). Fig.28C The re-prepared arginine salt form A (818159-11-B) is shown. 1 H NMR spectrum.

[0058] Fig.29A Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting with the free acid Form B in water. Fig.29B Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in SGF. Fig.29C Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in FaSSIF-V2. Fig.29D Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in FeSSIF-V2. Fig.29EShown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in pH 1.2 buffer. Fig.29F Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in pH 4.5 buffer. Figure 29G Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the free acid Form B in pH 6.8 buffer.

[0059] Fig. 30A Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the K salt Form C in water. Fig. 30B Shown is an XRPD overlay of residual solids resulting from kinetic solubility starting from K salt Form C in SGF. Fig. 30C Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from K-salt Form C in pH 1.2 buffer. Fig.30D Shown is an XRPD overlay of residual solids resulting from kinetic solubility starting from K-salt Form C in pH 4.5 buffer.

[0060] Fig.31A Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from arginine salt Form A in SGF. Fig.31B Shown is an XRPD overlay of the residual solid resulting from kinetic solubility of arginine salt Form A in pH 1.2 buffer. Fig.31C Shown is an XRPD overlay of the residual solid resulting from kinetic solubility of arginine salt Form A in pH 4.5 buffer. Fig.31D Shown is the XRPD pattern of the residual solid resulting from kinetic solubility starting from arginine salt Form A in pH 6.8 buffer.

[0061] Fig.32A The XRPD pattern of the residual solid resulting from kinetic solubility starting from the Na salt Form A in water is shown. Fig.32B Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting from the Na salt Form A in SGF.

[0062] Fig.33 Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting with the free acid Form E (818159-61-B, 24 hours).

[0063] Fig.34 Shown is an XRPD overlay of the residual solid resulting from kinetic solubility starting with the free acid Form B (818159-71-B, 24 hours).

[0064] Fig.35 The kinetic solubility curve at 37°C is shown.

[0065] Fig.36 The kinetic solubility curves of free acid forms B and E are shown.

[0066] Fig.37A The DVS pattern of the free acid Form B (818159-08-B) is shown. Fig.37B Shown are XRPD overlays of the free acid Form B (818159-08-B) before and after DVS testing.

[0067] Fig.38A The DVS pattern of K salt Form C (818159-10-B) is shown. Fig.38B Shown are XRPD overlays of K salt Form C (818159-10-B) before and after DVS testing.

[0068] Fig.39A The DVS pattern of arginine salt Form A (818159-11-B) is shown. Fig.39B Shown are XRPD overlays of arginine salt Form A (818159-11-B) before and after DVS testing.

[0069] Fig.40A The DVS pattern of Na salt Form A (818159-09-B) is shown. Fig.40B Shown are XRPD overlays of Na salt Form A (818159-09-B) before and after DVS testing.

[0070] Fig.41 Shown are XRPD overlays of free acid Form B (818159-08-B) before and after solid stability evaluation.

[0071] Fig.42 Shown are XRPD overlays of the free acid Form E (818159-61-B) before and after solid stability evaluation.

[0072] Fig.43 Shown is the DSC curve of the free acid Form E (821755-05-A / B) after 8 weeks solid stability evaluation.

[0073] Fig.44 Shown are XRPD overlays of Na salt Form A (818159-09-B) before and after solid stability evaluation.

[0074] Fig.45Shown are XRPD overlays of K salt Form C (818159-10-B) before and after solid stability evaluation.

[0075] Fig.46 Shown are XRPD overlays of arginine salt Form A (818159-11-B) before and after solid stability assessment.

[0076] Fig.47 Shown are HPLC chromatograms of free acid Form B (818159-08-B) before and after solid stability evaluation.

[0077] Fig.48 Shown are HPLC chromatograms of the free acid Form E (818159-61-B) before and after solid stability evaluation.

[0078] Fig.49 Shown are HPLC chromatograms of Na salt Form A (818159-09-B) before and after solid stability evaluation.

[0079] Fig.50 Shown are HPLC chromatograms of K salt Form C (818159-10-B) before and after solid stability evaluation.

[0080] Fig.51 Shown are HPLC chromatograms of arginine salt Form A (818159-11-B) before and after solid stability evaluation.

[0081] Fig.52A The changes in serum TG in each group are shown. Data are expressed as mean ± SD; one-way ANOVA was performed by Prism GraphPad; n = 6. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 relative to the vehicle. Fig.52B The changes in serum NEFA in each group are shown. Data are expressed as mean ± SD; one-way ANOVA was performed by Prism GraphPad; n = 6. ****P < 0.0001 relative to vehicle.

[0082] Fig.53A The changes in body weight gain of each group of animals compared to day 0 are shown. Fig.53B The changes in the difference in body weight gain between each group of animals and the vehicle group are shown. (*: body weight gain of the treatment group minus the mean body weight gain of the vehicle group.)

[0083] Fig.54Effects of compounds on body weight changes of db / db animals are shown. Data are presented as mean ± SEM; two-way ANOVA followed by Dunnett's test performed by Prism GraphPad; n=6-9.

[0084] Fig.55A Shown are the effects of compounds on serum TG levels in db / db animals on day 6. Data are presented as mean ± SEM; one-way ANOVA followed by Dunnett's test performed by Prism GraphPad; n = 6-9. **P < 0.01, ***P < 0.001, ****P < 0.0001 relative to model. Fig.55B Shown are the effects of compounds on serum TG levels in db / db animals at day 12. Data are presented as mean ± SEM; one-way ANOVA followed by Dunnett's test performed by Prism GraphPad; n = 6-9. ****P < 0.0001 versus model.

[0085] Fig.56 Shown are the effects of compounds on random blood glucose in db / db animals. Data are presented as mean ± SEM, n=6-9.

[0086] Fig.57A Shown are the effects of compounds on oral glucose tolerance in db / db animals. Data are presented as mean ± SEM, n=6-9. Fig.57B The effects of compounds on oral glucose tolerance in db / db animals are shown. Data are expressed as mean ± SEM; one-way ANOVA followed by Dunnett's test performed by Prism GraphPad; n = 6-9. **P < 0.01, ***P < 0.001, ****P < 0.0001 relative to the model group.

[0087] Fig.58 The effect of Compound 2 on urinary albumin excretion is shown.

[0088] Figures 59A-59D The effects of Compound 2 on glomerular and tubular damage are shown.

[0089] Fig.60 The effect of Compound 2 on the improvement of renal injury in a rat model with unilateral ureteral obstruction is shown. DETAILED DESCRIPTION

[0090] Reference will now be made in detail to certain embodiments of the present disclosure, examples of which are shown in the attached structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it should be understood that the embodiments are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present disclosure as defined in the claims. Those skilled in the art will recognize many methods and materials that are similar or equivalent to the methods and materials described herein and can be used in practicing the present disclosure. The present disclosure is by no means limited to the methods and materials described. In the event that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, described technology, etc.) are different from or contradictory to the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are hereby incorporated by reference in their entirety.

[0091] It should be understood that certain features of the disclosure described in the context of separate embodiments for the sake of clarity may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a or an" and "the" include their plural forms unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0092] definition

[0093] 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) that has insulin sensitization and glucose-lowering effects as well as favorable effects on lipid profiles. The Aleglitazar is being studied for patients with type II diabetes to reduce the risk of cardiovascular mortality and morbidity in the patients. "Aleglitazar" has the following structure:

[0094]

[0095] As used herein, the term "Compound 2", which is deuterated aleglitazar, refers to a compound having the following structure:

[0096]

[0097] As used herein, the terms "crystalline form", "crystal form" and "form" refer interchangeably to a crystal structure (or polymorph) having a specific molecular packing arrangement in a crystal lattice. Crystal forms can be identified and distinguished from each other 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 moisture sorption (DVS). Therefore, as used herein, the term "crystal form [X] of compound 2" refers to a unique crystal form that can be identified and distinguished from each other 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 moisture sorption (DVS). In some embodiments, the novel crystal form is characterized by an X-ray powder diffraction pattern having one or more signals at one or more specified 2θ values ​​(°2θ).

[0098] As used herein, the term "solvate" refers to a crystal form comprising one or more molecules of a compound of the present disclosure and one or more molecules of a stoichiometric or non-stoichiometric amount of one or more solvents incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a "hydrate."

[0099] 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", "XRPD pattern" refer interchangeably to an experimentally obtained pattern that plots signal position (on the abscissa) versus signal intensity (on the ordinate). For amorphous materials, an X-ray powder diffraction pattern may include one or more broad signals; and for crystalline materials, an X-ray powder diffraction pattern may include one or more signals, each identified by its angular value, as measured in angle 2θ (°2θ), depicted on the abscissa of the X-ray powder diffraction pattern.

[0100] As used herein, a "peak" refers to a point in an XRPD pattern where the intensity, as measured in counts, is at a local maximum. One of ordinary skill in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may not be apparent, for example, to the naked eye. In fact, one of ordinary skill in the art will recognize that some industry-recognized methods are capable of and are applicable to determining whether a signal is present in a pattern, such as Rietveld refinement.

[0101] The repeatability of the measured angle value is within the range of ±0.2°2θ, that is, the angle value can be at the listed angle value +0.2°2θ, at the angle value -0.2°2θ, or at any value between these two end points (angle value +0.2°2θ and angle value -0.2°2θ). In some embodiments, the repeatability of the measured angle value is within the range of ±0.1°2θ.

[0102] The term "peak intensity" refers to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that may affect the relative signal or peak intensity include sample thickness and preferred orientation (eg, crystalline particles are not randomly distributed).

[0103] As used herein, an X-ray powder diffraction pattern is "substantially similar to the X-ray powder diffraction pattern in the [specific] figure" when at least 90% (e.g., at least 95%, at least 98%, or at least 99%) of the peaks in the two diffraction patterns overlap. In determining "substantial similarity," one of ordinary skill in the art will understand that even for the same crystalline form, there may be variations in the intensity and / or signal positions in the XRPD diffraction pattern. Thus, one of ordinary skill in the art will understand that a signal maximum in an XRPD diffraction pattern (referred to herein in units of °2θ) generally means that the value is identified as ±0.2 degrees 2θ of the reported value, which is an industry-recognized variance. In some embodiments, the signal variance is identified as ±0.1 degrees 2θ of the reported value.

[0104] As used herein, the terms "about" and "substantially" mean that their values ​​can vary with respect to features such as endotherms, endothermic peaks, exotherms, baseline shifts, etc. With respect to X-ray diffraction peak positions, "about" or "substantially" means that typical peak position and intensity variability are taken into account. For example, those skilled in the art will understand that the peak position (2θ) will show some inter-device variability, typically up to 0.2°. Sometimes, depending on equipment calibration differences, the variability may be higher than 0.2°. In addition, those skilled in the art will understand that the relative peak intensity will show inter-device variability as well as variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered only as a qualitative measure. For DSC, the observed temperature change will depend on the rate of temperature change as well as the sample preparation technique and the specific instrument used. Therefore, the endothermic / melting point values ​​associated with the DSC / TGA thermogram reported herein can vary by ±5°C (and are still considered to be unique to the specific crystalline form described herein). When used in the context of other features, for example, weight percent (wt%), reaction temperature, the term "about" means a variance of ±5%.

[0105] As used herein, "amorphous" refers to a solid form of molecules, atoms and / or ions that is not crystalline. Amorphous solids do not show a well-defined X-ray diffraction pattern.

[0106] As used herein, "substantially pure" when used to refer to a form means a compound having a purity greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98, and 99% by weight, based on the weight of the compound, and also including equal to about 100% by weight of Compound 2. The remaining material includes other forms of the compound and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a crystalline form of Compound 2 can be considered to be substantially pure because its purity is greater than 90% by weight, as measured by methods currently known and generally accepted in the art, wherein the remaining less than 10% by weight of the material includes other forms of Compound 2 and / or reaction impurities and / or processing impurities.

[0107] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound provided herein or a crystalline form thereof in a form suitable for administration to a subject.

[0108] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically and otherwise desirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used herein, a "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carriers" and "pharmaceutically acceptable diluents."

[0109] As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents an identified disease or condition, or shows a detectable therapeutic or modulatory effect. The effect can be detected by any assay 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 judgment 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.

[0110] 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, cats; and non-mammals, such as birds, amphibians, reptiles, etc. 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.

[0111] Crystal form

[0112] The present disclosure provides a crystalline form of Compound 2 or a salt of Compound 2:

[0113]

[0114] The invention also discloses methods for preparing these compounds, pharmaceutical compositions containing the same, and various uses of the disclosed compounds.

[0115] Form B of Compound 2

[0116] In one aspect, the present disclosure relates to Form B of Compound 2, characterized in that its X-ray powder diffraction (XRPD) pattern includes one or more peaks at 8.16, 13.23, and 13.90 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form B further includes one or more peaks at 4.94, 11.83, 14.97, 18.54, and 26.24 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form B further includes one or more peaks at 9.89, 19.74, and 20.92 (± 0.2° 2θ).

[0117] In some embodiments, Form B is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0118]

[0119] In some embodiments, Form B is characterized by an XRPD pattern comprising Figure 5A In some embodiments, Form B is characterized by being substantially as Figure 5A XRPD pattern shown.

[0120] In some embodiments, Form B is characterized by being substantially as Figure 5B Thermogravimetric analysis (TGA) thermogram shown.

[0121] In some embodiments, Form B is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic peak with a peak temperature of about 151.1 °C.

[0122] In some embodiments, Form B is characterized by being substantially as Figure 5B DSC thermogram shown.

[0123] In some embodiments, Form B is an anhydrate.

[0124] In some embodiments, Form B is in substantially pure form. In another embodiment, 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%.

[0125] Form C of Compound 2

[0126] In one aspect, the present disclosure relates to Form C of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 5.06, 10.09, and 20.24 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form C further includes one or more peaks at 15.15, 16.18, and 16.75 (± 0.2° 2θ). In some embodiments, the XRPD pattern of 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° 2θ).

[0127] In some embodiments, Form C is characterized in that its XRPD pattern includes one or more peaks selected from the group consisting of:

[0128]

[0129] In some embodiments, Form C is characterized by an XRPD pattern comprising Fig. 6A In some embodiments, Form C is characterized by being substantially as Fig. 6A XRPD pattern shown.

[0130] In some embodiments, Form C is characterized by being substantially as Figure 6B TGA thermogram shown.

[0131] In some embodiments, Form C is characterized by a DSC thermogram having an endothermic peak with a peak temperature of about 149.0°C.

[0132] In some embodiments, Form C is characterized by being substantially as Figure 6B DSC thermogram shown.

[0133] In some embodiments, Form C is an anhydrate.

[0134] In some embodiments, Form C is in substantially pure form. In another embodiment, the purity of Form C is 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%.

[0135] Form D of Compound 2

[0136] In one aspect, the present disclosure relates to Form D of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 5.03, 12.98, 15.91, and 21.58 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form D further includes one or more peaks at 5.90, 9.21, 20.47, and 26.08 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form D further includes one or more peaks at 11.76, 15.04, 22.38, and 24.47 (± 0.2° 2θ).

[0137] In some embodiments, Form D is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0138]

[0139] In some embodiments, Form D is characterized by an XRPD pattern comprising Figure 7 In some embodiments, Form D is characterized by being substantially as Figure 7 XRPD pattern shown.

[0140] In some embodiments, Form D is a hydrate.

[0141] In some embodiments, Form D is in substantially pure form. In another embodiment, 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%.

[0142] Crystalline Form E of Compound 2

[0143] In one aspect, the present disclosure relates to Form E of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 10.12, 11.97, 13.73, and 18.89 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form E further includes one or more peaks at 5.06, 8.14, 13.02, and 14.19 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form E further includes one or more peaks at 14.87, 21.30, 22.33, and 26.23 (± 0.2° 2θ).

[0144] In some embodiments, Form E is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0145]

[0146] In some embodiments, Form E is characterized by an XRPD pattern comprising Fig.12 In some embodiments, Form E is characterized by being substantially as Fig.12 XRPD pattern shown.

[0147] In some embodiments, Form E is an anhydrate.

[0148] In some embodiments, Form E is in substantially pure form. In some embodiments, 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%.

[0149] Form F of Compound 2

[0150] In one aspect, the present disclosure relates to Form F of Compound 2, characterized in that its XRPD pattern includes one or two peaks at 15.50 and 21.23 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form F further includes one or two peaks at 12.12 and 20.21 (± 0.2° 2θ).

[0151] In some embodiments, Form F is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0152]

[0153] In some embodiments, Form F is characterized by an XRPD pattern comprising Fig.14A In some embodiments, Form F is characterized by being substantially as follows Fig.14A XRPD pattern shown.

[0154] In some embodiments, Form F is characterized by being substantially as follows Fig. 14B TGA thermogram shown.

[0155] In some embodiments, Form F is characterized by a differential scanning calorimetry (DSC) thermogram having endothermic peaks with peak temperatures of about 111.2°C and / or about 149.8°C.

[0156] In some embodiments, Form F is characterized by a DSC thermogram having an exothermic peak with a peak temperature of about 118.9°C.

[0157] In some embodiments, Form F is characterized by being substantially as follows Fig. 14B DSC thermogram shown.

[0158] In some embodiments, Form F is a hydrate.

[0159] In some embodiments, Form F is in substantially pure form. In some embodiments, 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%.

[0160] Form G of Compound 2

[0161] In one aspect, the present disclosure relates to Form G of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 9.67, 11.60, 12.90, and 14.43 (± 0.2° 2θ). In some embodiments, the XRPD pattern of 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° 2θ). In some embodiments, the XRPD pattern of Form G further includes one or more peaks at 4.95, 11.83, 13.22, and 19.84 (± 0.2° 2θ).

[0162] In some embodiments, Form G is characterized in that its XRPD pattern includes one or more peaks selected from the group consisting of:

[0163]

[0164] In some embodiments, Form G is characterized by an XRPD pattern comprising Fig.15A In some embodiments, Form G is characterized by being substantially as Fig.15A XRPD pattern shown.

[0165] In some embodiments, Form G is characterized by being substantially as follows Fig. 15B TGA thermogram shown.

[0166] In some embodiments, Form G is characterized in that its DSC thermogram has endothermic peaks with peak temperatures of about 72.4°C and / or about 83.1°C.

[0167] In some embodiments, Form G is characterized by being substantially as follows Fig. 15B DSC thermogram shown.

[0168] In some embodiments, Form G is a DMSO solvate.

[0169] In some embodiments, Form G is in substantially pure form. In some embodiments, 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%.

[0170] Salt of Compound 2

[0171] In another aspect, the present disclosure provides a salt of Compound 2, wherein the salt of Compound 2 is selected from a sodium salt, a potassium salt, an arginine salt, a magnesium salt or a tromethamine salt of Compound 2.

[0172] Crystalline Form A of the Sodium Salt of Compound 2

[0173] In one aspect, the present disclosure relates to Form A of the sodium salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 4.09, 4.62, and 14.21 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form A of the sodium salt further includes one or two peaks at 16.43 and 17.72 (± 0.2° 2θ).

[0174] In some embodiments, Form A of the sodium salt is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0175]

[0176] In some embodiments, Form A of the sodium salt is characterized by an XRPD pattern comprising Fig.24A In some embodiments, Form A of the sodium salt is characterized by being substantially as follows Fig.24A XRPD pattern shown.

[0177] In some embodiments, Form A of the sodium salt is characterized by being substantially as follows Fig. 24B TGA thermogram shown.

[0178] In some embodiments, Form A of the sodium salt is characterized by a DSC thermogram having endothermic peaks with peak temperatures of about 163.5°C and / or about 204.0°C.

[0179] In some embodiments, Form A of the sodium salt is characterized by a DSC thermogram having an exothermic peak with a peak temperature of about 166.5°C.

[0180] In some embodiments, Form A of the sodium salt is characterized by being substantially as follows Fig. 24B DSC thermogram shown.

[0181] In some embodiments, the crystalline Form A of the sodium salt is in substantially pure form. In some embodiments, the purity of the crystalline Form A of the sodium salt is 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%.

[0182] Crystalline Form C of Potassium Salt of Compound 2

[0183] In one aspect, the present disclosure relates to Form C of the potassium salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 12.91, 14.96, and 21.23 (± 0.2° 2θ). In some embodiments, the XRPD pattern of Form C of the potassium salt further includes one or more peaks at 14.12, 20.68, 25.17, and 26.46 (± 0.2° 2θ). In some embodiments, the XRPD pattern of 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° 2θ).

[0184] In some embodiments, Form C of the potassium salt is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0185]

[0186] In some embodiments, Form C of the potassium salt is characterized by an XRPD pattern comprising Fig.26A In some embodiments, Form C of the potassium salt is characterized by being substantially as follows Fig.26A XRPD pattern shown.

[0187] In some embodiments, Form C of the potassium salt is characterized by being substantially as follows Fig.26B TGA thermogram shown.

[0188] In some embodiments, Form C of the potassium salt is characterized by a DSC thermogram having endothermic peaks with peak temperatures of about 108.1°C, about 140.2°C, and / or about 161.3°C.

[0189] In some embodiments, Form C of the potassium salt is characterized by being substantially as follows Fig.26B DSC thermogram shown.

[0190] In some embodiments, Form C of the potassium salt is in substantially pure form. In some embodiments, the purity of Form C of the potassium salt is 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%.

[0191] Crystalline Form A of the Arginine Salt of Compound 2

[0192] On the one hand, the present disclosure relates to Form A of the arginine salt of Compound 2, characterized in that its XRPD pattern includes one or more peaks at 12.93, 13.43, 18.21 and 19.49 (± 0.2° 2θ). In some embodiments, the XRPD pattern of 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° 2θ). In some embodiments, the XRPD pattern of 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° 2θ).

[0193] In some embodiments, Form A of the arginine salt is characterized in that its XRPD pattern comprises one or more peaks selected from the group consisting of:

[0194]

[0195] In some embodiments, Form A of the arginine salt is characterized by an XRPD pattern comprising Fig.28A In some embodiments, the crystalline form A of the arginine salt is characterized by being substantially as Fig.28A XRPD pattern shown.

[0196] In some embodiments, Form A of the arginine salt is characterized by being substantially as follows Fig.28B TGA thermogram shown.

[0197] In some embodiments, Form A of the arginine salt is characterized by a DSC thermogram having an endothermic peak with a peak temperature of about 195.2°C.

[0198] In some embodiments, Form A of the arginine salt is characterized by being substantially as follows Fig.28B DSC thermogram shown.

[0199] In some embodiments, the crystalline Form A of the arginine salt is in substantially pure form. In some embodiments, the purity of the crystalline Form A of the arginine salt is 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%.

[0200] Crystalline Form A of Potassium Salt of Compound 2

[0201] In one aspect, the present disclosure relates to Form A of the potassium salt of Compound 2, characterized in that its XRPD pattern comprises Fig.19A In some embodiments, Form A of the potassium salt is characterized by being substantially as follows Fig.19A The XRPD pattern shown in the upper curve.

[0202] In some embodiments, Form A of the potassium salt is characterized by being substantially as follows Fig.19B TGA thermogram shown.

[0203] In some embodiments, Form A of the potassium salt is characterized by a DSC thermogram having endothermic peaks with peak temperatures of about 91.1 °C, about 135.8 °C, and / or about 147.7 °C.

[0204] In some embodiments, Form A of the potassium salt is characterized by being substantially as follows Fig.19B DSC thermogram shown.

[0205] In some embodiments, Form A of the potassium salt is in substantially pure form. In some embodiments, the purity of Form A of the potassium salt is 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%.

[0206] Crystalline Form B of Potassium Salt of Compound 2

[0207] In one aspect, the present disclosure relates to Form B of the potassium salt of Compound 2, characterized in that its XRPD pattern includes Fig.19A In some embodiments, Form B of the potassium salt is characterized by being substantially as follows Fig.19A The XRPD pattern shown in the lower curve.

[0208] In some embodiments, Form B of the potassium salt is in substantially pure form. In some embodiments, the purity of Form B of the potassium salt is 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%.

[0209] Crystalline Form A of the Magnesium Salt of Compound 2

[0210] In one aspect, the present disclosure relates to Form A of the magnesium salt of Compound 2, characterized in that its XRPD pattern includes Fig.21A In some embodiments, the crystalline form A of the magnesium salt is characterized by being substantially as follows Fig.21A XRPD pattern shown.

[0211] In some embodiments, Form A of the magnesium salt is characterized by being substantially as follows Fig. 21B TGA thermogram shown.

[0212] In some embodiments, Form A of the magnesium salt is characterized by a DSC thermogram having endothermic peaks with peak temperatures of about 90.7°C, about 114.9°C, about 134.0°C, and / or about 154.2°C.

[0213] In some embodiments, Form A of the magnesium salt is characterized by being substantially as follows Fig. 21B DSC thermogram shown.

[0214] In some embodiments, the crystalline Form A of the magnesium salt is in substantially pure form. In some embodiments, the purity of the crystalline Form A of the magnesium salt is 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%.

[0215] Crystalline Form A of the Tromethamine Salt of Compound 2

[0216] In one aspect, the present disclosure relates to Form A of the tromethamine salt of Compound 2, characterized in that its XRPD pattern comprises Fig.22A In some embodiments, the crystalline form A of the tromethamine salt is characterized by being substantially as follows Fig.22A XRPD pattern shown.

[0217] In some embodiments, Form A of the tromethamine salt is characterized by being substantially as follows Fig. 22B TGA thermogram shown.

[0218] In some embodiments, Form A of the tromethamine salt is characterized by a DSC thermogram having endothermic peaks with peak temperatures of about 71.8°C, about 76.6°C, about 113.9°C, and / or about 213.1°C.

[0219] In some embodiments, Form A of the tromethamine salt is characterized by being substantially as follows Fig. 22B DSC thermogram shown.

[0220] In some embodiments, the crystalline Form A of the tromethamine salt is in substantially pure form. In some embodiments, the purity of the crystalline Form A of the tromethamine salt is 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%.

[0221] Synthesis of compound 2

[0222] Compound 2 can be synthesized according to methods known to those skilled in the art (such as the synthetic procedure described in Example 1).

[0223] Pharmaceutical composition

[0224] In another aspect, a pharmaceutical composition comprising Compound 2 or a salt of Compound 2 is provided, wherein Compound 2 or the salt of Compound 2 is in a crystalline form selected from the group consisting of Form B, Form C, Form D, Form E, Form F, Form G, Form A of the sodium salt, Form C of the potassium salt, Form A of the arginine salt, Form A of the potassium salt, Form B of the potassium salt, Form A of the magnesium salt, and Form A of the tromethamine salt disclosed herein.

[0225] On the other hand, a pharmaceutical composition comprising Compound 2 or a salt of Compound 2 is provided, wherein Compound 2 or the salt of Compound 2 is in a crystalline form selected from the group consisting of Form B, Form C, Form D, Form E, Form F, Form G, Form A of the sodium salt, Form C of the potassium salt, Form A of the arginine salt, Form A of the potassium salt, Form B of the potassium salt, Form A of the magnesium salt, and Form A of the tromethamine salt, and at least one pharmaceutically acceptable excipient.

[0226] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form B.

[0227] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form C.

[0228] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form D.

[0229] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form E.

[0230] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form F.

[0231] In some embodiments, at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9% or 99.99% of Compound 2 is in Form G.

[0232] 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 in Form A of the sodium salt.

[0233] 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 in Form C as the potassium salt.

[0234] 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 in Form A of the arginine salt.

[0235] 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 in Form A of the potassium salt.

[0236] 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 in Form B of the potassium salt.

[0237] 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 in Form A of the magnesium salt.

[0238] 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 in Form A of the tromethamine salt.

[0239] The specific excipient used in the pharmaceutical composition provided herein will depend on the means and purpose of applying the disclosed compound. The solvent is usually selected based on the solvent considered safe by those skilled in the art to be applied to mammals including humans. Usually, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

[0240] In some embodiments, suitable excipients may include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, Such as serum albumin, gelatin or immunoglobulin; 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 dextran; 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 nonionic surfactants such as TWEEN TM 、PLURONICS TM or polyethylene glycol (PEG).

[0241] In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromatics, flavoring agents and other known additives to provide the best presentation form of the drug (i.e., the compound of the present disclosure or its pharmaceutical composition) or to help manufacture a pharmaceutical product (i.e., medicine). Active pharmaceutical ingredients can also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, 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 in macroemulsions, respectively. Such technology is disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Editor (1980). "Liposomes" are small vesicles containing various types of lipids, phospholipids and / or surfactants that can be used to deliver drugs (such as compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of liposomes are usually arranged in a bilayer form, similar to the lipid arrangement of biological membranes.

[0242] The pharmaceutical compositions provided herein may be in any form that permits administration of the composition to a subject, including but not limited to humans, and that permits formulation of the composition to be compatible with the intended route of administration.

[0243] A variety of approaches have been considered for the pharmaceutical compositions provided herein, and therefore the pharmaceutical compositions provided herein can be supplied in bulk or unit dosage forms according to the expected route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, soft capsules and caplets can be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions and solutions can be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions can be acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions can be acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders and aerosols can be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches can be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams and sprays can be acceptable dosage forms.

[0244] The amount of active ingredient in the unit dosage form of the composition is a therapeutically effective amount and varies according to the specific treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, improves, or prevents an identified disease or condition or shows a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount of the 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 judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experiments within the skill and judgment of the clinician.

[0245] In some embodiments, the effective amount of the compound provided herein can be in the range of about 0.5 μg to about 90 mg per day, 1 μg to about 50 mg per day, 2 μg to about 10 mg per day, 3 μg to about 1 mg per day, 5 μg to about 800 μg per day, 5 μg to about 600 μg per day, 5 μg to about 500 μg per day, 10 μg to about 500 μg per day, 12 μg to about 500 μg per day, 15 μg to about 500 μg per day, 20 μg to about 500 μg per day, 25 μg to about 500 μg per day. In some embodiments, the effective amount of the compound provided herein can be in the range of about 25 μg to about 300 μg per day. In some embodiments, the effective amount of the compound provided herein can be in the range of about 50 μg to about 150 μg per day.

[0246] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for oral administration.

[0247] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of tablet formulations. Pharmaceutically acceptable excipients suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case, using conventional coating agents and procedures well known in the art.

[0248] In certain embodiments, the 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 in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil.

[0249] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which typically includes the active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; a dispersant 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 fatty alcohol, such as heptadecaethyleneoxycetanol; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitan monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (for example, ethyl or propyl p-hydroxybenzoate), antioxidants (for example, ascorbic acid), coloring agents, flavoring agents and / or sweetening agents (for example, sucrose, saccharin or aspartame).

[0250] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of an oily suspension, which is generally contained in a suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspension can also contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners (such as those stated above) and flavorings can be added to provide a palatable oral formulation. These compositions can be preserved by adding an antioxidant (such as ascorbic acid).

[0251] In certain embodiments, the pharmaceutical composition of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, flavorings, and preservatives.

[0252] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners, such as glycerol, propylene glycol, sorbitol, aspartame or sucrose; demulcents; preservatives; flavorings and / or coloring agents.

[0253] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for administration by injection.

[0254] In certain embodiments, the pharmaceutical composition of the present disclosure can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated using those suitable dispersants or wetting agents and suspending agents mentioned above according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenteral acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. The acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be used as solvents or suspension media conventionally. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injectables.

[0255] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for administration by inhalation.

[0256] In certain embodiments, the 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 with the requirements of the specific compound, but typically include nonionic surfactants (Tween, Pluronic, 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.

[0257] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of formulations for topical or transdermal administration.

[0258] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, which are generally 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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0259] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches well known to those of ordinary skill in the art.

[0260] 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 the present disclosure. Such excipients and carriers are described in, for example, Remington's Pharmaceutical Sciences, Mark Publishing Company, New Jersey (1991); Remington: The Science and Practice of Pharmacy, ed. University of the Sciences in Philadelphia, 21st ed., LWW (2005), which are incorporated herein by reference.

[0261] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into 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.

[0262] In some embodiments, the pharmaceutical compositions of the present disclosure can be formulated into short-acting, fast-release, long-acting, and sustained-release forms. Therefore, the pharmaceutical formulations of the present disclosure can also be formulated for controlled release or slow release.

[0263] In a further aspect, veterinary compositions are also provided, comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof and a veterinary carrier. A veterinary carrier is a material that can be used for the purpose of administering the composition, and can be a solid, liquid or gaseous material that is otherwise inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0264] Pharmaceutical compositions or veterinary compositions can be packaged in various ways depending on the method for administering the drug. For example, the article for distribution can include a container in which the composition in appropriate form is stored. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), medicine capsules, ampoules, plastic bags, metal cylinders, etc. The container can also include an anti-disassembly assembly to prevent easy access to the contents of the package. In addition, a label describing the contents of the container is placed on the container. The label can also include appropriate warnings. The composition can also be packaged in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze drying (freeze drying) conditions that only require the addition of a sterile liquid carrier (e.g., water for injection) before use. Extemporaneous injection solutions and suspensions are prepared by sterile powders, granules, and tablets of the types described previously.

[0265] In a further aspect, a pharmaceutical composition is also provided, comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient and a second active ingredient.

[0266] For a pharmaceutical composition comprising a second active agent, the effective amount of the second active agent is about 20% to 100% of the dosage normally utilized in a monotherapy regimen using only the medicament. Preferably, the effective amount is between about 70% and 100% of the normal monotherapy dosage. The normal monotherapy dosage of these second active agents is well known in the art. See, for example, Wells et al., ed., Pharmacotherapy Handbook, 2nd ed., Appleton and Lange, Stamford, Conn.; PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, hardcover, Tarascon Publishing, Loma Linda, Calif. (2000), each of which is incorporated herein by reference in its entirety.

[0267] It is expected that some of the second active agents in the second active agent will synergize with the compound provided herein. When this occurs, the effective dose of the second active agent and / or the compound provided herein will be allowed to be reduced relative to the dose required in the monotherapy. This has the advantages of minimizing the toxic and side effects of the compound or the second active agent provided herein, improving the synergistic effect, improving the ease of use or use and / or reducing the total cost of the compound preparation or formulation.

[0268] 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) nicotinic acid, nicotinic acid, or a salt thereof; (5) a phenolic antioxidant; (6) an ACAT inhibitor; and (7) a CTEP inhibitor.

[0269] Methods of treating diseases

[0270] In another aspect, the present disclosure provides a crystalline form of Compound 2 or a salt of Compound 2 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.

[0271] 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 Compound 2 or a crystalline form of a salt of Compound 2 or a pharmaceutical composition of the present disclosure.

[0272] In another aspect, the present disclosure provides use of a crystalline form of Compound 2 or a salt of Compound 2 or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating and / or preventing a disease regulated by a PPARα and / or PPARγ agonist.

[0273] As used herein, the terms "treat, treating and treatment" are intended to include improving, preventing, alleviating or eliminating a condition; or alleviating, preventing or eliminating one or more of the symptoms associated with a condition; and / or preventing, alleviating or eradicating the cause of the condition itself, i.e., causing clinical symptoms to not develop significantly in a mammal that may be susceptible to the disease but has not yet experienced or shown symptoms of the disease. This can include improving the subject's ability to perform daily living activities, do housework, manage finances and / or engage in a career or reducing the level of care required by the subject. Treatment (treat, treating or treatment) can include an improvement in symptoms of at least 20%, 30%, 50%, 80%, 90% or 100%. The symptoms associated with a specific condition depend on the specific condition that is about to be suffered from.

[0274] As used herein, the terms "prophylaxis" or "prophylactic" are intended to have their normal meaning and include primary prevention, which is used to prevent the development of a disease, and secondary prevention, which is used after a disease has developed and to temporarily or permanently protect a patient from an exacerbation or worsening of the disease or the development of new symptoms associated with the disease.

[0275] 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.

[0276] In some embodiments, the disease is diabetes, non-insulin-dependent diabetes mellitus, hypertension, dyslipidemia, atherosclerotic disease, metabolic syndrome, or diabetic nephropathy.

[0277] In some embodiments, the disease is non-insulin dependent diabetes mellitus or diabetic nephropathy.

[0278] In some embodiments, the disease is diabetic nephropathy.

[0279] As used herein, the term "diabetes" refers to a disease in which a patient's ability to control the level of glucose in the blood is impaired due in part to a loss of the ability to respond appropriately to the action of insulin.

[0280] As used herein, the term "non-insulin-dependent diabetes mellitus" is also referred to as type II diabetes (T2D), which afflicts 80-90% of all diabetics in developed countries. The islets of Langerhans in the pancreas still produce insulin. However, the target organs, primarily muscle, liver, and adipose tissue, show strong resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. However, in the late stages of the disease, insulin secretion decreases due to pancreatic exhaustion.

[0281] 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 due to the invasion and accumulation of leukocytes (foam cells) and the proliferation of intimal-smooth muscle cells, producing atheromatous (fibrofatty) plaques.

[0282] As used herein, the term "metabolic syndrome" refers to a group of conditions that occur together, increasing the risk of developing heart disease, stroke, and type 2 diabetes. These conditions include elevated blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.

[0283] As used herein, the term "diabetic nephropathy" means kidney disease caused by diabetes, which is the number one cause of kidney failure. Almost one-third of people with diabetes will develop diabetic nephropathy. Early diabetic nephropathy usually has no symptoms. As kidney function worsens, symptoms may include: swelling of the hands, feet, and face; inability to sleep or concentrate; loss of appetite; nausea; weakness; itching (end-stage renal disease) and extreme dryness of the skin; drowsiness (end-stage renal disease); abnormal heart rhythms due to an increase in potassium in the blood; and muscle twitches.

[0284] In some embodiments, the disease is renal injury. In some embodiments, the renal injury is caused by ureteral obstruction. In some embodiments, the renal injury is caused by unilateral ureteral obstruction.

[0285] As used herein, the term "PPARα / γ dual agonist" refers to a compound that exhibits significant PPARα and PPARγ agonism. In some embodiments, the PPARα / γ dual agonist exhibits significant PPARα and / or PPARγ agonism, wherein the half-maximal concentration potency (EC) for activating hPPARγ is 50 ) and EC targeting activated hPPARα 50 The difference is less than 30-fold, 25-fold, 20-fold, 15-fold, 10-fold, 5-fold or 3-fold. In some embodiments, the PPARα / γ dual agonist exhibits significant PPARα and / or PPARγ agonism, wherein the half-maximal concentration potency (EC 50 ) and EC targeting activated hPPARα 50 The difference is more than 30 times, 25 times, 20 times, 15 times, 10 times, 5 times or 3 times.

[0286] In certain embodiments, the dual agonist of PPARα and PPARγ is Compound 2 or a crystalline form thereof provided herein.

[0287] In another aspect, the present disclosure provides a method for regulating PPARα and / or PPARγ in a subject in need thereof, comprising administering to the subject an effective amount of Compound 2 or a crystalline form of a salt of Compound 2 or a pharmaceutical composition of the present disclosure.

[0288] Examples

[0289] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure, and are intended only to show methods of practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to prepare a variety of other compounds of the present disclosure, and alternative methods for preparing compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, non-exemplary compounds according to the present disclosure can be successfully synthesized by modifications apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and building blocks other than the described reagents and building blocks, and / or by making conventional modifications to reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered to be applicable to preparing other compounds of the present disclosure.

[0290] Example 1: Synthesis of Compound 2

[0291]

[0292] At 0 ° C, under N2, THF (60 mL) containing 2- (5-methyl-2-phenyloxazol-4-yl) methyl acetate (7.0 g, 30.3 mmol) was added to a suspension of LiAlD4 (1.9 g, 45.4 mmol) in THF (40 mL). The reaction was stirred at 0 ° C for 2 hours and then quenched with water (3 mL). The resulting solid was filtered out. The filter cake was washed with EtOAc (500 mL), DCM / MeOH (10 / 1, 500 mL). The filtrate was concentrated under vacuum to give 2- (5-methyl-2-phenyloxazol-4-yl) second -1,1-d2-1-ol (5.0 g, yield 80.6%) as a yellow solid.

[0293] 1 H NMR(400MHz, CDCl3)δ:8.05-7.87(m,1H),7.50-7.33(m,2H),2.71(s,2H),2.34(s,3H).

[0294] LC-MS (ESI + ):m / z=206.2([M+H] + ).

[0295] Et3N (5.4g, 53.7mmol) was added to a solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2-1-ol (5.0g, 24.4mmol) in DCM (100mL). The reaction mixture was cooled to 0°C and MsCl (5.6g, 48.8mmol) was added under N2. The reaction was stirred at 0°C for 2 hours and then poured into water. 1N HCl (40mL) was added and the mixture was extracted with DCM (100mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether: EtOAc=20:1 to 10:1) to obtain 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2 mesylate (5.0g, 72.5% yield) as a white solid.

[0296] 1 H NMR (400MHz, CDCl3) δ: 7.97 (dd, J=7.4, 2.2Hz, 2H), 7.53-7.34 (m, 3H), 3.04-2.90 (m, 5H), 2.36 (s, 3H).

[0297] LC-MS (ESI + ):m / z=284.0([M+H] +).

[0298] K2CO3 (2.9 g, 21.2 mmol) was added to a solution of 4-hydroxybenzo[b]thiophene-7-carboxaldehyde (3.2 g, 17.7 mmol) in DMF (30 mL). The reaction mixture was heated to 85 ° C under N2. At this temperature, DMF (15 mL) containing 2-(5-methyl-2-phenyloxazol-4-yl)ethyl-1,1-d2 methanesulfonate (5.0 g, 17.7 mmol) was added dropwise. The reaction was stirred at 85 ° C for 5 hours, then cooled to room temperature and poured into water and extracted with EtOAc (300 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated by 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, yield 88.2%) as a brown solid.

[0299] 1 H NMR (300MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.07 (d, J = 8.2Hz, 1H), 8.00-7.86 (m, 2H), 7.82 (d,J=5.5Hz,1H),7.62-7.38(m,4H),7.23(d,J=8.1Hz,1H),3.06(s,2H),2.40(s,3H).

[0300] LC-MS (ESI + ):m / z=366.0([M+H] + ).

[0301] At 0 ° C, under argon, TiCl4 (10.8 g, 57.2 mmol) was added to a solution of 2-methoxyacetic acid methyl ester (5.9 g, 57.2 mmol) in THF (40 mL). The yellow solution was stirred at 0 ° C for 15 minutes, and DIEA (7.9 mg, 61.6 mmol) was added. The black solution was stirred for another 15 minutes, and DCM (60 mL) containing 4- (2- (5-methyl-2-phenyloxazol-4-yl) ethoxy-1,1-d2) benzo [b] thiophene-7-carboxaldehyde (4.0 g, 11.0 mmol) was added dropwise. The reaction was stirred at 0 ° C for 1 hour and warmed to room temperature overnight. The reaction was then cooled to 0 ° C and quenched with water and extracted with DCM (200 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product 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), which was used directly in the next step without further purification.

[0302] LC-MS (ESI + ):m / z=470.2([M+H] + ).

[0303] To a solution of methyl 3-hydroxy-2-methoxy-3-(4-(2-(5-methyl-2-benzooxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-yl)propanoate (7.7 g, crude product) in DMF (40 mL) was added concentrated H2SO4 (10 mL) dropwise at ambient temperature. The reaction was stirred at 100 ° C overnight, then the reaction was diluted with EtOH (40 mL) and stirred at 0 ° C for 1 hour. The solid was filtered and washed with EtOH (10 mL) and water (50 mL). The wet cake was dried to give (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-yl)acrylate (2.3 g, 46.4% yield for 2 steps) as a yellow solid.

[0304] 1 H NMR (400MHz, CDCl3) δ: 8.09 (d, J = 8.4Hz, 1H), 7.99 (dd, J = 7.6, 1.8Hz, 2H), 7.53-7.37 (m, 4H), 7.34 (d, J=5.5Hz,1H),7.21(s,1H),6.85(d,J=8.4Hz,1H),3.88(s,3H),3.77(s,3H),3.08(s,2H),2.40(s,3H).

[0305] LC-MS (ESI + ):m / z=452.2([M+H] + ).

[0306] To a solution of (Z)-2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy-1,1-d2)benzo[b]thiophene-7-yl)methyl 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 hours. The reaction mixture was cooled to room temperature, diluted with HO (50 mL) and adjusted to pH=3 with 6N 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 hour, cooled to 0 ° C and stirred for 1 hour. 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.

[0307] 1 H NMR (400MHz, CDCl3) δ: 8.09 (d, J = 8.4Hz, 1H), 8.00 (dd, J = 7.6, 1.9Hz, 2H), 7.49 (d, J = 5.5Hz, 1H), 7.4 8-7.39(m,3H),7.35(t,J=2.7Hz,2H),6.87(d,J=8.4Hz,1H),3.78(s,3H),3.10(s,2H),2.41(s,3H).

[0308] LC-MS (ESI + ):m / z=438.2([M+H] + ).

[0309] 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 hours. When LCMS showed about half of the starting material remaining, Ir-cat (10.3 mg) was added, and the reaction was stirred for another day. After opening the autoclave, the pale yellow solution was rotary evaporated to dryness (45°C). The crude product is dissolved in EtOAc (150mL) and washed with 1N HCl (40mL x 2). The organic layer is dried over NaSO, filtered and evaporated to dryness. The crude product is dissolved in isopropyl acetate under reflux and cooled to 0 ° C, thus starting crystallization. The formed crystals are filtered out, washed with isopropyl acetate (50mL) and dried to obtain a yellow solid (920mg), which is further purified by preparative HPLC (0.1% FA / CHCN and water) to obtain compound 2 (518mg, 34.5% yield) as a white solid.

[0310] 1 H NMR (400MHz, CDCl3) δ: 7.99 (dd, J=6.4, 2.4Hz, 2H), 7.48 (d, J=5.6Hz, 1H), 7.43–7.41 (m, 3H), 7.32 (d, J=5.6Hz, 1H), 7.15 (d, J= 8.0Hz,1H),6.73(d,J=8.0Hz,1H),4.20(dd,J=7.9,4.7Hz,1H),3.39-3.28(m,4H),3.23-3.18(m,1H),3.05(s,2H),2.40(s,3H).

[0311] LC-MS (ESI + ):m / z=440.2([M+H] + ).

[0312] Chiral HPLC (Chiralpak AD-3 4.6 mm*250 mm 3 μm, 90% hexane / 9.99% EtOH / 0.01% TFA, 210 nm): 99.57% ee.

[0313] Example 2: Preparation of a crystalline form of Compound 2

[0314] 2.1 Abbreviations of solvents used

[0315] The following abbreviations are used in the examples:

[0316] Table 1. List of solvent abbreviations

[0317]

[0318] 2.2 Characterization of starting materials

[0319] A total of two batches of AP-303 (i.e., Compound 2) free acid (Batch No.: 01321040801) were received separately and then characterized by XRPD, TGA, and DSC. The results are summarized in Table 2. Upon 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. Figure 1A and Figure 2A The XRPD pattern is shown in .

[0320] like Figure 1B As shown, for the first batch of free acid materials, the TGA results showed a weight loss of 0.9% when the temperature reached 100°C, and the DSC results showed two endothermic peaks at 148.9°C and 151.7°C (peak temperatures). Figure 2B As shown, for the second batch of free acid material, the TGA results showed a weight loss of 3.9% when the temperature reached 100°C, and the DSC results showed three endothermic peaks at 73.5°C, 149.0°C and 151.6°C (peak temperature).

[0321] Table 2. Summary of information on starting materials and characterization results

[0322]

[0323] The approximate solubility of AP-303 (818159-01-A) in 14 single solvents was determined at room temperature (25 ± 3 ° C). Approximately 2 mg of sample was added to a 3 mL glass vial. The corresponding solvent was added to the vial stepwise (50 μL → 50 μL → 100 μL → 200 μL → 600 μL → 1000 μL) until the solid was visually dissolved or a total volume of 2 mL was reached. The approximate solubility range was calculated based on the sample mass, solvent volume, and observations. The results summarized in Table 3 are used to guide solvent selection in polymorph screening.

[0324] Table 3. Approximate solubility of AP-303 (818159-01-A) at room temperature

[0325]

[0326] 2.3 Polymorph screening experiment

[0327] Starting with the free acid (818159-01-A) material, polymorph screening was performed under 100 experimental conditions. A total of 10 methods were used, including antisolvent addition / reversible antisolvent addition, slurry at room temperature, slurry at 50°C, 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. Figure 3 As shown in the XRPD results, six free acid forms were obtained, namely free acid forms B to G.

[0328] Table 4. Summary of polymorph screening

[0329]

[0330] 2.3.1 Slow Cooling

[0331] Slow cooling experiment is carried out in 6 kinds of solvent systems.About 20mg starting material (818159-01-A) is dissolved in 1.0mL solvent or solvent mixture at 50 ℃, and is filtered into a new vial using a 0.45 μm PTFE membrane.The filtrate is slowly cooled to 5 ℃ from 50 ℃ at a rate of 0.05 ℃ / minute.Before separation for XRPD analysis, the obtained solid is kept isothermal at 5 ℃ or -20 ℃.If solid is not observed, slow evaporation is carried out.The results summarized in Table 5 show that free acid form E / F, form E+C, form B+ peak (unidentified peak except form B) and low crystallinity are obtained.

[0332] Table 5. Summary of slow cooling experiments

[0333]

[0334] 2.3.2 Liquid vapor diffusion

[0335] Liquid vapor diffusion experiment is carried out under 6 conditions.About 20mg starting material (818159-01-A) is dissolved in 0.2~0.8mL solvent, to obtain clear solution in 3mL bottle, and uses 0.45μm PTFE membrane to filter it into new bottle.The filtrate is transferred to 3mL bottle, and then it is placed in 20mL bottle with 3mL volatile solvent.20mL bottle is sealed with cap and kept at room temperature, so as to allow organic vapor to interact with solution enough time.If sample is still clear, then slowly evaporate at room temperature.Precipitate is separated for XRPD analysis.The result of summary in table 6 shows, obtains free acid form F, form B+E, low crystallinity and amorphous.

[0336] Table 6. Summary of liquid vapor diffusion experiments

[0337]

[0338] 2.3.3 Antisolvent addition

[0339] Antisolvent addition experiments were performed under 12 conditions. About 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 0.2 mL of antisolvent was subsequently added in each step until a precipitate appeared or the total amount of antisolvent reached 5 mL. The clear solution was transferred to stir at 5 ° C or -20 ° C to induce precipitation. If the sample is still clear, it is slowly evaporated at room temperature. The obtained precipitate is separated for XRPD analysis. The results in Table 7 show that free acid forms C / E / F / G, forms C+E, forms B+C+E, amorphous and low crystallinity were observed.

[0340] Table 7. Summary of antisolvent addition experiments

[0341]

[0342]

[0343] 2.3.4 Reversible Antisolvent Addition

[0344] Reversible antisolvent addition experiments were performed under 8 conditions. About 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 added to the antisolvent. The clear solution was transferred to stir at 5 ° C or -20 ° C to induce precipitation. If the sample is still clear, it is slowly evaporated at room temperature. The obtained precipitate is separated for XRPD analysis. The results in Table 8 show that free acid forms C / E / F, forms B+E, amorphous and low crystallinity are observed.

[0345] Table 8. Summary of reversible antisolvent addition experiments

[0346]

[0347] 2.3.5 Slow evaporation

[0348] Slow evaporation experiments were carried out in 5 solvent systems. About 20 mg of starting material (818159-01-A) was dissolved in 0.6-3.0 mL of solvent or solvent mixture and filtered into a new vial using a 0.45 μm PTFE membrane. The filtrate was slowly evaporated at room temperature and the obtained solid was separated for XRPD analysis. The results summarized in Table 9 show that free acid form C / F, form B+E and form E+ peaks were obtained.

[0349] Table 9. Summary of slow evaporation experiments

[0350]

[0351] 2.3.6 Slurry at 50°C

[0352] Slurry conversion experiments were performed in 17 solvent systems at 50°C. About 20 mg of the starting material (818159-01-A) was suspended in 0.5 mL of solvent at 50°C for 2 days. The remaining solid was separated for XRPD analysis. The results summarized in Table 10 indicated that free acid Form E, Form B+E, Form E+C, and Form E+ peaks were obtained.

[0353] Table 10. Summary of slurry conversion experiments at 50°C

[0354]

[0355] *: Due to limited solids, samples were transferred to 5°C for 6 days; a w : Water activity.

[0356] 2.3.7 Temperature Cycle

[0357] Temperature cycling experiments were performed under 9 conditions. About 20 mg of the starting material (818159-01-A) was suspended in 0.5 mL of solvent. The suspension was then magnetically stirred for two cycles at 50° C. to 5° C., with a heating / cooling rate of 0.1° C. / minute. The remaining solid was separated for XRPD analysis. The results summarized in Table 11 show that free acid forms B+E were obtained.

[0358] Table 11. Summary of temperature cycling experiments

[0359]

[0360] 2.3.8 Solid vapor diffusion

[0361] 8 kinds of different solvent systems are used to carry out solid vapor diffusion experiment.About 20mg starting material (818159-01-A) is weighed into 3mL bottle, and described starting material is placed in 20mL bottle with 3.0mL volatile solvent.20mL bottle is sealed with cap and kept at room temperature for 10 days, thus allows solvent vapor and sample to interact.By XRPD, solid is tested.The result of summarizing in table 12 shows, obtains free acid form E+B, form C+E, form C+E+B and form F+ peak.

[0362] Table 12. Summary of solid vapor diffusion experiments

[0363]

[0364] *: Solid obtained after evaporation at room temperature.

[0365] 2.3.9 Humidity-induced crystallization

[0366] The crystallization experiment of humidity induction was carried out under 5 conditions respectively. About 20mg starting material (818159-01-A) was weighed into a 3mL bottle, and the starting material was placed in a 20mL bottle with a 2mL saturated inorganic salt solution. The 20mL bottle was sealed with a cap and kept at room temperature for 9 days, thereby allowing water vapor to interact with the sample. Solid was tested by XRPD. The results summarized in Table 13 show that free acid form C+E+B was obtained.

[0367] Table 13. Summary of humidity-induced crystallization experiments

[0368]

[0369] 2.3.10 Polymer-induced crystallization

[0370] Polymer-induced crystallization experiments were performed with two sets of polymer mixtures in different solvent systems. Approximately 20 mg of the starting material (818159-01-A) was dissolved in 0.4-2.0 mL of solvent in a 3 mL glass vial. Approximately 2 mg of the polymer mixture was added to a 3 mL glass vial. All solutions and suspensions were filtered using a 0.45 μm PTFE membrane. The resulting solution was subjected to evaporation at room temperature, wherein the The vial was sealed for slow evaporation. The solid was isolated for XRPD analysis. The results summarized in Table 14 show that free acid Form E / F and Form B+E were obtained.

[0371] Table 14. Summary of polymer-induced crystallization experiments

[0372]

[0373] Polymer mixture A: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC) (mass ratio is 1:1:1:1:1:1)

[0374] Polymer mixture B: polycaprolactone (PCL), polyethylene glycol (PEG), polymethyl methacrylate (PMMA), sodium alginate (SA) and hydroxyethyl cellulose (HEC) (mass ratio is 1:1:1:1:1).

[0375] *: The color changes to reddish brown.

[0376] 2.3.11 Slurrying at room temperature

[0377] Slurry conversion experiments were performed at room temperature in 17 solvent systems. About 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 separated for XRPD analysis. The results summarized in Table 15 show that free acid forms B / D / E and forms B+E were obtained.

[0378] Table 15. Summary of slurry conversion experiments performed at room temperature

[0379]

[0380] a w : Water activity.

[0381] Example 3: Characterization of the crystalline form of Compound 2

[0382] General approach

[0383] X-ray powder diffraction (XRPD)

[0384] For XRPD analysis, a PANalytical X'pert 3 X-ray powder diffractometer was used. The samples were dispersed in the middle of a zero-background Si holder. Table 16 lists the XRPD parameters used.

[0385] Table 16. Parameters of XRPD test

[0386]

[0387] Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0388] TGA data were collected using a TA Q5000 TGA from TA Instruments, and DSC was performed using a TA2500DSC from TA Instruments. Table 17 lists the detailed parameters used.

[0389] Table 17. Parameters of TGA and DSC tests

[0390]

[0391] Dynamic Vapor Sorption (DVS)

[0392] DVS was measured by SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25°C was calibrated for the deliquescent points of LiCl, Mg(NO3)2, and KCl. Table 18 lists the parameters of the DVS test.

[0393] Table 18. Parameters of DVS test

[0394]

[0395] Solution 1 H NMR

[0396] Solution proton NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6 or MeOD.

[0397] HPLC / IC

[0398] An Agilent 1260 HPLC with a DAD / VWD detector was used 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.

[0399] Table 19. Chromatographic conditions for purity and solubility analysis

[0400]

[0401]

[0402] Table 20. IC method for counterion content measurement

[0403]

[0404] 3.1 Form B of Compound 2

[0405] The free acid Form B (818159-08-B) was obtained by slurrying the starting material (818159-01-A) in EtOAc as Figure 4A The XRPD shown in Figure 4B As shown, the TGA results showed that when the temperature reached 100°C, the weight loss was 1.5%, and the DSC results showed two endothermic peaks at 81.3°C (peak temperature) and 151.1°C (onset temperature). 1 H NMR results showed that no residual EtOAc was detected. Figure 4C ).

[0406] like Figure 5A As shown by the XRPD in Table 21, the free acid Form B (818159-39-B) was purified by slurrying the free acid Form B (818159-08-B) in ACN at room temperature. Figure 5B As shown, the TGA results showed a weight loss of 1.9% when the temperature reached 100°C, and the DSC results showed two endothermic peaks at 84.7°C (peak temperature) and 150.4°C (onset temperature).

[0407] To investigate the origin of the form, variable temperature XRPD (VT XRPD) experiments were performed on the free acid form B (818159-08-B), as shown in Figure 4D As shown. The VT XRPD results show that: 1) no form change was observed after N2 outgassing at 30°C; 2) after heating to 100°C under N2 protection, it was converted to free acid form E; 3) after cooling to 30°C under N2 protection, it was partially converted back to free acid form B; 4) after being stored at ambient temperature for two days, it was completely converted back to free acid form B. Based on the VT XRPD results, it is speculated that free acid form B and form E are anhydrates. It is speculated that the endothermic peak at 84.7°C (peak temperature) is related to the form transition, and the endothermic peak at 150.4°C (onset temperature) is consistent with the endothermic peak of form E.

[0408] Table 21. XRPD of Free Acid Form B (818159-39-B)

[0409]

[0410] 3.2 Form C of Compound 2

[0411] The free acid Form C (818159-30-B) was obtained by slow evaporation in DCM. Fig. 6A and Table 22 and Figure 6BXRPD and TGA / DSC are shown in Figure 1. TGA results show that when the temperature reaches 100°C, the weight loss is 2.8%, and DSC results show an endothermic peak at 147.6°C (onset temperature), which is presumed to be the melting point. 1 H NMR results ( Figure 6C ) showed no residual DCM was detected. Considering the low TGA weight loss and neat DSC, the free acid Form C was presumed to be an anhydrate.

[0412] Table 22. XRPD of Free Acid Form C (818159-30-B)

[0413]

[0414]

[0415] 3.3 Form D of Compound 2

[0416] The free acid Form D (818159-25-A11) was obtained by slurrying the starting material (818159-01-A) in DCM / cyclohexane (2:1, v / v) at room temperature. Figure 7 The XRPD results are shown in Table 23. The free acid Form D (818159-36-B) was re-prepared using the same method for characterization. Figure 8 and Fig.9A The XRPD and TGA / DSC results are shown in Figure 2. The TGA results show that the weight loss is 2.9% when the temperature reaches 100°C, and the DSC results ( Fig.9A ) showed an endothermic peak at 150.7°C (one temperature) and an exothermic peak at 92.8°C (peak temperature). 1 H NMR results ( Fig. 9B ) shows that the molar ratio of cyclohexane to API is 0.05 (0.9 wt%). Fig. 9C As shown, after 1 month of storage at room temperature, it converted to free acid Form E. Based on the characterization results, free acid Form D was speculated to be a hygroscopic free acid anhydrate or hydrate (theoretical weight loss of monohydrate is 2.1%).

[0417] Another batch of free acid form D (818159-68-B) was re-prepared using the same method for crystal form identification. Fig.10 As shown, the re-prepared free acid form D is a mixture of form D and a small amount of form E. TGA results ( Fig.11A ) showed a weight loss of 5.0% when the temperature reached 100°C, and the DSC results ( Fig.11A) showed an endothermic peak at 150.4°C (onset temperature) and an exothermic peak at 95.5°C (peak temperature). 1 H NMR results ( Fig. 11B ) showed that the molar ratio of cyclohexane to API was 0.09 (1.8 wt%). To investigate the origin of the form, VT XRPD was performed. Fig. 11C As shown, 1) a peak shift was observed after N2 outgassing at 30°C; 2) after heating to 100°C under N2 protection, it was converted to free acid form E; 3) after cooling to 30°C under N2 protection, no form change was observed. Combining the characterization and VT results, it is speculated that it is a hydrate. Combined with the VTXRPD results, it is speculated that the exotherm at 95.5°C (peak temperature) is a form transition, and the endothermic peak at 150.4°C (starting temperature) is consistent with the endothermic peak of form E.

[0418] Table 23. XRPD of Free Acid Form D (818159-25-A11)

[0419]

[0420] 3.4 Form E of Compound 2

[0421] Free acid Form E was observed in a few 50°C slurry experiments. However, pure free acid Form E (818159-40-A2_July 30) was obtained by suspension competition experiments in MIBK at 50°C. Fig.12 The XRPD is shown in Table 24. Fig.13A As shown, the free acid Form E (818159-32-B) was prepared by slurrying the starting material in IPA at 50°C. Upon further comparison, a small amount of Form B was observed in the free acid Form E (818159-32-B). TGA results ( Fig. 13B ) showed a weight loss of 2.8% when the temperature reached 100°C, and the DSC results ( Fig. 13B ) showed an endothermic peak at 151.1°C (onset temperature), which was presumed to be a melting signal. 1 H NMR results ( Fig. 13C ) showed no residual IPA was observed. Considering the low TGA weight loss and neat DSC, it was presumed to be anhydrous.

[0422] Table 24. XRPD of Free Acid Form E (818159-40-A2_July 30)

[0423]

[0424]

[0425] The blue peak is a characteristic peak different from that of the crystal form B.

[0426] 3.5 Form F of Compound 2

[0427] like Fig.14A As shown in Table 25, free acid Form F (818159-37-B) was obtained by evaporation in THF / H2O (4:1, v / v) at room temperature. Free acid Form F was also observed in the residual solids of kinetic solubility starting from different salts. TGA results ( Fig. 14B ) showed a weight loss of 3.9% when the temperature reached 100°C, and the DSC results ( Fig. 14B ) showed four endothermic peaks at 44.8°C, 77.1°C, 111.2°C and 149.8°C (peak temperature) and one exothermic peak at 118.9°C (peak temperature). 1 H NMR results ( Fig. 14C ) showed that no residual THF was observed. In order to investigate the origin of the form, VTXRPD was performed. Fig.14D As shown, 1) no form change was observed after N2 outgassing at 30°C; 2) after heating to 130°C under N2 protection, it was converted to free acid form E; 3) after cooling to 30°C under N2 protection, no form change was observed. Combined with the characterization and preparation conditions, it is speculated that it is a hydrate. The endothermic before 100°C is speculated to be dehydration, and the exothermic at 118.9°C (peak temperature) is speculated to be a form transition. The endothermic peak at 149.8°C (peak temperature) is consistent with the endothermic peak of Form E.

[0428] Table 25. XRPD of Free Acid Form F (818159-37-B)

[0429]

[0430] 3.6 Form G of Compound 2

[0431] The free acid Form G (818159-41-B) was obtained by evaporation in DMSO / MTBE at room temperature. Fig.15A and Table 26 and Fig. 15B The XRPD and TGA / DSC results are shown in Figure 1. The TGA results show that the weight loss is 36.7% when the temperature reaches 150°C, and the DSC results show two endothermic peaks at 72.4°C and 83.1°C (peak temperature). CD3OD was used as the solvent for the test. 1 H NMR ( Fig. 15C), and the results showed that the molar ratio of DMSO / free acid was 1.7 (23.0wt%). In order to further study the source of the form, a heating experiment was performed. As a result, after heating to 110°C and then cooling to ambient temperature, melting was observed. Based on the characterization and heating experiment results, it is speculated that the free acid form G is a DMSO solvate. It is speculated that the endothermic peak is a desolvation signal.

[0432] Table 26. XRPD of Free Acid Form G (818159-41-B)

[0433]

[0434]

[0435] Example 4: Study on mutual conversion relationship

[0436] 4.1 Suspension competition of anhydrous substances

[0437] To investigate the interconversion relationship between the free acid anhydrate forms B / C / E, suspension competition experiments were performed in IPA, ACN and n-heptane at room temperature and 50°C. Procedure: Approximately equal masses of the corresponding forms were added to the presaturated solution and stirred at the corresponding temperature. The residual solid was extracted for XRPD analysis. The results are summarized in Table 27 and Figures 16A-16E XRPD results are shown in . Based on the results, Form B was obtained in all tested solvents at room temperature, and Form E was observed in IPA and n-heptane at 50°C. However, Form B was observed in ACN at both room temperature and 50°C, which may be due to solvent effects. In order to further study the transition temperatures of Form B and Form E, suspension competition experiments were carried out in MIBK and IPAc at 40°C and 50°C, resulting in Form B (mainly) at 40°C and Form E (mainly) at 50°C. In the following experiments (which were performed before identifying Form D), Form D material was added to IPA at 50°C and to IPAc at 40°C and 50°C. The results show that Form B was observed at 40°C, and a mixture of Form B and Form E was observed at 50°C.

[0438] Most importantly, Form B and Form E are in an interconversion relationship, with Form B being the low temperature stable form. The transition temperature between Form B and Form E is between 40°C and 50°C.

[0439] Table 27. Summary of suspension competition between anhydrous compounds

[0440]

[0441]

[0442] 4.2 Suspension competition between anhydrate and hydrate

[0443] To investigate the interconversion relationship between the free acid anhydrate Form B and the hydrate Forms D / F, suspension competitions were performed in IPA / water at room temperature at different water activities. Procedure: Approximately equal masses of the Form B / D / F mixture were added to the presaturated solution and stirred at room temperature. The residual solid was extracted for XRPD analysis. The results are summarized in Table 28 and Fig.17A and Fig. 17B The XRPD results are shown in . Based on the results, free acid Form B was obtained under all conditions tested.

[0444] Table 28. Summary of suspension competition at different water activities

[0445]

[0446] a w : Water activity

[0447] Example 5: Salt screening and characterization

[0448] 5.1 Salt type screening

[0449] Starting with the free acid form A (818159-01-A), 30 salt screening experiments were performed using 10 bases and three solvent systems based on pKa (acidity, 3.36) and approximate solubility. About 20 mg of the free acid and equimolar base were added to 0.5 mL of solvent at room temperature. The solid was centrifuged for XRPD. As shown in the results summarized in Table 29, a total of six salt forms were observed. The salt forms were analyzed by TGA, DSC, 1 All salt forms were characterized by H NMR or HPLC / IC and the results are summarized in Table 30.

[0450] Table 29. Summary of salt screening

[0451]

[0452] *: The molar ratio of free acid / base is 1.0.

[0453] Table 30. Summary of characterization of salt forms obtained from salt form screening

[0454]

[0455] *: endothermic peak (onset temperature); # : Exothermic peak (peak temperature).

[0456] 5.1.1 Na salt form A

[0457] Na salt Form A (818159-03-B1) was prepared by slurrying free acid Form A (818159-01-A) and NaOH in a 1:1 (base / acid) molar ratio in EtOAc at room temperature for 3 days, followed by centrifugation and drying under vacuum at 50 °C. Fig.18A and Fig.18B The XRPD and TGA / DSC results are shown in. The TGA results show that when the temperature reaches 220°C, the weight loss is 4.5%, and the DSC results show that there are three endothermic peaks at 155.7°C, 201.8°C (onset temperature) and 288.7°C (peak temperature) and one exothermic peak at 166.3°C (peak temperature). 1 H NMR ( Fig.18C ) The results showed that the molar ratio of EtOAc / free acid was 0.19 (0.8 wt %). HPLC / IC showed that the molar ratio of base / acid was 1.1.

[0458] 5.1.2 K Salt Form A / B

[0459] like Fig.19A As shown, K salt Form A / B (818159-03-B2 / C2) was prepared by slurrying the free acid Form A (818159-01-A) and KOH in a 1:1 (base / acid) molar ratio in EtOAc and acetone / H2O at room temperature for 3 days, followed by centrifugation and vacuum drying at 50°C. For K salt Form A, Fig.19B The TGA / DSC results are shown in . The TGA results showed that the weight loss was 3.6% when the temperature reached 150° C., and the DSC results showed three endothermic peaks at 91.1° C., 135.8° C., and 147.7° C. (peak temperature). 1 H NMR ( Fig.19C ) The results showed that no EtOAc was detected. HPLC / IC showed 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 collected.

[0460] 5.1.3 Arginine Salt Form A

[0461] Arginine salt Form A (818159-03-B3) was prepared by slurrying free acid Form A (818159-01-A) and arginine in a 1:1 (base / acid) molar ratio in EtOAc at room temperature for 3 days, followed by centrifugation and drying under vacuum at 50 °C. Fig. 20A and Fig. 20B The XRPD and TGA / DSC results are shown in . The TGA result showed that the weight loss was 4.0% when the temperature reached 180°C, and the DSC result showed an endothermic peak at 186.9°C (onset temperature). 1 H NMR ( Fig. 20C ) The 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 %).

[0462] 5.1.4 Mg Salt Form A

[0463] Mg salt Form A (818159-03-C5) was prepared by slurrying free acid Form A (818159-01-A) and MgOH in a 1:1 (base / acid) molar ratio in acetone at room temperature for 3 days, followed by centrifugation and drying under vacuum at 50 °C. Fig.21A and Fig. 21B XRPD and TGA / DSC results are shown in . The TGA result showed that when the temperature reached 150° C., the weight loss was 6.9%, and the DSC result showed four endothermic peaks at 90.7° C., 114.9° C., 134.0° C., and 154.2° C. (peak temperature). 1 H NMR ( Fig. 21C ) The results showed that the molar ratio of acetone / free acid was 0.01 (0.2 wt%). HPLC / IC showed that the molar ratio of base / acid was 0.8.

[0464] 5.1.5 Tirs Salt Form A

[0465] Tris salt Form A (818159-03-B10) was prepared by slurrying free acid Form A (818159-01-A) and tris in a 1:1 (base / acid) molar ratio in EtOAc at room temperature for 3 days followed by centrifugation and drying under vacuum at 50 °C. Fig.22A and Fig. 22B XRPD and TGA / DSC results are shown in . The TGA result showed that the weight loss was 6.5% when the temperature reached 150° C., and the DSC result showed four endothermic peaks at 71.8° C., 76.6° C., 113.9° C., and 213.1° C. (peak temperature). 1 H NMR ( Fig. 22C ) The 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 %).

[0466] 5.2 Re-preparation of candidate salt forms

[0467] Based on the characterization results, it is inferred that arginine salt form A is an anhydrous substance, and other salts are hydrates or solvates. Considering the safety of salt co-former, the dehydration temperature of each salt type, Na salt form A, K salt form A and arginine salt form A are selected as candidate salt types to be re-prepared and evaluated. New K salt (K salt form C) was obtained during re-preparation, and other salts were successfully re-prepared. Table 31 and Table 32 summarize detailed preparation procedures and characterization results.

[0468] Table 31. Re-preparation procedures for candidate salt forms

[0469]

[0470] Table 32 Summary of characterization of candidate salt forms

[0471]

[0472] *: starting temperature; # : Exothermic peak.

[0473] 5.2.1 Na salt form A

[0474] like Fig.24A , Fig.23 Na Salt Form A (818159-09-B) was re-prepared as shown by the XRPD results in Table 33. A new form was observed in the wet sample and converted to Na Salt Form A. Fig. 24B The TGA / DSC results are shown in . The TGA results showed that when the temperature reached 220°C, the weight loss was 6.2%, and the 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 ( Fig.24C ) The results showed that the molar ratio of EtOAc / free acid was 0.31 (5.8 wt %). HPLC / IC showed that the molar ratio of base / acid was 0.9.

[0475] Table 33. XRPD of Na Salt Form A (818159-09-B)

[0476]

[0477] 5.2.2 K Salt Form C

[0478] like Fig.26A , Fig.25 As shown in Table 34, a new K salt was observed during the re-preparation, designated K Salt Form C (818159-10-B). Fig.26BThe TGA / DSC results are shown in . The TGA results showed that the weight loss was 5.5% when the temperature reached 200° C., and the DSC results showed three endothermic peaks at 108.1° C., 140.2° C., and 161.3° C. (peak temperature). 1 HNMR Fig.26C ) The results showed that no EtOAc was detected. HPLC / IC showed that the molar ratio of base / acid was 0.9.

[0479] Table 34 XRPD of K Salt Form C (818159-10-B)

[0480]

[0481]

[0482] 5.2.3 Arginine Salt Form A

[0483] like Fig.28A , Fig. 27 As shown in Table 35, arginine salt form A (818159-11-B) was re-prepared. TGA results ( Fig.28B ) shows that when the temperature reaches 150°C, the weight loss is 1.3%, and the DSC results ( Fig.28B ) showed an endothermic peak at 194.0 °C (onset temperature). 1 H NMR ( Fig.28C ) The results showed that the molar ratio of arginine / free acid was 1.0 and no EtOAc was detected.

[0484] Table 35. XRPD of Arginine Salt Form A (818159-11-B)

[0485]

[0486]

[0487] Example 6: Evaluation

[0488] Based on the salt form screening and characterization results, using free acid form B as a control, Na salt form A, K salt form C and arginine salt form A were selected for evaluation, including kinetic solubility, hygroscopicity and solid stability.

[0489] 6.1 Kinetic Solubility Evaluation

[0490] Kinetic solubility curves were measured at 37°C in water, SGF, FaSSIF-V2, FeSSIF-V2, and four pH buffers (pH 1.2, 4.5, 6.8, and 8.0 buffers) with a solid loading of about 2 mg / mL (calculated as free acid). Na salt Form A was measured only in water, SGF, FaSSIF-V2, and FeSSIF-V2. Specifically, the salt solids were suspended in the culture medium and the suspension was stirred on a rolling incubator. Samples were taken at 2 hours 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 Fig.35 The kinetic solubility curves are shown in Figure 1. The results show that: 1) Na salt form A, K salt form C and arginine salt form A show comparable solubility in water and three biologically relevant culture media, and the solubility is improved compared to the free acid form B; 2) K salt form C and arginine salt form A show comparable solubility in pH 4.5 and 6.8 buffers, and the solubility is improved compared to the free acid form B; 3) No form change was observed after the solubility test of the free acid form B, while after the solubility test of the Na salt form A, K salt form C and arginine salt form A, the form changed to the free acid form F or amorphous.

[0491] Table 36. Summary of kinetic solubility results at 37°C

[0492]

[0493]

[0494] S: solubility (mg / mL); LOD: 0.04 μg / mL; N / A: not available due to limited solids;

[0495] *: K2HPO3+KH2PO3; Form F: Free acid Form F. All samples were suspensions during solubility testing.

[0496] Based on the characterization and suspension competition results of different free acid forms, free acid form B and form E are anhydrous and interconvertible, wherein form B is a low-temperature stable form. The transition temperature between form B and form E is between 40°C and 50°C. In order to evaluate the difference in solubility, solubility tests were performed at 37°C in water, SGF, FaSSIF-V2, FeSSIF-V2 and four pH buffers (pH 1.2, 4.5, 6.8 and 8.0 buffers), with a solid loading of about 2 mg / mL. Specifically, the salt solid was suspended in the culture medium and the suspension was stirred on a rolling incubator. Samples were taken at 2 hours 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 solid was collected for XRPD characterization ( Fig.33 and Fig.34 ). The results are summarized in Table 37, and Fig.36 The kinetic solubility curves are shown in Figure 1. The results show that: 1) free acid forms B and E show comparable solubility in water and pH 8.0 (almost clear); 2) free acid form E shows slightly higher solubility than form B in other media; 3) no form change was observed after solubility testing.

[0497] Table 37. Kinetic Solubility of Free Acid Form B and Form E at 37°C

[0498]

[0499] S: solubility (mg / mL); LOD: 0.5-0.6 μg / mL; N / A: not available due to clear solution.

[0500] *:K2HPO3+KH2PO3

[0501] 6.2 Hygroscopicity evaluation

[0502] DVS isotherms of free acid form B, Na salt form A, K salt form C and arginine salt form A were collected at 25°C to study the change in solid form stability relative to humidity (0%RH, 50%RH and 60%RH). DVS graphs and XRPD after DVS test are shown in Figures 37-40. The water absorption of free acid form B and arginine salt form A at 80%RH is 0.07% and 0.5%, respectively, indicating that free acid form B is not hygroscopic, and arginine salt form A is slightly hygroscopic. No form changes of free acid form B and arginine salt form A were observed. The water absorption of Na salt form A and K salt form C at 80%RH is 5.5% and 12.0%, respectively, and after DVS test, form changes were observed.

[0503] 6.3 Solid Stability Assessment

[0504] In order to understand the solid stability, the physical and chemical stability of free acid form B (Table 39) / free acid form E (Table 40), Na salt form A (Table 41), K salt form C (Table 42) and arginine salt form A (Table 43) were placed under 60°C / closed and 40°C / 75%RH / open conditions for 2 / 4 / 8 weeks. The results are summarized in Table 38. Fig.41 , Fig.42 , Fig.44 , Fig.45 and Fig.46 The XRPD results are shown in Figure 2. Fig.43 ) Form E samples after solid stability testing, and no significant differences were observed. Figure 47-51 HPLC results are shown in . No decrease in form or purity was observed for free acid Form B / E and arginine salt Form A. No decrease in purity was observed for K salt Form C after storage under the conditions tested, but form changes were observed. After storage at 60°C for 8 weeks, a slight decrease in purity and form changes were observed for Na salt Form A.

[0505] Table 38. Summary of solid stability evaluation

[0506]

[0507]

[0508] *: A small amount of Form E was observed after further comparison; **: A small amount of Form B was observed after further comparison.

[0509] Table 39. Purity characteristics of free acid Form B (818159-08-B) before and after solid stability assessment

[0510]

[0511] Table 40. Purity characteristics of free acid Form E (818159-61-B) before and after solid stability assessment

[0512]

[0513] Table 41. Purity characteristics of Na salt Form A (818159-09-B) before and after solid stability assessment

[0514]

[0515] Table 42. Purity characteristics of K salt Form C (818159-10-B) before and after solid stability assessment

[0516]

[0517] Table 43. Purity characteristics of arginine salt Form A (818159-11-B) before and after solid stability assessment

[0518]

[0519] Example 7: Evaluation of the activity of compound 2 on PPARα / PPARγ using the luciferase reporter gene system

[0520] HEK293T cells were cultured according to ATCC culture guidelines. Experiments were performed when the cells were in the exponential growth phase. A total of 6 × 10 6 Cells were seeded into 60 mm cell culture dishes and cultured overnight at 37°C and 5% CO2. 3000 (transfection reagent) was mixed with a plasmid combination (pGL4.35 [luc2P / 9XGAL4 UAS / Hygro], a mixture of 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 culture dish. After incubation for 5 hours at 37°C and 5% CO2, the cells were trypsinized and seeded into 384-well assay plates, followed by incubation with test compounds at serial concentrations at 37°C and 5% CO2 overnight. The next day, the cells were lysed and luciferase was expressed using Steady-Glo TM Luciferase assay system was used for activation. The luminescent signal from the luciferase assay was measured by Envision HTS / 2105. Since peroxisome proliferator-activated transcription regulates the expression of luciferase, the agonist activity of the test compound can be identified by the luminescence intensity. The EC value of the test compound for PPARα / γ agonist potency was calculated by using Graphpad 8.0. 50 The values ​​were calculated and the results are shown in Table 44. The selectivity of the compounds for PPARα or PPARγ is expressed as PPARγEC 50 / PPARαEC 50 .

[0521] Table 44. Results of PPARα / γ agonism assay

[0522] Compound ID <![CDATA[PPARαEC 50 (nM)]]> <![CDATA[PPARγEC 50 (nM)]]> Optional* Alegreza 3.14 3.36 1.07 Compound 2 2.52 3.81 1.51

[0523] *Selectivity = PPARγEC 50 (nM) / PPARαEC 50 (nM)

[0524] Example 8: Effect of Compound 2 on a rat model of hyperlipidemia induced by a high cholesterol diet

[0525] 8.1 Experimental Materials:

[0526] Thirty male Sprague-Dawley rats aged 6-8 weeks; Source: SPF (Beijing) Biotechnology Co., Ltd.; Animal Certificate No.: 110324201104469613.

[0527] 8.2 Experimental methods:

[0528] 8.2.1 A high cholesterol diet (ASHF4) was used to induce an animal model of hyperlipidemia in SD rats.

[0529] 8.2.2 Male SD rats were fed with a high cholesterol diet (ASHF4, Dyet, China) for 14 days. The day before the start of administration (day 0), based on body weight and serum index, animals were divided into 5 groups and continuously fed with a high cholesterol diet. Compounds or vehicle were orally administered to the treatment group while continuing the high cholesterol diet for a total of 1 week. Animals were weighed every day before treatment, and compounds were given at 9:00-9:30 in the morning based on body weight on the day. Table 45 shows specific grouping and dosing regimen.

[0530] Table 45. Grouping and dosing of experimental animals

[0531]

[0532] Formulation: The formulation was prepared twice a week. 1. Vehicle: 0.5% sodium carboxymethylcellulose. Add 5 g sodium carboxymethylcellulose to 900 ml ddH2O and stir until completely dissolved, then fill to 1000 ml with ddH2O. 2. Working solution for 0.6 mg / kg administration: 0.12 mg / ml working solution. Add 12 mg of compound to 100 ml 0.5% sodium carboxymethylcellulose, and then vortex until completely suspended. 3. Working solution for 0.2 mg / kg administration: 0.04 mg / ml working solution. Mix 30 ml of 0.12 mg / ml compound solution with 60 ml 0.5% sodium carboxymethylcellulose, and then vortex until completely suspended.

[0533] 8.2.3 The blood of the animals was collected one day before treatment and at the end of the last day of the experiment and the serum was separated to analyze the serum lipid indexes.

[0534] 8.2.4 Determine serum indices of triglyceride (TG) and free fatty acid (NEFA) by automatic blood biochemical analyzer.

[0535] 8.3 Results:

[0536] 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 dose levels of 0.2 mg / kg and 0.6 mg / kg compared with the vehicle group. Fig.52A and 52B Animal serum TG and NEFA are shown, and Table 46 and Table 47 show their values, respectively. During the experiment, no abnormalities were observed in the clinical observations. For comparison purposes, the results of each compound at a dose of 0.2 mg / kg were statistically analyzed using the GraphPad 8.0 software package. At a dose level of 0.2 mg / kg, compound 2 can significantly reduce TG and NEFA (P<0.05) compared to aleglitazar.

[0537] Table 46. Changes in serum TG in each group (mean ± standard deviation)

[0538]

[0539] Note: Each group of data was analyzed by GraphPad 8.0 software package, and the statistical method was one-way ANOVA. Compared with the first group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0540] 1 : TG of Group 4 (Compound 2, 0.2 mg / kg) was statistically significantly lower than that of Group 2 (Aleglitazar, 0.2 mg / kg) (p<0.05).

[0541] Table 47. Changes in serum NEFA in each group (mean ± standard deviation)

[0542]

[0543] Note: Each group of data was analyzed by GraphPad 8.0 software package, and the statistical method was one-way ANOVA. ****p<0.0001 compared with the first group.

[0544] 1 : NEFA in Group 4 (Compound 2, 0.2 mg / kg) was statistically significantly lower (p<0.05) compared to NEFA in Group 2 (Aleglitazar, 0.2 mg / kg).

[0545] Example 9: Effects of 7-day repeated oral administration on the body weight of ICR mice

[0546] 9.1 Experimental Materials:

[0547] Fifty male ICR mice aged 6-8 weeks; Source: Laboratory Animal Business Department, Shanghai Institute of Planned Parenthood Research.

[0548] 9.2 Methods:

[0549] After 3 days of adaptation, ICR mice were grouped according to their body weight. The grouping day was designated as day 0. After grouping, the mice were administered vehicle or compound orally by gavage for 7 consecutive days, once a day. Table 48 shows the dosage and grouping. The animals were weighed and recorded every day.

[0550] Table 48. Grouping and dosing of experimental animals

[0551]

[0552] a: 0.5% sodium carboxymethyl cellulose aqueous solution

[0553] Formulation: Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g sodium carboxymethylcellulose was weighed and mixed with 500 ml ddH2O until completely dissolved. 2. Working solution for 1 mg / kg administration: 0.1 mg / ml working solution. 3 mg of compound was added to 30 ml 0.5% sodium carboxymethylcellulose and then vortexed until completely suspended. 3. Working solution for 0.2 mg / kg administration: 0.02 mg / ml working solution. 6 ml 0.1 mg / ml compound solution and 24 ml 0.5% sodium carboxymethylcellulose were mixed and then stirred until completely suspended.

[0554] 9.3 Results:

[0555] Table 49 and Fig.53A The effect of compound on the weight change of ICR mice is shown. During the experiment, the weight of animals gradually increased over time. The average daily weight gain of the aleglitazar group at a dosage of 0.2mg / kg (day 4 and day 5) and 1mg / kg (day 6) was significantly higher than the average daily weight gain of the vehicle group. Compared with the vehicle group, the daily weight gain of the compound 2 group at a low dose of 0.2mg / kg was not significantly different throughout the study. The average daily weight gain of the compound 2 group at a high dose of 1mg / kg (day 4 and day 5) was significantly higher than the average daily weight gain of the vehicle group. Table 49 shows all the data. For comparison purposes, the net weight increase of the treatment obtained by subtracting the average weight gain of the vehicle group from the average weight gain of each treatment group was calculated and displayed in Fig.53B middle.

[0556] Table 49. Changes in body weight gain of animals in each group compared to day 0

[0557]

[0558]

[0559] Note: Each group of data was analyzed by GraphPad 8.0 software package, and the statistical method was one-way ANOVA. Compared with the vehicle, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

[0560] Example 10: Pharmacodynamic study of compound 2 in db / db type 2 diabetes model

[0561] 10.1 Experimental Materials:

[0562]

[0563] 10.2 Experimental methods:

[0564] 10.2.1 Grouping in the experiment: 6 wild-type mice were used as a control group (Group 1). Before the start of treatment, 45 db / db mice were evenly divided into 5 groups based on body weight, serum triglyceride (TG) level, and random blood glucose level.

[0565] 10.2.2 Formulations: Formulations were prepared twice weekly. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g sodium carboxymethylcellulose was weighed and mixed with 500 ml ddH2O until completely dissolved. 2. Working solution for 1 mg / kg administration: 0.1 mg / ml working solution. 3 mg of compound was added to 30 ml 0.5% sodium carboxymethylcellulose and then vortexed until completely suspended. 3. Working solution for 0.2 mg / kg administration: 0.02 mg / ml working solution. 6 ml 0.1 mg / ml compound solution and 24 ml 0.5% sodium carboxymethylcellulose were mixed and then stirred until completely suspended. 4. Working solution for 0.05 mg / kg administration: 0.005 mg / ml working solution. 6 ml 0.02 mg / ml compound solution and 18 ml 0.5% sodium carboxymethylcellulose were mixed and then stirred until completely suspended.

[0566] 10.2.3 Dosing: Animals were orally dosed according to their grouping: vehicle (Group 2), aleglitazar at a dose level of 0.2 mg / kg (Group 3), and Compound 2 at a dose level of 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 dosing and handled daily for 14 consecutive days.

[0567] 10.2.4 Study results included daily body weight throughout the study; serum TG levels before dosing on study days 6 and 12; random blood glucose levels before dosing on study days 7 and 14; and results of an oral glucose tolerance test (OGTT) performed on study day 14.

[0568] 10.3 Data Analysis:

[0569] All data were entered into Excel files and expressed as mean ± SEM. Graphpad Prism 7.0 software was used to perform statistical analysis of data by one-way or two-way ANOVA, with P < 0.05 as the standard for significant differences.

[0570] 10.4 Experimental results:

[0571] Compared with the vehicle group, all groups of aleglitazar and compound 2 significantly reduced the levels of lipids, free fatty acids, and blood glucose, and significantly increased body weight.

[0572] 10.4.1 Animal weight

[0573] Fig.54 The figure shows the changes in body weight of db / db model animals treated with aleglitazar and different doses of compound 2. Fig.54 As shown, during the experiment, the body weight of animals in the dose groups of Aleglitazar (0.2 mg / kg) and Compound 2 (0.05 mg / kg, 0.2 mg / kg, 1 mg / kg) gradually increased over time, and the average daily body weight (Day 10 to Day 15) was significantly higher than that of the vehicle group.

[0574] 10.4.2 Animal blood biochemical indicators

[0575] The blood biochemical indexes TG of the animals were measured on the 6th and 12th days, and Fig.55A and 55B The results are shown. Fig.55A and 55BAs shown, on days 6 and 12, the serum TG levels of the groups treated with different doses of aleglitazar or compound 2 were significantly lower than those of the vehicle group, with the maximum effect observed in group 6 (compound 2, 1 mg / kg).

[0576] 10.4.3 Random Blood Glucose

[0577] Fig.56 The effects of aleglitazar and different doses of compound 2 on random blood glucose of db / db model animals during the experimental period are shown. Compared with the vehicle group, the random blood glucose levels of animals treated with different doses of aleglitazar or compound 2 were reduced on the 7th day. Such reductions reached statistical significance in the 3rd group (aglitazar, 0.2mg / kg) and the 6th group (compound 2, 1mg / kg), but did not reach statistical significance in the 4th and 5th groups (compound 2, 0.05mg / kg and 0.2mg / kg). On the 14th day, compared with the 7th day, a more significant blood glucose lowering effect was observed in the 6th group (compound 2, 1mg / kg) to the 2nd group (vehicle), while the 3rd and 5th groups (aglitazar, 0.2mg / kg, and compound 2, 0.2mg / kg) showed similar effects. On the other hand, such effects in the 3rd group (compound 2, 0.05mg / kg) still did not reach statistical significance. Therefore, compared with aleglitazar, compound 2 had a slightly weaker effect on lowering blood glucose (Table 50).

[0578] Table 50. Statistical differences in blood glucose levels between each treatment group and the vehicle group

[0579]

[0580] 10.4.4 Glucose tolerance test in animals

[0581] At the end of the experiment, db / db animals treated with different compounds were subjected to an oral glucose tolerance test. Within 120 minutes after the test, Fig.57A and 57B The blood glucose value and the area under the blood glucose-time curve at each time point are shown. Compared with the vehicle group, the blood glucose levels of different doses of aleglitazar and compound 2 at each time point were significantly reduced. Among them, the AUC values ​​of the test products aleglitazar (0.2 mg / kg, P<0.001) and compound 2 (0.2 mg / kg, P<0.01 and 1 mg / kg, P<0.0001) were significantly lower than those of the vehicle group. 0-120分钟 Significantly lower than the AUC of the vehicle group 0-120分钟 In addition, compared with aleglitazar, the AUC of compound 2 at the same dose level (0.2 mg / kg) was 0-120分钟This indicates that PPARγ activity is lower. In addition, the results of Group 4 (Compound 2, 0.05 mg / kg) showed a downward trend compared with the vehicle group, but did not reach statistical significance at all time points.

[0582] Table 51: Statistical differences in blood glucose levels for each OGTT treatment group versus the vehicle group at each time point.

[0583]

[0584]

[0585] Note: Statistical analysis of OGTT vs. vehicle (two-way ANOVA followed by Dunnett's test performed by Prism Graphpad)

[0586] 10.5 Discussion

[0587] In the present disclosure, a novel compound, ie, Compound 2, having better α / γ activity was obtained.

[0588] In vitro transcriptional activity experiments showed that the compounds activated the ECs of PPARα and PPARγ pathways. 50 At the nanomolar level, it indicates that compound 2 has good in vitro biological activity. Compared with aleglitazar, compound 2 shows excellent PPARα agonist activity and weaker PPARγ agonist ability.

[0589] The hyperlipidemia rat model experiment showed that compound 2 can effectively and significantly reduce the blood lipid level of animals. In addition, compound 2 at a low dose level has a better lipid-lowering effect than aleglitazar at a corresponding concentration. Therefore, the results show that compound 2 has better PPARα activity at a low dose level, thereby producing a better lipid-lowering effect.

[0590] The ICR mouse body weight experiment showed that after treatment with low-dose levels of compound 2, the weight of the animals was comparable to that of the control group, with no significant changes. In contrast, the same dose level of aleglitazar caused a significant increase in body weight. Since weight gain is a well-known side effect of PPARγ, this indicates that at low dose levels, the PPARγ activity of compound 2 is weaker than that of aleglitazar.

[0591] Studies on db / db mice have shown that compound 2 can effectively reduce blood glucose levels and triglyceride content in type II diabetic mice. This suggests that compound 2 can demonstrate the in vivo biological effects of PPARγ on blood glucose control. In addition, compound 2 at the same dose level can achieve a similar hypoglycemic effect as aleglitazar. Therefore, the agonistic effect of compound 2 on the PPARγ pathway is sufficient to achieve the regulation of glucose homeostasis.

[0592] Example 11: Pharmacodynamic Model of Diabetic Nephropathy

[0593] 11.1 Experimental Methods

[0594] 11.1.1 Animals: Five-week-old wild-type mice and db / db:BLKS male mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. The animals were housed in an SPF environment with a 12-hour light / dark cycle. The housing temperature was maintained at 22°C-26°C, and the humidity was maintained at 40%-60%. Mice were allowed ad libitum access to food and water. At 6 weeks of age, db / db mice were anesthetized with 2.5% isopentane and underwent unilateral nephrectomy with removal of the right kidney. Buprenorphine was applied after the surgery.

[0595] 11.1.2 Procedure: Two weeks after surgery, db / db mice were randomly divided into 5 groups. Wild-type mice were used for control animals. Then, a total of 5 animal groups were included in this study: Group 1, a control group including 6 animals dosed with vehicle; Group 2, a vehicle group including 10 animals dosed with vehicle; Group 3, a compound-low group including 10 animals dosed with compound 2 at 0.1 mg / kg; Group 4, a compound-medium group including 10 animals dosed with compound 2 orally at 0.3 mg / kg; and Group 5, a compound-high group including 10 animals dosed with compound 2 at 1 mg / kg. The compound was orally administered once daily for 10 weeks.

[0596] 11.1.3 Formulations: Formulations were prepared twice a week. 1. Vehicle: 0.5% sodium carboxymethylcellulose. 2.5 g sodium carboxymethylcellulose was weighed and mixed with 500 ml ddH2O until completely dissolved. 2. Working solution for 1 mg / kg administration: 0.2 mg / ml working solution. 6 mg of compound was added to 30 ml 0.5% sodium carboxymethylcellulose and then vortexed until completely suspended. 3. Working solution for 0.3 mg / kg administration: 0.06 mg / ml working solution. 6 ml of 0.1 mg / ml compound solution was mixed with 14 ml 0.5% sodium carboxymethylcellulose and then stirred until completely suspended. 4. Working solution for 0.1 mg / kg administration: 0.02 mg / ml working solution. 2 ml of 0.2 mg / ml compound solution was mixed with 18 ml 0.5% sodium carboxymethylcellulose and then stirred until completely suspended.

[0597] 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 for renal dissection. Kidneys were fixed in 10% neutral buffered formalin and then paraffin embedded for histopathological analysis. Glomerulosclerosis was assessed by evaluating glomerular basement membrane, mesangial expansion, tuberous sclerosis, and glomerular sclerosis. Severity was graded as follows: 0: normal; 1: glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild nonspecific changes by light microscopy; 2: mild (IIa) or severe (IIb) mesangial expansion: glomeruli with mild or severe mesangial expansion in more than 50% of the glomeruli but without tuberous sclerosis or global glomerulosclerosis; 3: tuberous sclerosis: at least one glomerulus with nodular increase in mesangial matrix; 4: advanced diabetic glomerulosclerosis: more than 50% of global glomerulosclerosis with other clinical or pathological evidence that sclerosis is attributable to diabetic nephropathy. Tubular damage was scored as follows: 0: no obvious lesions; 1: up to 25% tubular lesions; 2: lesions of 25% to 50% of the tubules; 3: 50% to 75% tubular lesions; and grade 4: >75% tubular lesions.

[0598] 11.1.4 Data are expressed as mean + SEM. Graphpad 8.0 software was used for statistical analysis. Differences between values ​​were analyzed using one-way ANOVA. Differences between histopathological scores were analyzed using Kruskal-Wallis nonparametric test. All values ​​were compared with Group 2.

[0599] 11.2 Results: 1. 24-hour urine albumin: In vehicle-treated unilaterally nephrectomized db / db mice, 24-hour urine albumin increased more than 10-fold compared to controls. Compound 2 significantly reduced 24-hour urine albumin at weeks 5 and 9 after compound administration. Treatment with Compound 2 achieved a reduction in urine albumin of more than 50% ( Fig.58 2. Glomerular sclerosis: Fig.59A As shown in Figure 2, control animals had normal glomerular appearance and glomerular volume. However, mesangial expansion, glomerular basement membrane thickening, and tuberous sclerosis were observed in vehicle-treated db / db animals. Compound 2 inhibited glomerular damage and improved glomerular hypertrophy. After animals received a high dose of Compound 2, both histopathological scores and glomerular volume were statistically significantly reduced ( Fig.59B and 59C). 3. Renal tubular injury: Histopathological analysis showed that the control animals had normal renal tubular structure, but the animals treated with the vehicle had tubular dilatation, basement membrane thickening / tubular atrophy and tubular shedding. Compound 2 at all dose levels improved renal tubular injury to some extent ( Fig.59D ).

[0600] Example 12: Effect of Compound 2 on the Improvement of Renal Injury in a Rat Model with Unilateral Ureteral Obstruction

[0601] 12.1 Experimental methods:

[0602] 12.1.1 Male SD rats weighing 240-260 g were housed in an SPF environment with a 12-hour light / dark cycle. The housing temperature was maintained at 20°C-26°C, and the humidity was maintained at 40%-60%. The rats were fed a standard diet and allowed to access food and water ad libitum.

[0603] 12.1.2 Formulation: Formulations were prepared twice a week. 1. Vehicle: Prepare 0.5% sodium carboxymethylcellulose as described in 17.1.3. 2. 0.2 mg / ml solution of Compound 2 or Aleglitazar. Add 6 mg of compound to 30 ml of 0.5% sodium carboxymethylcellulose and then vortex until completely suspended. 3. 0.02 mg / ml solution of Compound 2 or Aleglitazar, dosed at 0.2 mg / kg. Mix 2 ml of 0.2 mg / ml solution with 18 ml of 0.5% sodium carboxymethylcellulose and then stir until completely suspended.

[0604] 12.1.3 Procedure: After adaptation, the animals were randomly divided into the following groups: a control group of 8 rats administered with 10 ml / kg of vehicle; a model group of 10 rats administered with 10 ml / kg of vehicle; a reference group of 10 animals administered with 0.2 mg / kg of aleglitazar; and a compound group of 10 animals administered with 0.2 mg / kg of compound 2. Vehicle or compound was administered orally by gavage every day. Unilateral ureteral obstruction was performed on the second day of compound treatment. Animals in the model group, reference group, and compound group were urethral ligated under isoflurane anesthesia one hour after receiving compound administration. A flank incision was cut to expose the left ureter, and two-point ligation was performed using 4-0 surgical sutures to achieve urethral obstruction. The ureter was cut between the two ligature points. In addition to ligation and cutting, the animals in the control group were subjected to the same surgical treatment. After surgery, the animals in each group received vehicle or compound continuously for more than 12 days, for a total of 14 treatment days.

[0605] Rats were killed after 14 days of compound treatment. Obstructed kidneys were weighed and collected for histology. Tissue samples were fixed with formalin and then paraffin embedded. Embedded tissue sections were stained with hematoxylin and eosin and Masson trichrome to assess renal structure and fibrosis. Focal lesions include defects, tubular dilatation, tubular obstruction and necrosis, which are given scores between 0 and 4 according to the percentage of the affected area of ​​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 score of the lesion. According to the area percentage stained with Masson trichrome, renal fibrosis was graded as 0-4 (score 0: none; 1: <25%; 2: 25%-50%, 3: 50%-75%, 4: >75%).

[0606] 12.1.4 Data are expressed as mean + SEM. Multiple comparisons were analyzed using the Kruskal-Wallis nonparametric test. Dunn's test was used to compare differences from the model group. p values ​​< 0.05 were considered statistically significant.

[0607] 12.1.5 Results: Compared with the model group administered with the vehicle, 0.2 mg / kg of Compound 2 significantly improved the total score of renal focal lesions including defects, tubular dilatation, tubular obstruction, fibrosis and necrosis ( Fig.60 ). On the other hand, at the same dose of 0.2 mg / kg, the reference compound aleglitazar did not achieve statistically significant improvement in the total score. Therefore, compound 2 is superior to aleglitazar in preventing and alleviating renal injury caused by unilateral ureteral obstruction.

[0608] The foregoing description is considered to be only an illustration of the principles of the present disclosure. Further, since many modifications and variations will be apparent to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and process shown as described above. Therefore, all suitable modifications and equivalents may be considered to fall within the scope of the present invention as defined by the appended claims.

Claims

1. A crystalline form B of compound 2: Features Its X-ray powder diffraction (XRPD) pattern includes the following peaks: 4.94°±0.2°, 8.16°±0.2°, 11.83°±0.2°, 13.23°±0.2°, 13.90°±0.2°, 14.97°±0.2°, 18.54°±0.2° and 26.24°±0.2°2θ.

2. Form B according to claim 1, wherein the XRPD pattern further comprises one or more peaks at 9.89°±0.2°, 19.74°±0.2° and 20.92°±0.2° 2θ.

3. Form B according to claim 1, characterized in that The XRPD pattern includes the following peaks:

4. Form B according to claim 1, characterized in that The XRPD pattern was substantially as shown in Figure 5A.

5. Form B according to claim 1, characterized in that Its differential scanning calorimetry (DSC) thermogram has an endothermic peak with a peak temperature of about 151.1°C.

6. Form B according to claim 5, characterized in that A DSC thermogram substantially as shown in Figure 5B.

7. The crystalline form B according to any one of claims 1 to 6, wherein the crystalline form B is an anhydrate.

8. A crystalline form C of compound 2: Features Its XRPD pattern includes the following peaks: 5.06°±0.2°, 10.09°±0.2°, 15.15°±0.2°, 16.18°±0.2°, 16.75°±0.2° and 20.24°±0.2° 2θ.

9. Form C according to claim 8, wherein the XRPD pattern further comprises one or more peaks at 7.99°±0.2°, 8.37°±0.2°, 11.71°±0.2°, 12.22°±0.2°, 12.87°±0.2°, 13.60°±0.2° and 14.04°±0.2° 2θ.

10. The crystalline form C according to claim 8, characterized in that The XRPD pattern includes the following peaks:

11. The crystalline form C according to claim 8, characterized in that The XRPD pattern was substantially as shown in Figure 6A.

12. The crystalline form C according to claim 8, characterized in that Its DSC thermogram has an endothermic peak with a peak temperature of about 149.0°C.

13. The crystalline form C according to claim 12, characterized in that A DSC thermogram substantially as shown in Figure 6B.

14. The crystalline form C according to any one of claims 8 to 13, wherein the crystalline form C is an anhydrate.

15. A crystalline form D of compound 2: Features Its XRPD pattern includes the following peaks: 5.03°±0.2°, 5.90°±0.2°, 9.21°±0.2°, 12.98°±0.2°, 15.91°±0.2°, 20.47°±0.2°, 21.58°±0.2° and 26.08°±0.2° 2θ.

16. Form D according to claim 15, wherein the XRPD pattern further comprises one or more peaks at 11.76°±0.2°, 15.04°±0.2°, 22.38°±0.2° and 24.47°±0.2° 2θ.

17. The crystalline form D according to claim 15, characterized in that The XRPD pattern includes the following peaks:

18. The crystalline form D according to claim 15, characterized in that The XRPD pattern is substantially as shown in Figure 7.

19. The crystalline form D according to any one of claims 15 to 18, wherein the crystalline form D is a hydrate.

20. A crystalline form E of compound 2: Features Its XRPD pattern includes the following peaks: 5.06°±0.2°, 8.14°±0.2°, 10.12°±0.2°, 11.97°±0.2°, 13.02°±0.2°, 13.73°±0.2°, 14.19°±0.2° and 18.89°±0.2° 2θ.

21. Form E according to claim 20, wherein the XRPD pattern further comprises one or more peaks at 14.87°±0.2°, 21.30°±0.2°, 22.33°±0.2° and 26.23°±0.2° 2θ.

22. The crystalline form E according to claim 20, characterized in that Its XRPD pattern Includes the following peaks:

23. The crystalline form E according to claim 20, characterized in that The XRPD pattern is substantially as shown in Figure 12.

24. The crystalline form E according to any one of claims 20 to 23, wherein the crystalline form E is an anhydrate.

25. A crystalline form F of compound 2: Features Its XRPD pattern includes the following peaks: 12.12°±0.2°, 15.50°±0.2°, 20.21°±0.2° and 21.23°±0.2° 2θ.

26. Form F according to claim 25, characterized in that Its XRPD pattern Includes the following peaks:

27. Form F according to claim 25, characterized in that An XRPD pattern substantially as shown in Figure 14A.

28. Form F according to claim 25, characterized in that The DSC thermogram thereof has endothermic peaks with peak temperatures of about 111.2°C and / or about 149.8°C.

29. Form F according to any one of claims 25, characterized in that Its DSC thermogram has an exothermic peak with a peak temperature of about 118.9°C.

30. Form F according to claim 29, characterized in that A DSC thermogram substantially as shown in Figure 14B.

31. The crystalline Form F according to any one of claims 25 to 30, wherein the crystalline Form F is a hydrate.

32. A crystalline form G of compound 2: Features Its XRPD pattern includes the following peaks: 8.16°±0.2°, 9.67°±0.2°, 11.60°±0.2°, 12.90°±0.2°, 13.69°±0.2°, 13.91°±0.2°, 14.43°±0.2°, 16.15°±0.2°, 18.51°±0.2°, 18.93°±0.2° and 20.47±0.2°2θ.

33. Form G according to claim 32, wherein the XRPD pattern further comprises one or more peaks at 4.95°±0.2°, 11.83°±0.2°, 13.22°±0.2° and 19.84°±0.2° 2θ.

34. Form G according to claim 32, characterized in that Its XRPD pattern Includes the following peaks:

35. Form G according to claim 32, characterized in that An XRPD pattern substantially as shown in Figure 15A.

36. Form G according to claim 32, characterized in that The DSC thermogram thereof has endothermic peaks with peak temperatures of about 72.4°C and / or about 83.1°C.

37. Form G according to claim 36, characterized in that A DSC thermogram substantially as shown in Figure 15B.

38. The crystalline Form G according to any one of claims 32 to 37, wherein the crystalline Form G is a DMSO solvate.

39. A salt of compound 2: The salt of compound 2 is the tromethamine salt of compound 2.

40. A salt of compound 2: The salt of compound 2 is in the form A of the sodium salt of compound 2, and the form A is characterized in that its XRPD spectrum includes the following peaks: 4.09°±0.2°, 4.62°±0.2°, 14.21°±0.2°, 16.43°±0.2° and 17.72°±0.2°2θ.

41. The salt of Compound 2 according to claim 40, wherein the crystalline Form A of the sodium salt is characterized in that its XRPD pattern comprises the following peaks:

42. The salt of Compound 2 according to claim 40, wherein Form A of the sodium salt is characterized by an XRPD pattern substantially as shown in Figure 24A.

43. The salt of Compound 2 according to claim 40, wherein the crystalline Form A of the sodium salt is characterized in that its DSC thermogram has an endothermic peak with a peak temperature of about 163.5°C and / or about 204.0°C.

44. The salt of Compound 2 according to claim 40, wherein the crystalline Form A of the sodium salt is characterized by a DSC thermogram having an exothermic peak with a peak temperature of about 166.5°C.

45. The salt of Compound 2 according to claim 44, wherein Form A of the sodium salt is characterized by a DSC thermogram substantially as shown in Figure 24B.

46. ​​A salt of compound 2: The salt of compound 2 is in the form C of the potassium salt of compound 2, and the form C is characterized in that its XRPD spectrum includes the following peaks: 12.91°±0.2°, 14.12°±0.2°, 14.96°±0.2°, 20.68°±0.2°, 21.23°±0.2°, 25.17°±0.2° and 26.46°±0.2°2θ.

47. The salt of Compound 2 according to claim 46, wherein the XRPD pattern further comprises one or more peaks at 3.92°±0.2°, 18.08°±0.2°, 22.48°±0.2°, 24.70°±0.2°, and 25.81°±0.2° 2θ.

48. The salt of Compound 2 according to claim 46, wherein Form C of the potassium salt is characterized in that its XRPD pattern comprises the following peaks:

49. The salt of Compound 2 according to claim 46, wherein Form C of the potassium salt is characterized by an XRPD pattern substantially as shown in Figure 26A.

50. The salt of Compound 2 according to claim 46, wherein Form C of the potassium salt is characterized in that its DSC thermogram has endothermic peaks with peak temperatures of about 108.1°C, about 140.2°C, and / or about 161.3°C.

51. The salt of Compound 2 according to claim 50, wherein Form C of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 26B.

52. A salt of compound 2: The salt of compound 2 is in the form A of the arginine salt of compound 2, and the form A is characterized in that its XRPD spectrum includes the following peaks: 10.91°±0.2°, 12.93°±0.2°, 13.43°±0.2°, 15.83°±0.2°, 18.21°±0.2°, 19.14°±0.2°, 19.49°±0.2°, 20.93°±0.2°, 21.15°±0.2° and 22.02°±0.2°2θ.

53. The salt of Compound 2 according to claim 52, wherein the XRPD pattern further comprises one or more peaks at 11.34°±0.2°, 19.84°±0.2°, 20.45°±0.2°, 25.63°±0.2°, and 26.15°±0.2° 2θ.

54. The salt of Compound 2 according to claim 52, wherein the crystalline Form A of the arginine salt is characterized in that its XRPD pattern comprises the following peaks:

55. The salt of Compound 2 according to claim 52, wherein Form A of the arginine salt is characterized by an XRPD pattern substantially as shown in Figure 28A.

56. The salt of Compound 2 according to claim 52, wherein the crystalline Form A of the arginine salt is characterized in that its DSC thermogram has an endothermic peak with a peak temperature of about 195.2°C.

57. The salt of Compound 2 according to claim 56, wherein Form A of the arginine salt is characterized by a DSC thermogram substantially as shown in Figure 28B.

58. A salt of compound 2: The salt of Compound 2 is in the form A of the potassium salt of Compound 2, and the form A is characterized by an XRPD pattern substantially as shown in the upper curve of Figure 19A.

59. The salt of Compound 2 according to claim 58, wherein Form A of the potassium salt is characterized in that its DSC thermogram has endothermic peaks with peak temperatures of about 91.1°C, about 135.8°C and / or about 147.7°C.

60. The salt of Compound 2 according to claim 59, wherein Form A of the potassium salt is characterized by a DSC thermogram substantially as shown in Figure 19B.

61. A salt of compound 2: The salt of Compound 2 is in the form of the potassium salt of Compound 2, Form B being characterized by an XRPD pattern substantially as shown in the lower curve of FIG. 19A .

62. A salt of compound 2: The salt of Compound 2 is in the form A of the magnesium salt of Compound 2, and the form A is characterized by an XRPD pattern substantially as shown in FIG. 21A .

63. The salt of Compound 2 according to claim 62, wherein Form A of the magnesium salt is characterized in that its DSC thermogram has endothermic peaks with peak temperatures of about 90.7°C, about 114.9°C, about 134.0°C and / or about 154.2°C.

64. The salt of Compound 2 according to claim 63, wherein Form A of the magnesium salt is characterized by a DSC thermogram substantially as shown in Figure 21B.

65. The salt of Compound 2 according to claim 39, wherein the salt of Compound 2 is in Form A of the tromethamine salt of Compound 2, wherein the Form A is characterized by an XRPD pattern substantially as shown in Figure 22A.

66. The salt of Compound 2 according to claim 65, wherein the crystalline Form A of the tromethamine salt is characterized in that its DSC thermogram has endothermic peaks with peak temperatures of about 71.8°C, about 76.6°C, about 113.9°C and / or about 213.1°C.

67. The salt of Compound 2 according to claim 66, wherein Form A of the tromethamine salt is characterized by a DSC thermogram substantially as shown in Figure 22B.

68. 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 Form B according to any one of claims 1 to 7, Form C according to any one of claims 8 to 14, Form D according to any one of claims 15 to 19, Form E according to any one of claims 20 to 24, Form F according to any one of claims 25 to 31, and Form G according to any one of claims 32 to 38.

69. A pharmaceutical composition comprising a salt of Compound 2 according to any one of claims 39 to 67 and a pharmaceutically acceptable excipient.

70. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 40 to 45, wherein at least 50% of the salt of Compound 2 is in Form A of the sodium salt.

71. The pharmaceutical composition of claim 70, wherein at least 95% of the salt of Compound 2 is in Form A of the sodium salt.

72. The pharmaceutical composition of claim 70, wherein at least 99% of the salt of Compound 2 is in Form A of the sodium salt.

73. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 46 to 51, wherein at least 50% of the salt of Compound 2 is in Form C of the potassium salt.

74. The pharmaceutical composition of claim 73, wherein at least 95% of the salt of Compound 2 is in Form C of the potassium salt.

75. The pharmaceutical composition of claim 73, wherein at least 99% of the salt of Compound 2 is in Form C of the potassium salt.

76. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 52 to 57, wherein at least 50% of the salt of Compound 2 is in Form A of the arginine salt.

77. The pharmaceutical composition of claim 76, wherein at least 95% of the salt of Compound 2 is in Form A of the arginine salt.

78. The pharmaceutical composition of claim 76, wherein at least 99% of the salt of Compound 2 is in Form A of the arginine salt.

79. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 58 to 60, wherein at least 50% of the salt of Compound 2 is in Form A of the potassium salt.

80. The pharmaceutical composition of claim 79, wherein at least 95% of the salt of Compound 2 is in Form A of the potassium salt.

81. The pharmaceutical composition of claim 79, wherein at least 99% of the salt of Compound 2 is in Form A of the potassium salt.

82. The pharmaceutical composition of claim 69, comprising the salt of Compound 2 of claim 61, wherein at least 50% of the salt of Compound 2 is in Form B of the potassium salt.

83. The pharmaceutical composition of claim 82, wherein at least 95% of the salt of Compound 2 is in Form B of the potassium salt.

84. The pharmaceutical composition of claim 82, wherein at least 99% of the salt of Compound 2 is in Form B of the potassium salt.

85. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 62 to 64, wherein at least 50% of the salt of Compound 2 is in Form A of the magnesium salt.

86. The pharmaceutical composition of claim 85, wherein at least 95% of the salt of Compound 2 is in Form A of the magnesium salt.

87. The pharmaceutical composition of claim 85, wherein at least 99% of the salt of Compound 2 is in Form A of the magnesium salt.

88. The pharmaceutical composition of claim 69, comprising a salt of Compound 2 according to any one of claims 65 to 67, wherein at least 50% of the salt of Compound 2 is in Form A of the tromethamine salt.

89. The pharmaceutical composition of claim 88, wherein at least 95% of the salt of Compound 2 is in Form A of the tromethamine salt.

90. The pharmaceutical composition of claim 88, wherein at least 99% of the salt of Compound 2 is in Form A of the tromethamine salt.

91. Use of a crystalline form of Compound 2 or a salt of Compound 2 according to any one of claims 1 to 67 or a pharmaceutical composition according to any one of claims 68 to 90 in the preparation of a medicament for treating and / or preventing a disease regulated by a PPARα and / or PPARγ agonist.

92. The use according to claim 91, wherein the disease is diabetes, hypertension, dyslipidemia, atherosclerotic disease, metabolic syndrome or diabetic nephropathy.

93. The use according to claim 92, wherein the diabetes is non-insulin dependent diabetes.

94. The use according to claim 91, wherein the disease is renal damage.

95. The use according to claim 94, wherein the renal injury is caused by ureteral obstruction.

96. The use according to claim 94, wherein the renal injury is caused by unilateral ureteral obstruction.

Images