Crystalline form of N-{[(S)-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl][4-(trifluoromethyl)benzenesulfonamido]methylidene}amino]methanimidoyl}acetamide

Abstract

Compounds of Formula I: A crystalline form of JPEG2025506454000055.jpg38170(I) is provided. Crystalline form C is one of the crystalline forms that has been identified. Form C has an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86, and a differential scanning calorimetry (DSC) thermogram exhibiting an endotherm with an onset of 157.1° C.

Description

[Technical field]

[0001] The technical field relates to crystalline forms of the compound N-N'-((S)-3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)carbamimidoyl)acetamide, as well as pharmaceutical compositions, therapeutic uses thereof, and methods of preparation. [Background technology]

[0002] It is commonly known that activation of the cannabinoid CB1 receptor increases appetite, increases lipid biosynthesis and storage, inhibits the action of insulin and leptin, and promotes inflammation and fibrosis. Thus, research has focused on developing CB1 receptor inhibitors for the potential treatment of obesity and its associated metabolic disorder, called metabolic syndrome. Rimonabant was shown to be effective in treating metabolic syndrome, but it caused neuropsychiatric (i.e., CNS-related) side effects, which led to its withdrawal from the market.

[0003] Compounds that do not interact with CB1 receptors in brain tissue, while preferentially targeting CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophages, splenic beta cells, and gastrointestinal tract), thereby avoiding or reducing CNS-related side effects, are disclosed by George Kunos et al. in U.S. Patent No. 5,333,363.

[0004] One of the compounds is N-{[(S)-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl][4-(trifluoromethyl)benzenesulfonamido]methylidene}amino]methanimidoyl}acetamide, for which it is desirable to identify a stable crystalline form that may be suitable for therapeutic use. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 9,765,031 Summary of the Invention

[0006] In one embodiment, a compound of formula I, [ka] A compound is provided that is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86.

[0007] In some embodiments, the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 7.46, 22.15, and 26.24.

[0008] In some embodiments, the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 9.85, 19.07, and 22.77.

[0009] In some embodiments, the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 3.81, 17.17, and 20.84.

[0010] In some embodiments, the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 17.95, 15.43, and 24.24.

[0011] In another embodiment, the compound of formula I is [ka] is provided, which is crystalline and has a differential scanning calorimetry (DSC) thermogram exhibiting an endotherm with an onset of about 157.1°C.

[0012] In another embodiment, the compound of formula I is [ka] A compound is provided which is crystalline and has a differential scanning calorimetry (DSC) thermogram exhibiting an endotherm with a peak temperature of about 167.9°C.

[0013] In another embodiment, the compound of formula I is [ka] Provided is a compound having an X-ray powder diffraction pattern substantially the same as that shown in Figure 4A - Form C.

[0014] In another embodiment, the compound of formula I is [ka] A compound is provided that is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.89 and 17.39.

[0015] In some embodiments, the XRPD pattern further has characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 9.39 and 17.80.

[0016] In some embodiments, the XRPD pattern further has a characteristic peak expressed in degrees 2θ (±0.2° 2θ) of 12.96.

[0017] In some embodiments, the XRPD pattern further has a characteristic peak expressed in degrees 2θ (±0.2° 2θ) of 19.85.

[0018] In some embodiments, the XRPD pattern further has a characteristic peak expressed in degrees 2θ (±0.2° 2θ) of 16.96.

[0019] In another embodiment, the compound of formula I is [ka] A compound is provided which is crystalline and has a differential scanning calorimetry (DSC) thermogram exhibiting an endotherm with an onset of about 152.2°C.

[0020] In another embodiment, the compound of formula I is [ka] A compound is provided which is crystalline and has a differential scanning calorimetry (DSC) thermogram exhibiting an endotherm with a peak temperature of about 162.3°C.

[0021] In another embodiment, the compound of formula I is [ka] A compound is provided having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 2A.

[0022] In some embodiments, the compound of formula I comprises one crystalline form with a purity of 95% or greater.

[0023] In some embodiments, the purity is 99% or greater.

[0024] In some embodiments, the purity is 99.8% or greater.

[0025] In some embodiments, the compound of formula I is substantially pure.

[0026] In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula I as described herein and a pharma- ceutically acceptable carrier or excipient.

[0027] In some embodiments, the pharmaceutical composition is formulated as an oral dosage form.

[0028] In some embodiments, the oral dosage form is a tablet, capsule, lozenge, lozenge, or granule.

[0029] In some embodiments, the pharmaceutical compositions are formulated as oral suspensions.

[0030] In another aspect, there is provided a use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the treatment of a disease or disorder selected from the group consisting of obesity (type 1 or type 2), non-alcoholic and alcoholic fatty liver disease (risk factor for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout.

[0031] In another aspect, there is provided a use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for the treatment of a disease or disorder selected from the group consisting of obesity (type 1 or type 2), non-alcoholic and alcoholic fatty liver disease (risk factor for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout.

[0032] In another aspect, there is provided a method for the treatment of a disease or disorder selected from the group consisting of obesity (type 1 or type 2), non-alcoholic and alcoholic fatty liver disease (risk factor for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout, comprising administering a compound of formula I as described herein or a pharmaceutical composition as described herein to a subject in need thereof.

[0033] In some embodiments, the comorbidities of obesity are selected from metabolic syndrome, dementia, cardiac disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcers, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.

[0034] In some embodiments, the comorbidities of diabetes (eg, type 1) are selected from diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0035] In some embodiments, the disease or disorder is selected from diabetes (type 1 or type 2), obesity, and non-alcoholic fatty liver disease (eg, non-alcoholic steatohepatitis).

[0036] In another embodiment, there is provided a process for preparing a compound of Formula I, Form C, as defined herein, comprising: suspending a first crystalline form of Formula I in water, wherein the first crystalline form exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ of 5.89 and 17.39 (±0.2° 2θ); subjecting the suspension to temperature cycling between a first temperature and a second temperature lower than the first temperature; and recovering the compound of formula I as a second crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86.

[0037] In some embodiments, the first temperature is between 45°C and 65°C.

[0038] In some embodiments, the first temperature is between 50°C and 60°C.

[0039] In some embodiments, the second temperature is between 5°C and 35°C.

[0040] In some embodiments, the second temperature is between 5°C and 25°C.

[0041] In some embodiments, the first temperature is about 60°C and the second temperature is about 25°C.

[0042] In some embodiments, the method further comprises stirring and maintaining the suspension at the second temperature between temperature cycling and recovering the second crystalline form.

[0043] In some embodiments, stirring and maintaining the suspension at the second temperature occurs for about 1 hour to about 12 hours.

[0044] In some embodiments, stirring and maintaining the suspension at the second temperature occurs for about 3 hours to about 6 hours.

[0045] In some embodiments, recovering the compound of formula I as a second crystalline form comprises filtering the suspension.

[0046] In another aspect, there is provided a method for preparing a compound of Formula I, Form C, as described herein, comprising: solubilizing a compound of formula I in a solvent selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol to obtain a solution; adding water to the solution until a solid precipitates; and recovering the compound of formula I as a crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86.

[0047] In some embodiments, the solvent is selected from the group consisting of methanol, ethanol, and n-propanol.

[0048] In some embodiments, the solvent is ethanol.

[0049] In some embodiments, solubilizing the compound of formula I in a solvent comprises solubilizing the compound of formula I as a crystalline form exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ of 5.89 and 17.39 (±0.2° 2θ).

[0050] In some embodiments, solubilizing the compound of formula I in the solvent is carried out at a first temperature between about 30° C. and the boiling point of the solvent.

[0051] In some embodiments, the first temperature is from about 35°C to about 60°C.

[0052] In some embodiments, the adding of water occurs at a first temperature.

[0053] In some embodiments, the method further comprises cooling the solvent / water mixture to a second temperature that is lower than the first temperature.

[0054] In some embodiments, the second temperature is from about 5°C to about 30°C.

[0055] In some embodiments, the second temperature is from about 20°C to about 30°C.

[0056] In some embodiments, the solvent:water ratio (by volume) is from about 1:1 to about 3:1.

[0057] In some embodiments, the ratio of solvent:water is from about 2:1 to about 3:1.

[0058] In some embodiments, recovering the compound of formula I comprises filtering and drying the compound of formula I.

[0059] In another embodiment, there is provided a process for preparing a compound of Formula I, Form C, as defined herein, comprising: providing a slurry of a first crystalline form of Formula I in a solvent selected from the group consisting of water, n-butanol, and an MIBK / n-heptane mixture, wherein the first crystalline form exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.89 and 17.39; agitating the slurry; and and recovering the compound of formula I as a crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86.

[0060] In some embodiments, the solvent is water.

[0061] In some embodiments, the solvent is a 1:4 (v / v) mixture of MIBK:n-heptane.

[0062] In some embodiments, the stirring of the slurry is performed at a temperature of about 50°C to about 70°C.

[0063] In some embodiments, the temperature is from about 55°C to about 65°C.

[0064] In some embodiments, the method further comprises adding a seed of a compound of Formula I, Form C to the mixture. [Brief description of the drawings]

[0065] [Figure 1A] FIG. 1A is a phase map of the anhydrous crystalline form of the compound of formula I. [Figure 1B] FIG. 1B is a phase interconversion map of the solvate and hydrate crystal forms of the compound of formula I. [Figure 2A] FIG. 2A is an XRPD of compound of Formula I, Form A. [Figure 2B] FIG. 2B is a graph including the TGA and DSC thermograms of Form A. [Figure 2C] FIG. 2C is an overlay XRPD of Form A and Form J. [Figure 3A] FIG. 3A is an overlay XRPD of Form A with Form I and Form B from temperature cycling in IPA. [Figure 3B] FIG. 3B is a graph including the TGA and DSC thermograms of Form B. [Figure 4A] FIG. 4A is an overlay XRPD of Form A and Form C obtained from temperature cycling in HO. [Figure 4B] FIG. 4B is a graph including the TGA and DSC thermograms of Form C. [Figure 5A] FIG. 5A is an overlay XRPD of Form A with Forms D and H obtained from temperature cycling in toluene. [Figure 5B] FIG. 5B is a graph including the TGA and DSC thermograms of Form D. [Figure 6A] FIG. 6A is an overlay XRPD of Form A with Forms E and P obtained from temperature cycling in IPAc / MTBE (1:3 v / v). [Figure 6B] FIG. 6B is a graph including the TGA and DSC thermograms of Form E. [Figure 6C] FIG. 6C is a graph containing a cycling DSC thermogram of Form E. [Figure 7A] FIG. 7A is an overlay XRPD of Form A with Forms G and F from a RT slurry in THF / H2O (0.92 / 0.08 v / v Aw=0.2 and 0.83 / 0.17 v / v Aw=0.4, respectively). [Figure 7B] FIG. 7B is a graph including the TGA and DSC thermograms of Form F. [Figure 8A] FIG. 8A is an overlay XRPD of Form A and Form K from crash cooling in anisole. [Figure 8B] FIG. 8B is a graph including the TGA and DSC thermograms of form K. [Figure 8C] FIG. 8C is an overlay XRPD of Form K and Form K heated to 90° C. and cooled back to room temperature. [Figure 9A] FIG. 9A is an overlay XRPD of Form A and Form L from crash cooling in anisole. [Figure 9B] FIG. 9B is a graph including the TGA and DSC thermograms of Form L. [Figure 10A] FIG. 10A is an overlay XRPD of Form A and Form M from crash cooling in IPAc. [Figure 10B] FIG. 10B is a graph including the TGA and DSC thermograms of Form M. [Figure 11A] FIG. 11A is an overlay XRPD of Form A and Form N obtained from temperature cycling in CHCl3 / n-heptane (1:3 v / v). [Figure 11B] FIG. 11B is a graph including the TGA and DSC thermograms of Form N. [Figure 12A]FIG. 12A is an overlay XRPD of Form A and Form O from slow evaporation in MeOH. [Figure 12B] FIG. 12B is a graph including the TGA and DSC thermograms of Form O. [Figure 13A] FIG. 13A is an overlay XRPD of Form A and Form Q from slow evaporation of slurry Form A in n-butanol at 100° C. [Figure 13B] FIG. 13B is a graph including the TGA and DSC thermograms of form Q. [Figure 14] FIG. 14 is an overlaid XRPD of a 5 gram scale-up batch showing that Form C was obtained. [Figure 15] FIG. 15 is an overlay of the simulated XRPD from single crystal X-ray diffraction data and the experimental XRPD pattern of Form B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] definition The term "stable" as used herein includes chemical stability and / or solid state stability. A compound is considered to be chemically stable if the compound can be stored under normal storage conditions without any significant degree of chemical deterioration or decomposition, either in isolated solid form or in the form of a solid formulation, which may be provided in admixture with a pharma- ceutically acceptable carrier, diluent, or adjuvant.

[0067] A compound is considered to have solid-state stability if the compound can be stored under normal storage conditions without any significant degree of solid-state alteration (e.g., crystallization, recrystallization, loss of crystallinity, solid-state phase transition, hydration, dehydration, deliquescence, solvation, or desolvation) in the form of a solid formulation, which may be provided in isolated solid form or in admixture with a pharma- ceutically acceptable carrier, diluent, or adjuvant.

[0068] The crystalline form of solid compounds not only affects their dissolution behavior (i.e., bioavailability), but also their solid-state stability. One way to compare the solid-state stability of crystalline forms is to evaluate their relative "thermodynamic stability". To evaluate the thermodynamic stability of crystalline forms, typical techniques include, but are not limited to, slurrying, slow evaporation, slow cooling, slow antisolvent addition, or a combination of these methods. Calorimetric techniques (e.g., differential scanning calorimetry) can be used to measure thermal events and phase transitions over a wide temperature range, and comparison between crystalline forms can provide an indication of their relative thermodynamic stability.

[0069] The expression "pharmaceutically acceptable carrier or excipient" as used herein includes, but is not limited to, any adjuvant, carrier, lubricant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier known to be acceptable for pharmaceutical use in humans or veterinary medicine.

[0070] The phrase "pharmaceutical composition," as used herein, refers to a formulation of a compound with a pharma- ceutically acceptable carrier or excipient.

[0071] The term "about" as used herein generally means within an acceptable standard error when examined by one of ordinary skill in the art. For example, depending on the value or range being examined, the term "about" can mean within 10%, within 5%, or within 1% of the value or range.

[0072] As used herein, the term "hydrate" refers to a crystalline form of a molecule in which water molecules are further incorporated into the crystal lattice structure. The water molecules in a hydrate may be present in an ordered arrangement and / or a disordered arrangement. A hydrate may contain either stoichiometric or non-stoichiometric amounts of water molecules. For example, a hydrate having a non-stoichiometric amount of water molecules may result from partial loss of water from a hydrate.

[0073] As used herein, the terms "anhydrate" or "anhydrous" further refer to the crystalline form of the molecule itself, in which no water molecules are incorporated into the crystal lattice structure.

[0074] As used herein, the term "solvate" further refers to a crystalline form of a molecule in which the solvent(s) molecules are incorporated into the crystal lattice structure. The solvent molecules in a solvate may be present in an ordered arrangement and / or a disordered arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. For example, a solvate having a non-stoichiometric amount of solvent molecules may result from partial loss of solvent from a solvate. The solvent may include various organic solvents. It should also be understood that a "solvate" may include a single solvent, a mixture of solvents, or a mixture of a solvent(s) and water.

[0075] The term "substantially the same" as used herein to describe an X-ray diffraction pattern is meant to include a pattern in which the peaks are within a standard deviation of ±0.2° 2θ, or an X-ray diffraction pattern in which at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 peaks are in common with the reference pattern. Furthermore, one skilled in the art will appreciate that the relative peak intensities will show variability between instruments, as well as variability due to the degree of crystallinity, preferred orientation, sample surface prepared, and other factors. Thus, the relative peak intensities should be understood as a qualitative measure.

[0076] The present specification provides a crystalline form of the compound of formula I. [ka] The structures depicted for the compounds of formula I are also meant to include all tautomeric forms of the compounds of formula I. In addition, the structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14Compounds having the structure of the compounds of formula I except for the replacement of a carbon with a C-enriched carbon are within the scope of this specification.

[0077] The term "substantially pure" when used in reference to a crystalline form of the compound of formula I, means to include a crystalline form having a purity of more than about 90%. This means that the crystalline form may not contain more than about 10% of any other compounds, and in particular does not contain more than about 10% of any other crystalline form of the compound of formula I. Preferably, the term "substantially pure" means a crystalline form having a purity of more than about 95%. This means that the crystalline form may not contain more than about 5% of any other compounds, and in particular does not contain more than about 5% of any other crystalline form of the compound of formula I. More preferably, the term "substantially pure" means a crystalline form having a purity of more than about 99%. This means that the crystalline form may not contain more than about 1% of any other compounds, and in particular does not contain more than about 1% of any other crystalline form of the compound of formula I.

[0078] The term "solid" or "solid mixture" when used in connection with a compound of formula I refers to a mixture of crystalline forms. For example, a solid or solid mixture may contain at least two different crystalline forms of a compound of formula I. For example, a solid mixture may contain crystalline form C and one or more additional crystalline forms, such as form A, form B, form D, form E, form F, form G, form H, form I, form J, form K, form L, form M, form N, form O, form P, and / or form Q.

[0079] XRPD data was obtained using a Panalytical™ X-ray powder diffractometer used in reflector mode. The radiation used was Cu Kα (λ=1.540598 Å). Of course, the 2θ values ​​recited herein depend on the form of radiation used, and one of skill in the art will understand that the XRPD of a given crystalline form will exhibit different 2θ values ​​when different radiation (e.g., molybdenum radiation) is used.

[0080] The term "optically pure," as used herein, refers to a compound that has a greater proportion of a desired enantiomer than that of the other enantiomer. An optically pure compound is generally made up of at least about 90%, 95%, or 99% of a desired enantiomer, based on 100% total weight of the compound.

[0081] As used herein, the term "crystalline form" or "polymorph" refers to crystal structures of compounds that have the same chemical composition but differ in the spatial arrangement of the molecules, atoms, and / or ions that form the crystal structures.

[0082] Seventeen crystalline forms are obtained from polymorph screening of the compound of formula I, including forms A through Q. Some of the crystalline forms can be converted to other crystalline forms, as detailed herein.

[0083] Form A Crystalline form A is anhydrous. According to DSC, form A has an endotherm with an onset of about 152.2° C. and a peak temperature of about 162.3° C. TGA analysis of form A shows a weight loss of about 0.01% up to 200° C.

[0084] Form A has an XRPD pattern substantially the same as that shown in FIG. 2A. Form A exhibits an XRPD pattern having characteristic peaks expressed at 5.89 and 17.39 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks expressed at 9.39 and 17.80 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks expressed at 12.96 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks expressed at 19.85 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form A may also exhibit additional characteristic peaks expressed at 16.96 degrees 2θ (±0.2° 2θ).

[0085] Form A can be prepared by anti-solvent addition of water to a solution of the compound of formula I in acetonitrile. Form A can also be prepared by anti-solvent addition of water to a solution of the compound of formula I in acetone. Form A can also be prepared by anti-solvent addition of heptane to a solution of the compound of formula I in acetone. Form A can be prepared by anti-solvent addition of MTBE to a solution of the compound of formula I in acetonitrile.

[0086] Form A can be prepared by dissolving the compound of formula I in a solvent and evaporating the solvent until a crystalline material is formed (e.g., slow evaporation crystallization). The solvent can be selected from the group consisting of, for example, DCM, CHCl3, MEK, and acetonitrile.

[0087] Form A can also be prepared by slow cooling a solution of the compound of formula I in a solvent or solvent mixture selected from the group consisting of IPA, toluene, MTBE, EtOH / n-heptane, and CHCl3 / MTBE. For example, the solvent mixture can have the following ratio (v:v): EtOH / n-heptane (1:4) and CHCl3 / MTBE (1:4).

[0088] Form A can also be prepared by triturating a compound of formula I in DCM / n-heptane (e.g., 1 / 1 v / v). Trituration can be carried out, for example, at a temperature of about 25° C. to about 35° C.

[0089] Form B Crystalline form B is an IPA solvate. According to DSC, form B has an endotherm with an onset of about 126.4° C. and a peak temperature of about 136.3° C. TGA analysis of form B shows a weight loss of about 5.34% up to 174.0° C.

[0090] Form B has an XRPD pattern substantially the same as that shown in Figure 3A (Form B). Form B exhibits an XRPD pattern having characteristic peaks expressed at 6.60, 6.83, and 15.02 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks expressed at 9.09 and 9.73 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks expressed at 15.40 and 9.88 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks expressed at 21.90, 19.84, and 14.32 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form B may also exhibit additional characteristic peaks expressed at 26.56, 15.82, and 23.39 degrees 2θ (±0.2° 2θ).

[0091] Form C Crystalline form C is anhydrous. According to DSC, form C has an endotherm with an onset of about 157.1° C. and a peak temperature of about 167.9° C. TGA analysis of form C shows a weight loss of about 0.32% up to 175.0° C.

[0092] Form C has an XRPD pattern substantially the same as that shown in Figure 4A (Form C). Form C exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.86. The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 7.46, 22.15, and 26.24. The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 3.81, 17.17, and 20.84. The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 17.95, 15.43, and 24.24. The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed at 21.53, 25.11, and 23.34 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed at 14.94, 27.38, and 28.41 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form C may also exhibit additional characteristic peaks expressed at 30.57, 12.94, and 14.50 degrees 2θ (±0.2° 2θ).

[0093] Form C can be prepared by suspending the compound of formula I, Form A, in water, subjecting the suspension to temperature cycling between a first temperature and a second temperature lower than the first temperature, and recovering Form C. In some embodiments, the first temperature is 45° C. to 65° C. or about 50° C. to about 60° C. In some embodiments, the second temperature is about 5° C. to about 35° C. or about 5° C. to about 25° C. In some embodiments, the first temperature is about 60° C. and the second temperature is about 25° C. In some embodiments, preparing Form C further comprises stirring and maintaining the suspension at the second temperature between temperature cycling and recovering Form C. In some embodiments, stirring and maintaining the suspension at the second temperature is performed for about 1 hour to about 12 hours, or about 3 hours to about 6 hours, or about 4.5 hours. In some embodiments, preparing Form C further comprises recovering the compound of formula I as a second crystalline form, including filtering the suspension.

[0094] Form C can also be prepared by solubilizing the compound of formula I in a solvent selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol to obtain a solution, adding water to the solution until a solid precipitates, and recovering the precipitated solid as Form C. In some embodiments, the solvent is selected from the group consisting of methanol, ethanol, and n-propanol. In some embodiments, the solvent is ethanol. In some embodiments, solubilizing the compound of formula I in the solvent comprises solubilizing the compound of formula I as Form A. In some embodiments, solubilizing the compound of formula I in the solvent is performed at a first temperature between about 30° C. and the boiling point of the solvent. In some embodiments, the first temperature is about 35° C. to about 60° C. In some embodiments, adding water is performed at the first temperature. In some embodiments, preparing Form C further comprises cooling the solvent / water mixture to a second temperature lower than the first temperature. In some embodiments, the second temperature is about 5° C. to about 30° C. or about 20° C. to about 30° C. In some embodiments, the ratio of solvent:water (v / v) is about 1:1 to about 3:1 or about 2:1 to about 3:1. In some embodiments, recovering the compound of formula I, Form C, includes filtering and drying.

[0095] Form C can also be prepared by providing a slurry of the compound of formula I, Form A, in a solvent selected from the group consisting of water and an MIBK / n-heptane mixture, stirring the slurry, and obtaining the compound of formula I as Form C. In some embodiments, the solvent is water. In other embodiments, the solvent is a 1:4 (v / v) MIBK:n-heptane mixture. In some embodiments, stirring the slurry is performed at a temperature of about 50° C. to about 70° C. or about 55° C. to about 65° C.

[0096] As shown in FIG. 1A, Form C can also be prepared by slurrying any one of the anhydrous crystalline forms A, D, E, N, and Q in n-butanol at 25° C. or 50° C., converting the respective anhydrous crystalline form to Form C.

[0097] In some embodiments, Form C seeds can be added to any one of the methods for producing Form C described herein.

[0098] Form D Crystalline form D is anhydrous. According to DSC, form D has an endotherm with an onset of about 155.9° C. and a peak temperature of about 163.9° C. TGA analysis of form D shows a weight loss of about 0.07% up to 180.0° C.

[0099] Form D has an XRPD pattern substantially the same as that shown in Figure 5A (Form D). Form D exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.94, 11.27, and 11.86. The XRPD pattern of Form D may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 20.75, 8.82, and 24.74. The XRPD pattern of Form D may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 4.43, 22.79, and 19.66. The XRPD pattern of Form D may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 19.41, 12.34, and 26.91. The XRPD pattern of Form D may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 12.08 and 20.98. The XRPD pattern of Form D may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 18.53 and 16.89.

[0100] Form E Crystalline form E is anhydrous. According to DSC, form E has two endotherms with onsets at 120.6° C. and 146.0° C. and peak temperatures at 129.5° C. and 154.6° C., respectively. TGA analysis of form E shows a weight loss of about 0.317% up to 177.9° C.

[0101] Form E has an XRPD pattern substantially the same as that shown in Figure 6A (Form E). Form E exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.62, 8.95, and 8.01. The XRPD pattern of Form E may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 17.94, 22.30, and 24.31. The XRPD pattern of Form E may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 16.29, 12.82, and 18.83. The XRPD pattern of Form E may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 23.45, 26.11, and 20.62. The XRPD pattern of Form E may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 15.95 and 13.86. The XRPD pattern of Form E may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 25.65 and 10.22.

[0102] Form F Crystalline form F is a THF solvate. According to DSC, form F has a broad endotherm with an onset of about 119.5° C. and a peak temperature of about 132.4° C. TGA analysis of form F shows a weight loss of about 1.85% up to 165.0° C.

[0103] Form F has an XRPD pattern substantially the same as that shown in Figure 7A (Form F). Form F exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 7.51, 22.37, and 7.89. The XRPD pattern of Form F may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 18.95, 20.25, 17.62, and 11.22. The XRPD pattern of Form F may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 11.73, 23.13, 9.26, and 5.66. The XRPD pattern of Form F may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 12.53, 9.64, 15.69, and 4.17. The XRPD pattern of Form F may also exhibit additional characteristic peaks expressed at 19.91, 14.32, 12.22, and 13.51 degrees 2θ (±0.2° 2θ).

[0104] Form G Crystalline form G is an unstable solvate that converts to form F upon drying.

[0105] Form G has an XRPD pattern substantially the same as that shown in Figure 7A (Form G). Form G exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 18.86, 25.22, and 6.28. The XRPD pattern of Form G may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 38.23, 31.67, and 21.95. The XRPD pattern of Form G may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 10.88 and 8.36. The XRPD pattern of Form G may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 19.75 and 12.56. The XRPD pattern of Form G may also exhibit additional characteristic peaks expressed at 20.51 and 22.74 degrees 2θ (±0.2° 2θ).

[0106] Form H Crystalline form H is an unstable solvate that converts to form D upon drying.

[0107] Form H has an XRPD pattern substantially the same as that shown in Figure 5A (Form H). Form H exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.73, 10.90, and 11.45. The XRPD pattern of Form H may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 19.12, 16.68, and 18.86. The XRPD pattern of Form H may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 20.35, 23.96, 26.36, and 22.03. The XRPD pattern of Form H may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 24.18, 12.02, 22.62, and 15.90. The XRPD pattern of Form H may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 16.43, 6.01, 8.73, 20.84, and 4.36.

[0108] Form I Crystalline Form I is an unstable solvate that converts to Form B upon drying.

[0109] Form I has an XRPD pattern substantially the same as that shown in Figure 3A (Form I). Form I exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.28, 8.43, and 18.77. The XRPD pattern of Form I may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 17.18, 7.78, and 21.51. The XRPD pattern of Form I may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 11.77, 19.40, and 17.96. The XRPD pattern of Form I may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 10.39, 25.55, and 15.56. The XRPD pattern of Form I may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 9.00, 14.23, 23.00, and 15.25. The XRPD pattern of Form I may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 20.84, 16.47, 21.02, and 26.47.

[0110] Form J Crystalline form J is an unstable solvate that converts to form J upon drying.

[0111] Form J has an XRPD pattern substantially the same as that shown in Figure 2C (Form J). Form J exhibits an XRPD pattern having characteristic peaks expressed at 5.59 and 16.76 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form J may also exhibit additional characteristic peaks expressed at 9.35 and 22.43 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form J may also exhibit additional characteristic peaks expressed at 22.75, 21.63, and 26.63 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form J may also exhibit additional characteristic peaks expressed at 18.78, 21.11, and 24.05 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form J may also exhibit additional characteristic peaks expressed at 18.10, 24.62, and 16.17 degrees 2θ (±0.2° 2θ).

[0112] Form K Crystalline form K is a hemihydrate. According to DSC, form K shows two endothermic events with onsets of 53.6° C. and 106.3° C. and peak temperatures of 68.7° C. and 125.9° C., respectively. TGA analysis of form K shows a weight loss of about 1.35% up to 160.0° C.

[0113] Form K has an XRPD pattern substantially the same as that shown in Figure 8A (Form K). Form K exhibits an XRPD pattern having characteristic peaks expressed at 6.65 and 6.92 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form K may also exhibit additional characteristic peaks expressed at 26.74 and 20.02 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form K may also exhibit additional characteristic peaks expressed at 15.55 and 27.75 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form K may also exhibit additional characteristic peaks expressed at 15.13, 9.94, and 17.89 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form K may also exhibit additional characteristic peaks expressed at 13.79, 30.57, and 9.13 degrees 2θ (±0.2° 2θ).

[0114] Form L Crystalline form L is a partially desolvated anisole solvate with a stoichiometry API:anisole of about 0:0.26. According to DSC, form L shows a single endothermic event in the DSC curve after the solvent is driven off with an onset of 126.4° C. and a peak temperature of 133.8° C. TGA analysis of form L shows a weight loss of about 4.56% up to 165° C.

[0115] Form L has an XRPD pattern substantially the same as that shown in Figure 9A (Form L). Form L exhibits an XRPD pattern having characteristic peaks represented at 6.07 and 6.65 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form L may also exhibit an additional characteristic peak represented at 5.24 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form L may also exhibit an additional characteristic peak represented at 20.64 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form L may also exhibit an additional characteristic peak represented at 8.03 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form L may also exhibit an additional characteristic peak represented at 22.38 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form L may also exhibit an additional characteristic peak represented at 17.99 degrees 2θ (±0.2° 2θ).

[0116] Form M Crystalline form M is an IPAc mono-solvate. According to DSC, form M shows two overlapping endothermic events with an onset of 109° C. and peak temperatures of 116.7° C. and 128.2° C., which occur simultaneously with the TGA weight loss process. TGA analysis of form M shows a weight loss of 13.33% up to 165.0° C.

[0117] Form M has an XRPD pattern substantially the same as that shown in Figure 10A (Form M). Form M exhibits an XRPD pattern having characteristic peaks expressed at 6.59, 8.26, and 19.79 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form M may also exhibit additional characteristic peaks expressed at 22.71 and 26.49 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form M may also exhibit additional characteristic peaks expressed at 17.84 and 14.38 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form M may also exhibit additional characteristic peaks expressed at 4.73, 24.57, and 12.25 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form M may also exhibit additional characteristic peaks expressed at 20.69, 13.29, and 16.40 degrees 2θ (±0.2° 2θ).

[0118] Form N Crystalline form N is anhydrous. According to DSC, form N shows a single endotherm with an onset at 141.9° C. and a peak temperature at 152.1° C. TGA analysis of form N shows a weight loss of 0.46% up to 179.0° C.

[0119] Form N has an XRPD pattern substantially the same as that shown in Figure 11A (Form N). Form N exhibits an XRPD pattern having characteristic peaks expressed at 6.12, 4.16, and 19.29 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form N may also exhibit additional characteristic peaks expressed at 3.32 and 16.65 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form N may also exhibit additional characteristic peaks expressed at 4.63 and 3.11 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form N may also exhibit additional characteristic peaks expressed at 21.81, 22.45, and 26.20 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form N may also exhibit additional characteristic peaks expressed at 9.93, 9.12, and 18.05 degrees 2θ (±0.2° 2θ).

[0120] Form O Crystalline form O is a methanol monosolvate. According to DSC, form O shows a broad endotherm with an onset of 107.4° C. and a peak temperature of 110.6° C. TGA analysis of form O shows a weight loss of 5.11% up to 160.0° C.

[0121] Form O has an XRPD pattern substantially the same as that shown in Figure 12A (Form O). Form O exhibits an XRPD pattern having characteristic peaks represented at 5.59 and 16.76 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form O may also exhibit additional characteristic peaks represented at 28.10 and 6.63 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form O may also exhibit additional characteristic peaks represented at 11.16 and 22.41 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form O may also exhibit additional characteristic peaks represented at 33.87 and 25.38 degrees 2θ (±0.2° 2θ). The XRPD pattern of Form O may also exhibit additional characteristic peaks represented at 11.89 and 16.20 degrees 2θ (±0.2° 2θ).

[0122] Form P Crystalline form P is an unstable solvate that converts to form E upon drying.

[0123] Form P has an XRPD pattern substantially the same as that shown in Figure 6A (Form P). Form P exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.38, 16.69, and 6.93. The XRPD pattern of Form P may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 11.61, 21.89, and 8.95. The XRPD pattern of Form P may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 19.84 and 17.85. The XRPD pattern of Form P may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 20.82 and 15.86. The XRPD pattern of Form P may also exhibit additional characteristic peaks expressed at 12.35 and 22.99 degrees 2θ (±0.2° 2θ).

[0124] Form Q Crystalline form Q is anhydrous. According to DSC, form Q shows a single broad endotherm with an onset of 101.4° C. and a peak temperature of 130.1° C. TGA analysis of form N shows a weight loss of 0.63% up to 160.0° C.

[0125] Form Q has an XRPD pattern substantially the same as that shown in Figure 13A (Form N). Form Q exhibits an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 13.58, 5.61, and 16.82. The XRPD pattern of Form Q may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 12.34, 21.73, and 19.39. The XRPD pattern of Form Q may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 14.95, 20.94, and 18.73. The XRPD pattern of Form Q may also exhibit additional characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 12.78, 23.31, 26.25, and 28.21. The XRPD pattern of form Q may also exhibit additional characteristic peaks expressed at 17.69, 8.37, 24.47, and 31.84 degrees 2θ (±0.2° 2θ).

[0126] Formulations, Methods, and Uses As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or amelioration of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving such amount. This term also includes within its scope an amount that is effective to promote normal physiological function.

[0127] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have disappeared, for example, to prevent or delay their recurrence.

[0128] As used herein, the term "patient or subject" refers to a mammal. Thus, a subject refers to, for example, a dog, a cat, a horse, a cow, a pig, a guinea pig, and the like. Preferably, the subject is a human. When the subject is a human, the subject may be either a patient or a healthy human.

[0129] The compounds of formula I are useful for treating diseases and disorders in which inhibition of cannabinoid receptor CB1 is indicated, such as those described in US Patent No. 9,765,031.Such diseases and disorders are generally related to diabetes and metabolic disorders (e.g., metabolic syndrome).Preferably, the active ingredient selectively targets CB1 receptors in peripheral tissues (e.g., adipose tissue, liver, muscle, lung, kidney, macrophage, splenic beta cells, and gastrointestinal tract) while not interacting with CB1 receptors in brain tissue, thereby avoiding or reducing CNS-related side effects.

[0130] The effects of the compounds of formula I may include reducing food intake, reducing body weight, reversing insulin and leptin resistance, reversing hepatic steatosis (fatty liver), and improving dyslipidemia. Examples of diseases and disorders that may be treated include obesity, diabetes (type 1 or type 2), non-alcoholic and alcoholic fatty liver disease (risk factors for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), and gout. For example, the comorbidities of obesity are selected from metabolic syndrome, dementia, heart disease, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, osteoarthritis, venous stasis ulcer, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arteriosclerosis, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignant tumors of the liver, ovary, cervix, uterus, breast, prostate, or gallbladder.In a preferred example, the disease or disorder includes diabetes (type 1 or type 2), obesity, and non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis).Examples of comorbidities of diabetes (e.g., type 1) include diabetic nephropathy, chronic kidney disease, diabetic retinopathy, and peripheral and autonomic neuropathy.

[0131] The compounds of formula I, and pharmaceutical compositions comprising the compounds of formula I, may also be used in methods for preventing or reversing the deposition of adipose tissue in a subject, which is expected to contribute to reducing the incidence or severity of obesity, which in turn will reduce the incidence or severity of associated comorbidities.

[0132] The present specification provides a method for treating a disorder (described herein) in a subject, comprising administering a compound of formula I to a subject identified as needing the method. Identifying patients who need the above-mentioned disorder treatment is well within the ability and knowledge of those skilled in the art. Certain methods for identifying patients at risk of developing the above-mentioned disorder that can be treated by the subject method are understood in the medical arts, such as family history and the presence of risk factors associated with the development of the disease state in the subject patient. A clinician in the art can easily identify such candidate patients, for example, by using clinical tests, physical examinations, medical / family history, and genetic determination.

[0133] The method of evaluating the effectiveness of treatment in a subject includes determining pre-treatment symptoms of the disorder by methods known in the art, and then administering a therapeutically effective amount of a compound of the present invention to the subject. After an appropriate period (e.g., 1 week, 2 weeks, 1 month, 6 months) from administration of the compound, the symptoms of the disorder are determined again. Modulation (e.g., reduction) of the symptoms and / or biomarkers of the disorder indicates the effectiveness of the treatment. The symptoms and / or biomarkers of the disorder may be determined periodically throughout the treatment. For example, the symptoms and / or biomarkers of the disorder may be checked every few days, weeks, or months to evaluate the further effectiveness of the treatment. The reduction of the symptoms and / or biomarkers of the disorder indicates that the treatment is effective.

[0134] The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0135] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0136] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0137] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0138] In order to prolong the effect of the provided compound, it may be desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled.

[0139] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0140] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0141] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound comprises at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as, for example, cetyl alcohol and glycerol monostearate; h) moisture absorbing agents, such as kaolin and bentonite clay; and i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0142] Solid compositions of similar form may also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, lozenges, capsules, troches, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. They may optionally contain opacifying agents, and may be of a composition that optionally releases the active ingredient only or preferentially in a certain part of the intestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar form may also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like.

[0143] The provided compounds can also be in microencapsulated form with one or more of the excipients mentioned above. The solid dosage forms of tablets, dragees, lozenges, capsules, troches, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. They can optionally contain opacifying agents, and can also be of a composition that optionally releases the active ingredient in a delayed manner, only or preferentially in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0144] The dosage forms for topical or transdermal administration of the compounds herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any necessary preservatives or buffers as necessary. Ophthalmic preparations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0145] The pharma- ceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation.Such compositions are prepared according to techniques known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to promote bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0146] The pharma- ceutically acceptable compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered without food. In some embodiments, the pharma- ceutically acceptable compositions of the present disclosure are administered with food.

[0147] The pharma- ceutically acceptable compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. The compositions are formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete pharmaceutical unit suitable for the patient to be treated. However, it is to be understood that the total daily dosage of the compositions of the present disclosure is determined by the attending physician within the scope of sound medical judgment.

[0148] The amount of the compound of formula I that may be included in a single dosage form varies depending on the patient being treated (e.g., child vs. adult, etc.). The compositions provided may be formulated such that a total daily dose of the compound, for example, 0.01-20 mg / kg body weight / day, may be administered to a patient receiving these compositions. Such amounts may be included in a single dose composition, or the total daily dose may be divided into multiple dosage forms, for example, to be taken once, twice, or three times a day. For example, a single dose may contain 5-500 mg of active ingredient, or 20-200 mg. A treatment regimen may include administering to a patient a total amount of the compound herein of about 10 mg to about 1000 mg per day, either in a single dose or divided into multiple doses.

[0149] Of course, the total daily dose of the compound of formula I will be determined by the attending physician within the scope of sound medical judgment. For example, the specific dose or treatment regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of symptoms associated with the disease or disorder.

[0150] Depending on the disease or disorder to be treated, additional therapeutic agents may also be present in the composition of the present disclosure or may be separately co-administered.Non-limiting examples of additional therapeutic agents that can be used in combination with the compound of formula I include antidiabetic drugs, cholesterol-lowering drugs, anti-inflammatory agents, antibacterial agents, matrix metalloproteinase inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, anticancer drugs, antiviral drugs, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferation compounds.Treatment may also be complemented by other treatments or interventions, such as surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and whole body radioisotopes), biological response modifiers (e.g., interferons, interleukins, tumor necrosis factor (TNF)), and agents used to attenuate the adverse effects of the compound or co-administered components.

[0151] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiment or portions thereof.

[0152] In some embodiments, a therapeutically effective amount of a compound defined herein, or a pharma- ceutically acceptable salt thereof, may be administered to a patient, either alone or in admixture with a pharma- ceutically acceptable carrier.

[0153] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat.

[0154] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound herein which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound herein, or an inhibitory active metabolite or residue thereof.

[0155] Experiments and Examples Materials and Equipment Polarized light microscopy (PLM) images were captured on a Nikon™ DS-Fi2 upright microscope at room temperature.

[0156] Powder X-ray diffraction (XRPD) was performed using a Panalytical™ XPert powder XRPD with a Si zero background. The XRPD parameters used were: [Table 1]

[0157] Differential scanning calorimetry (DSC) was performed on a TA Q2000 DSC from TA Instruments™. The DSC method was as follows: N2 was used as the purge gas, with a heating rate of 10°C / min from room temperature to the desired temperature, and a pinhole in the crimped pan lid. The DSC parameters were: [Table 2]

[0158] Thermogravimetric analysis (TGA) was performed on a TA Instruments TA Q500 TGA. The TGA method was as follows: Rise from room temperature to the desired temperature (300° C.) at a heating rate of 10° C. / min using N2 as the purge gas. The TGA parameters were as follows: [Table 3]

[0159] Karl Fisher (KF) was performed on a Mettler Toledo™ volumetric KF titrator to determine water content in the samples.

[0160] The solvent abbreviations are as follows: [Table 4]

[0161] Summary of Experimental Results Polymorph screening of the compound of formula I was performed to identify the most stable crystalline form.

[0162] A first crystalline form of the compound of formula I was obtained via the method described in Example 2. This crystalline form was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Characterization results showed that the starting material was anhydrous crystalline material with rod-like particles. DSC showed a single melting endotherm with an onset of 152.2°C. This crystalline form was designated as Form A.

[0163] Starting with form A, polymorph screening was performed under 100 different conditions using the following methods: slurry conversion at room temperature (RT) and 60°C, temperature cycling, antisolvent addition, slow cooling, slow evaporation, polymer-induced crystallization, crash cooling, bulk solvent slurry, and reverse antisolvent addition. Screening produced 17 crystalline forms (forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, and Q). - Forms A, C, D, E, N and Q were found to be anhydrous. - Forms A, D and E were found to be the products of desolvation of the unstable solvate forms J, H and P, respectively. - Forms C, N, and Q were found to be true anhydrates with no change in the XRPD patterns observed between wet and dry cake samples. - Form K was found to be a hemihydrate (API:H2O ratio of 1:0.5). - Forms B, F, L, M and O were found to be solvates. - Wet cake XRPD analysis of the solvate produced two new crystal patterns, Forms I and G, which upon drying at ambient conditions produced Forms B and F, respectively.

[0164] Thermodynamic evaluation of the six anhydrates (Forms A, C, D, E, N, Q) was performed in the nonsolvating solvent n-butanol to determine the most stable phase at room temperature and at 50° C. Both experiments showed complete conversion to Form C, indicating that Form C is the thermodynamically most stable anhydrate form under those conditions.

[0165] Example 1: Polymorph Screening Polymorph screening experiments were performed using different solution crystallization or solid phase transition methods starting from Form A. The methods used and the crystal forms identified are summarized in Table 1-1. [Table 5]

[0166] Antisolvent addition Approximately 20-50 mg of Form A was dissolved in a suitable solvent to obtain a clear solution. After magnetic stirring of the solution, 0.2 mL of anti-solvent was added stepwise until a precipitate appeared or the total amount of anti-solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis. A total of 20 experiments were performed. The results in Table 1-2 showed that Forms A, C, E, G, J, N, and P were obtained. [Table 6]

[0167] Slow Evaporation Slow evaporation experiments were performed under 10 conditions. Approximately 20 mg of Form A was dissolved in 1.0 mL of solvent in a 3 mL glass vial. The visually clear solution was allowed to slow evaporate at room temperature. The solid was isolated for XRPD analysis. The results summarized in Tables 1-3 showed that Forms A, E, F, G, J, and K were obtained. [Table 7]

[0168] Crash Cooling Approximately 25-50 mg of Form A was dissolved in 0.2-0.6 mL of solvent to obtain a suspension. The suspension was then heated to 60°C using magnetic stirring, equilibrated for 2 hours, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was immediately transferred to a 5°C environment. A total of four experiments were performed. The results in Tables 1-4 showed that Forms E, K, L, M, and P were obtained. [Table 8]

[0169] Slurry at room temperature Slurry conversion experiments were carried out at room temperature in 20 solvent systems. Approximately 15-20 mg of Form A was suspended in 0.5 mL-1.0 mL of solvent at room temperature. The remaining solid was isolated for XRPD analysis. The results summarized in Tables 1-5 showed that Forms A, B, E, F, G, I, N, and P were obtained. [Table 9]

[0170] Slurry at 60℃ Slurry conversion experiments were carried out at 60° C. in 10 solvent systems. Approximately 25-75 mg of Form A was suspended in 0.5 mL of solvent at 60° C. for 3 days. The remaining solid was isolated for XRPD analysis. The results summarized in Tables 1-6 showed that Forms B, C, D, H, I, K, and N were obtained from all experiments. [Table 10]

[0171] Slurry in bulk solvent Slurry conversion experiments were carried out at 60°C and 100°C in six different bulk solvent systems. Approximately 25-75 mg of Form A was suspended in 0.5 mL of bulk solvent at the corresponding temperature and magnetically stirred. The remaining solid was isolated for XRPD analysis. The results summarized in Tables 1-7 showed that Forms N and Q were obtained from all experiments. [Table 11]

[0172] slow cooling Approximately 25-50 mg of Form A was dissolved in 0.2-0.6 mL of solvent to obtain a suspension. The suspension was then heated to 50° C. using magnetic stirring, equilibrated for 2 hours, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was slowly cooled to 5° C. at a rate of 0.1° C. / min. A total of five experiments were performed. The results in Tables 1-8 showed that Forms D, H, K, and L were obtained. [Table 12]

[0173] Polymer-induced crystallization Polymer-induced crystallization experiments were performed with two different polymers in five solvents. Approximately 20 mg of Form A was dissolved in 0.5-2.0 mL of the appropriate solvent to obtain a clear solution in a 3 mL vial. Approximately 2 mg of the polymer mixture was added to a 3 mL glass vial. All samples were allowed to evaporate at room temperature to induce precipitation. Solids were isolated for XRPD analysis. The results summarized in Tables 1-9 indicated that Forms A, J, and K were obtained. [Table 13]

[0174] Temperature Cycling A suspension of approximately 50-100 mg / ml of Form A in 0.5 ml of solvent was magnetically stirred and exposed to high (50 °C) and low (5 °C) temperatures in cycles. Solids were isolated on days 1 and 3 and analyzed by XRPD. A total of 10 experiments were performed, yielding Forms A, B, C, D, E, F, G, H, I, J, and N, as summarized in Tables 7-15. [Table 14]

[0175] Reverse antisolvent addition Approximately 20-50 mg of Form A was dissolved in a suitable solvent to obtain a clear solution. The solution was then added dropwise to the corresponding anti-solvent under magnetic stirring. The resulting precipitate was isolated for XRPD analysis. A total of 10 experiments were performed. The results in Tables 1-11 showed that Forms A, J, and N were obtained. [Table 15]

[0176] The XRPDs of the isolatable forms can be seen in the figures. The characterization results are summarized in Table 1. Phase maps of the six anhydrates are shown in Figure 1A. Phase interconversion maps of all solvates and hydrates are shown in Figure 1B. [Table 16-1] [Table 16-2]

[0177] Example 2: Form A and Form J Form A was obtained via the following synthetic steps. [ka] 1) 7.75 L of DMF was pumped into a 50 L enamel jacketed kettle with vacuum stirring. 2) 1.58 kg of compound 2 was added at once to the solution at 25-30°C. 3) 0.595 kg of compound 3 was added in one portion to the solution at 25-30°C. 4) The reaction mixture was stirred at 20-30°C for 0.5 hours. 5) 1.49 kg of TEA was added to the solution at 25-30°C under nitrogen. 6) The reaction mixture was stirred at 20-30°C for 1.0 hour. 7) The reaction was monitored by HPLC until completion. 8) Once complete, add the reaction mixture slowly to 31 L of water and stir at 10-15°C for 30 minutes. 9) The reaction mixture was then filtered and the filter cake was washed with water (2000 mL). The washed filter cake was dissolved in DCM (4000 mL) and water (1000 mL) was added. 10) The organic layer was washed with brine (3000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound with 93.1% purity (by HPLC). 11) The crude compound of formula I was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1 to 2 / 1, TLC:PE:EA=1:1, p1:Rf=0.5). 12) The collected fractions were concentrated under reduced pressure to give a residue. 13) The residue was triturated with DCM (5.0 L) and n-heptane (5.0 L) at 30° C. for 1.0 h. 14) The mixture was then filtered and the filter cake was dried under vacuum at 45°C. 15) Crystalline compound of formula I, Form A (1.48 kg, 85% yield, 99.8% purity) was obtained as a white solid, which was confirmed by HPLC, LCMS, and H / FNMR.

[0178] Form A was characterized by XRPD (FIG. 2A) and PLM and was shown to be crystalline and possess small rod-like particles with aggregates.

[0179] Thermal analysis performed on Form A showed a weight loss of 0.01% up to 200° C. and a single endothermic peak with an onset of 152.2° C. and a peak temperature of 162.3° C., as shown in FIG. 2B.

[0180] Form A obtained from anti-solvent addition in ACN / H2O was further investigated by analyzing the wet solid by XRPD. The sample was covered with 3511 Kapton film to minimize solvent evaporation from the wet cake. A unique pattern different from Form A was observed, indicating an unstable solvate phase form in this solvent system. This crystalline form was designated Form J. Upon drying in ambient environment, Form J converted to Form A. An XRPD overlay of Form A and Form J is shown in Figure 2C.

[0181] The approximate solubility of Form A was determined at room temperature in each of 20 single solvents. Approximately 2 mg of Form A was added to a 3 mL glass vial. The corresponding solvent was added stepwise to the vial (50 μL - 50 μL - 200 μL - 700 μL) until the solid visibly dissolved or a total volume of 1 mL was reached. The approximate solubility range was calculated according to the mass of the sample, the volume of the solvent, and the observations. The results summarized in Table 2 were used to guide solvent selection in the polymorph screening.

[0182] Form A had high solubility (> 10 mg / mL) in most solvents including MeOH, EtOH, acetone, MIBK, MEK, EtOAc, IPAc, THF, 2-MeTHF, 1,4-dioxane, anisole, ACN, CHCl3, DMSO, and DCM. Moderate solubility (2.0 < S < 10.0) was observed in toluene. Low solubility (< 3.0 mg / mL) was observed in IPA, MTBE, n-heptane, and H2O.

Table 17

[0183] Example 3: Form B and Form I Form B was obtained by temperature cycling in IPA. Formation of Form B was also observed in IPA slurries at room temperature and 60°C. Form B was further characterized by analyzing the wet cake by XRPD. The sample on the XRPD sample holder was covered with 3511 Kapton film to minimize solvent evaporation from the wet cake. A unique pattern different from forms A and B was observed, which was designated as Form I. Upon drying in ambient environment, Form I converted to Form B, indicating that Form I is an unstable solvate. A comparison of the XRPD patterns of Forms A, B, and I is shown in Figure 3A. PLM showed small irregularly shaped birefringent particles. Thermal analysis in Figure 3B showed a weight loss of 5.34% by TGA up to 174.0°C and a broad endotherm with an onset of 126.4°C and a peak temperature of 136.3°C by DSC. KF analysis of Form B showed a water content of 0.5%. Comparing the KF results with the TGA results, it was concluded that Form B is an IPA solvate, more specifically a hemisolvate as determined by calculating the API:solvent stoichiometry to be 1:0.6 from the TGA weight loss.

[0184] Example 4: Form C Form C was obtained by temperature cycling from 60° C. to 25° C. in H2O. Formation of Form C was also observed in antisolvent addition and screening experiments at 60° C. A comparison of the XRPD patterns of Forms A and C is shown in FIG. 4A. The PLM image of Form C showed small irregularly shaped birefringent particles. Thermal analysis in FIG. 4B showed a weight loss of 0.32% up to 175.0° C. with a single endotherm with an onset at 157.1° C. and a peak temperature of 167.9° C. The minimal weight loss observed indicated an anhydrous phase.

[0185] Example 5: Form D and Form H Form D was obtained by temperature cycling in toluene. Formation of Form D was also observed in 60° C. slurries and slow cooling with toluene. Form D was further characterized by analyzing the wet solid by XRPD. The sample on the XRPD sample holder was covered with 3511 Kapton film to minimize solvent evaporation from the wet cake. A unique pattern distinct from forms A and D was observed, indicating an unstable solvated phase, designated as Form H. Upon drying in ambient environment, Form H converted to Form D. A comparison of the XRPD patterns of Forms A, D, and H is shown in FIG. 5A. The PLM image of Form D showed small irregular needles with aggregation. Thermal analysis in FIG. 5B showed a weight loss of 0.07% up to 180.0° C. with a single endotherm with an onset of 155.9° C., an enthalpy of 23.5 J / g, and a peak temperature of 163.9° C. The minimal weight loss observed indicated an anhydrous phase.

[0186] Example 6: Form E and Form P Form E was obtained by temperature cycling in IPAc / MTBE (1:3 v / v). Formation of Form E was also observed in anti-solvent addition, crash-cooling, and room temperature slurry experiments using MTBE, 2-MeTHF, or toluene. Form E was further characterized by analyzing the wet solid by XRPD. The sample on the XRPD sample holder was covered with 3511 Kapton film to minimize solvent evaporation from the wet cake. A unique pattern distinct from forms A and E was observed, indicating an unstable solvated phase, which was designated as form P. Upon drying in ambient environment, form P converted to form E. A comparison of the XRPD patterns of forms A, E, and P is shown in Figure 6A. The PLM image of form E showed small irregularly shaped birefringent particles. Thermal analysis, Figure 6B, showed a weight loss of 0.31% up to 177.9°C, with two endotherms with onsets of 120.6°C and 146.0°C, respectively, and peak temperatures of 129.5°C and 154.6°C. The minimal weight loss observed indicated an anhydrous phase.

[0187] The first small endotherm was further investigated to determine whether conversion to another form occurs when heating after the first small endotherm and before the final melting endotherm, followed by cooling back to room temperature. Cycle DSC, shown in FIG. 6C, was performed by heating to 135° C. in cycle 1, cooling to room temperature in cycle 2, and then heating to 300° C. in cycle 3 (after the final melt). In cycle 2, the endothermic event that occurred in cycle 1 (onset 122.1° C.) is observed upon cooling, indicating that this is a reversible event. In the final cycle, the first endotherm is observed again. This indicates that form E is converted to a high temperature melting point that cannot be isolated as it converts back to form E upon cooling. This indicates that form E and the high temperature melting form are enantiotropically related, with form E being more stable at temperatures below 122° C. The melting endotherm at 147.4° C. does not coincide with the melting of any of the other forms observed in the screen, providing additional evidence that a new form is present at elevated temperatures. This new form of XRPD can be obtained by in situ hot stage XRPD.

[0188] Example 7: Form F and Form G Form F was dissolved in THF / HO (0.92 / 0.08 v / v A w =0.2) by temperature cycling. The formation of form F was wForm F was also observed in room temperature slurries in THF / H2O at ΔE = 0.4 and 0.6, as well as temperature cycled in THF / H2O (1:3). Form F was further characterized by analyzing the wet solid by XRPD. The sample on the XRPD sample holder was covered with 3511 Kapton film to minimize solvent evaporation. A unique pattern distinct from forms A and F was observed, indicating an unstable solvated phase, which was designated as form G. Upon drying in ambient conditions, form G converted to form F. A comparison of the XRPD patterns of forms A, F, and G is shown in Figure 7A. PLM images showed small irregularly shaped birefringent particles. Thermal analysis in Figure 7B showed a weight loss of 1.85% by TGA up to 165.0°C, with a broad endotherm with an onset at 119.5°C and a peak temperature of 132.4°C. A KF was obtained from form F, resulting in a water content of 0.6%. Comparing the KF and TGA results, it was concluded that Form F is likely a THF solvate.

[0189] Example 8: Form K Form K was obtained by crash cooling from an EtOH solution. Form K formation was also observed in slow evaporation, 60° C. slurry, slow cooling, and polymer-induced crystallization using EtOH. A comparison of the XRPD patterns of Form A and Form K is shown in FIG. 8A. PLM images showed small irregularly shaped birefringent single particles and aggregates. Thermal analysis in FIG. 8B showed a weight loss of 1.35% by TGA up to 160.0° C. and two endothermic events with onsets of 53.6° C. and 106.3° C. and peak temperatures of 68.7° C. and 125.9° C., respectively. Form K was heated to 90° C. and cooled back down. XRPD of the resulting material showed a change in the compared patterns shown in FIG. 8C due to the expulsion of water by heating resulting in a dehydrated phase. The water content of the solid was determined to be 1.4% by KF. The weight loss of TGA and water content obtained by KF were complementary and it was concluded that form K is a hemihydrate.

[0190] Example 9: Form L Form L was obtained by crash cooling of anisole solution. Formation of Form L was also observed in slow cooling experiments using anisole. Comparison of XRPD patterns of Form A and Form L is shown in Figure 9A. PLM images showed small irregularly shaped birefringent primary particles and aggregates. Thermal analysis in Figure 9B showed a weight loss of 4.56% by TGA up to 165.0°C and a single endothermic event with an onset of 126.4°C and a peak temperature of 133.8°C in the DSC curve occurring after the solvent was driven. KF was obtained from Form L, resulting in a water content of 0.2%. Comparing the KF results with the TGA results, it was concluded that Form L is a partially desolvated anisole solvate since the stoichiometry of API:anisole is 0:0.26.

[0191] Example 10: Form M Form M was obtained by crash cooling of IPAc solution. A comparison of the XRPD patterns of Form A and Form M is shown in FIG. 10A. The PLM image showed small irregularly shaped birefringent particles. Thermal analysis in FIG. 10B showed a weight loss of 13.33% by TGA to 165.0° C. and two overlapping endothermic events in the DSC curve with an onset of 109° C. and peak temperatures of 116.7° C. and 128.2° C. occurring simultaneously with the TGA weight loss process. A KF was obtained from Form M, resulting in a water content of 0.2%. Comparing the KF results with the TGA results, it was concluded that Form M is an IPAc solvate, more specifically a monosolvate as determined by calculating the API:solvent stoichiometry from the TGA weight loss.

[0192] Example 11: Form N Form N was obtained by temperature cycling in CHCl3 / n-heptane (1:3 v / v). Formation of Form N was also observed in anti-solvent addition, room temperature and 60°C slurry, bulk solvent slurry, and reverse anti-solvent addition experiments using n-heptane. A comparison of the patterns of Form A and Form N is shown in Figure 11A. The PLM image of Form N showed small irregular birefringent particles. Thermal analysis in Figure 11B showed a weight loss of 0.46% up to 179.0°C with a single endotherm with an onset at 141.9°C and a peak temperature of 152.1°C. The minimal weight loss observed indicated an anhydrous phase.

[0193] Example 12: Form O Form O was obtained only by slow evaporation in MeOH. A comparison of the XRPD patterns of Form A and Form O is shown in Figure 12A. The PLM image showed crystals with large plate-like morphology. Thermal analysis in Figure 12B showed a 5.11% weight loss by TGA up to 160.0°C, with a broad endotherm with an onset of 107.4°C and a peak temperature of 110.6°C. Due to the method by which Form O was produced, minimal solids were isolated. Scale-up of Form O was attempted by cooling the crystallization and using the remaining solids as seeds. This was unsuccessful and no KF was performed on this form. However, calculation of the stoichiometry of API:MeOH from the TGA weight loss showed 1:0.99, providing some evidence that Form O is a MeOH monosolvate.

[0194] Example 13: Form Q Form Q was obtained by slurrying Form A in n-butanol at 100° C. Formation of Form Q was also observed in bulk solvent slurries at 100° C. using isobutanol, propylene glycol, ethylene glycol, and n-pentanol. A comparison of the XRPD patterns of Form A and Form Q is shown in FIG. 13A. The PLM image of Form Q showed small irregularly shaped birefringent particles. Thermal analysis in FIG. 13B showed a weight loss of 0.63% up to 160.0° C. with a single broad endotherm with an onset at 101.4° C. and a peak temperature of 130.1° C. The minimal weight loss observed indicated an anhydrous phase.

[0195] Example 14: Slurry competition experiments Anhydride: A total of six anhydrates were observed: Forms A, C, D, E, N, and Q. Thermodynamic evaluation of all anhydrates was performed by slurrying all anhydrates in equal mass ratios in the nonsolvating solvent n-butanol at room temperature and 50° C. Conversion of all anhydrates to Form C was observed at both room temperature and 50° C., indicating that this is the most stable anhydrate.

[0196] Hydrate: A monohydrate (form K) was observed and found to be a hemihydrate. Thermodynamic evaluation of form K was performed by creating slurries of form K and form C (the most stable anhydrous) in equal mass ratios at various water activities using a nonsolvating solvent. Initially, EtOH / H2O was used and results showed form K to be more stable from an Aw range of >0.1 and <0.9. However, in this experiment, form C was found to be more stable at Aw of 0.9 or greater. It is suspected that EtOH may be forming a solvate that favors the formation of form K, since hydrates should be more thermodynamically stable at higher water activities. Values ​​and results for obtaining critical water activity follow the laws of thermodynamics, and results obtained from this experiment can be transferred to other solvent / H2O systems. Additional critical water activity experiments were performed using forms K and C at Aws of 0.5 and 0.9 in acetone / H2O. wAt both water activities, conversion to form C was observed. These results indicate that form K is not a stable hydrate and that the formation of form K is affected by the presence of EtOH.

[0197] Example 15: Scale-up of Form C Form C was successfully scaled up to 5 grams. Starting with Form A, approximately 5 grams was weighed and transferred to a 100 mL bottle. 50 mL of EtOH was added to create a suspension and the mixture was magnetically stirred at 65° C. Once a clear solution was obtained, the solution was slowly cooled to 50° C. Once the sample reached 50° C., H2O was added to the solution at a rate of approximately 1 mL / min until a 1:1 ratio (v / v) of EtOH / H2O was obtained. The sample was filtered and the wet solid was evenly distributed onto a large weigh boat while breaking up any large clumps. A sample was extracted from the bulk solid for in-house baseline characterization. XRPD of the wet solid confirmed the formation of Form C, shown in FIG. 14. PLM images of the material showed a needle-like morphology with some aggregation. The extracted sample was dried under vacuum at 40° C. for several hours and then analyzed by TGA / DSC. TGA results confirmed the anhydrous nature of Form C, with an increase in enthalpy (AH) observed. The remaining bulk solid was then dried under vacuum over the weekend.

[0198] Example 16: Comparison of simulated and experimental XRPD data Single crystal data for the compound of Formula I is disclosed in Liu et al., Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB1R) Antagonist, ACS Pharmacology & Translational Science, 2021, which is incorporated herein by reference in its entirety.

[0199] This single crystal data was consistent with the experimental XRPD data through simulation, which was shown to correspond to Form B. The overlaid simulated and experimental XRPD data for Form B is shown in FIG.

[0200] The simulated XRPD pattern shows strong agreement with the experimentally obtained pattern for Form B at low angles with minor adjustments (0.1° 2θ). There is a noticeable drift across peak locations across the two spectra, but the peak intensity ratios and relative locations when viewed as a group are in excellent agreement. It was noted that the single crystal data was collected at 100K in CIF, while the XRPD data was collected at ambient conditions. The displacement on the x-axis is due to thermal contraction and expansion, which is not surprising with such a large temperature difference. It is important to note that the peak pattern retains a very good similarity to the simulation, and the temperature change results in a nearly uniform shift in the unit cell parameters, indicating no polymorphic transitions across the temperature range. In addition to the crystallographic evidence, the single crystal data indicates that the crystal is a monosolvate of isopropyl alcohol and hemihydrate. The solvents identified are consistent, although the ratios do not match those reported for Form B.

[0201] Example 17: Other experimental conditions for obtaining Form C Form C was obtained by temperature cycling in water. - 3 g of compound of formula I, Form A, was added to the flask. - 10 volumes of water was added to the flask. - Temperature cycling was performed from 60°C to 25°C. The mixture was stirred for 4.5 hours at 25°C. - The precipitated crystalline solid was filtered, dried under nitrogen at 20-25°C and identified as Form C by XRPD.

[0202] Form C may also be obtained by adding water to the ethanol solution. - 0.5 g of compound of formula I, Form A, was dissolved in 6 volumes of EtOH at 60°C. - 2 volumes of water was added to the mixture. - 0.5% Form C seeds were added to the mixture. The mixture was stirred for 1 hour at 60°C. - The mixture was then cooled to 25°C over 4 hours. - The mixture was then stirred for 8 hours at 25°C. - The precipitated crystalline solid was filtered, dried under nitrogen at 20-25°C and identified by XRPD as Form C. The yield was 81%.

[0203] Form C may be obtained by adding water to the methanol solution. - 0.5 g of compound of formula I, Form A, was dissolved in 5 volumes of MeOH at 60°C. - 0.2 volume of water was added to the mixture. - 0.5% Form C seeds were added to the mixture. The mixture was stirred for 1 hour at 60°C. - 2.3 volumes of water was added to the mixture. The mixture was stirred for 1 hour at 60°C. - The mixture was then cooled to 25°C over 4 hours. - The mixture was then stirred for 8 hours at 25°C. - The precipitated crystalline solid was filtered, dried under nitrogen at 20-25°C and identified by XRPD as Form C. The yield was 74%.

[0204] Form C may be obtained by adding water to the n-propanol solution. - 0.5 g of compound of formula I, Form A, was dissolved in 10 volumes of n-PrOH at 60°C. - 3.2 volumes of water was added to the mixture. - 0.5% Form C seeds were added to the mixture. - The mixture was stirred for 1 hour at 53°C. - 1.8 volumes of water was added to the mixture. - The mixture was stirred for 1 hour at 53°C. - The mixture was then cooled to 25°C over 4 hours. - The mixture was then stirred for 13 hours at 25°C. - The precipitated crystalline solid was filtered, dried under nitrogen at 20-25°C and identified by XRPD as Form C. The yield was 82%.

[0205] Form C was also obtained in 5 g, 18 g, and 115 g scale crystallization experiments beginning with dissolving Form A in ethanol at 40° C., adding water, cooling to 25° C., and recovering the crystalline compound of formula I, Form C (92% yield).

[0206] XRPD Peak List Form A: [Table 18] Form B: [Table 19] Form C: [Table 20] Form D: [Table 21] Form E: [Table 22] Form F: [Table 23] Form G: [Table 24] Form H: [Table 25] Form I: [Table 26] Form J: [Table 27] Form K: [Table 28] Form L: [Table 29] Form M: [Table 30] Form N: [Table 31] Form O: [Table 32] Form P: [Table 33] Form Q: [Table 34]

[0207] While the present invention has been shown and described with respect to one or more implementations, equivalent alterations and modifications will occur to those skilled in the art upon reading and understanding this specification. In addition, while certain features of the invention may have been disclosed with respect to only one of several implementations, such features may be combined with one or more other features of other implementations, as may be desirable or advantageous for any given or particular application.

[0208] It is therefore understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art in light thereof, which are within the spirit and scope of this application and the appended claims. Any publications, documents, patents, patent applications, or publications mentioned herein should be construed as being incorporated by reference in their respective entireties for all purposes.

Claims

1. A compound of formula I, 【Chemistry 1】 1. A compound that is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ (±0.2 degrees 2θ) at 6.46, 15.88, 19.44, and 5.86, when measured using Cu Kα radiation, and optionally further characteristic peaks expressed in degrees 2θ (±0.2 degrees 2θ) at 7.46, 22.15, and 26.24, when measured using Cu Kα radiation.

2. A compound of formula I, 【Chemistry 2】 A compound that is crystalline and has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm with an onset of about 157.1°C and / or has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm with a peak temperature of about 167.9°C.

3. A compound of formula I, 【Transformation 5】 1. A compound that is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 5.89 and 17.39 when measured using Cu Kα radiation, and optionally further having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 9.39 and 17.80 when measured using Cu Kα radiation.

4. The compound described in claim 3, which is crystalline and exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.89, 9.39, 12.96, 16.96, 17.39, 17.80 and 19.85 when measured using Cu Kα radiation.

5. A compound of formula I, 【Transformation 6】 A compound that is crystalline and has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm with an onset of about 152.2°C and / or has a differential scanning calorimetry (DSC) thermogram that exhibits an endotherm with a peak temperature of about 162.3°C.

6. 6. The compound of any one of claims 1 to 3 and 5, comprising one crystalline form in a purity of 95% or greater, optionally wherein the purity is 99% or greater, or wherein the purity is 99.8% or greater.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and 5 and a pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition of claim 7 formulated as an oral dosage form.

9. 9. The pharmaceutical composition of claim 8 formulated as an oral suspension.

10. 10. A medicament comprising a compound according to any one of claims 1 to 3 and 5 for the treatment of a disease or disorder selected from the group consisting of obesity, diabetes (type 1 or type 2), non-alcoholic and alcoholic fatty liver disease (risk factor for insulin resistance), comorbidities of obesity, comorbidities of diabetes, Prader-Willi syndrome (PWS), proopiomelanocortin (POMC) deficiency obesity, LepR deficiency obesity, POMC heterozygous deficiency obesity, POMC epigenetic disorders, Bardet-Biedl syndrome, Alström syndrome, dyslipidemia predisposing to atherosclerotic heart disease, diabetic nephropathy, fibrosis and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and Hermansky-Pudl syndrome pulmonary fibrosis (HPS-PF), and gout.

11. 10. A process for preparing a compound according to claim 1 or 3, comprising: suspending a first crystalline form of Formula I in water, wherein said first crystalline form exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2-theta (±0.2° 2-theta) of 5.89 and 17.39; subjecting the suspension to temperature cycling between a first temperature and a second temperature lower than the first temperature; recovering said compound of formula I as a second crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 6.46, 15.88, 19.44, and 5.

86.

12. The method of claim 11, wherein the first temperature is between 45°C and 65°C, preferably between 50°C and 60°C.

13. 13. The method of claim 12, wherein the second temperature is between 5°C and 35°C, preferably between 5°C and 25°C.

14. 12. The method of claim 11, wherein the first temperature is about 60°C and the second temperature is about 25°C.

15. 3. A process for preparing a compound according to claim 1 or 2, comprising: solubilizing a compound of formula I in a solvent selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol to obtain a solution; adding water to the solution until a solid precipitates; recovering said compound of formula I as a crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2-theta (±0.2° 2-theta) of 6.46, 15.88, 19.44, and 5.

86.

16. 16. The method of claim 15, wherein the solvent is selected from the group consisting of methanol, ethanol, and n-propanol, preferably the solvent is ethanol.

17. 16. The method of claim 15, wherein solubilizing the compound of formula I in the solvent comprises solubilizing the compound of formula I as a crystalline form exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees 2θ (±0.2° 2θ) of 5.89 and 17.

39.

18. 16. The method of claim 15, wherein the step of solubilizing the compound of formula I in the solvent is carried out at a first temperature between about 30°C and the boiling point of the solvent, preferably about 35°C to about 60°C, and further comprising the step of cooling the solvent / water mixture to a second temperature lower than the first temperature, preferably about 5°C to about 30°C, optionally about 20°C to about 30°C.

19. 16. The method of claim 15, wherein the solvent:water ratio (by volume) is from about 1:1 to about 3:1, optionally from about 2:1 to about 3:

1.

20. 3. A process for preparing a compound according to claim 1 or 2, comprising: providing a slurry of a first crystalline form of Formula I in a solvent selected from the group consisting of water, n-butanol, and an MIBK / n-heptane mixture, wherein said first crystalline form exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peaks expressed in degrees 2-theta (±0.2° 2-theta) of 5.89 and 17.39; agitating the slurry; recovering said compound of formula I as a crystalline form exhibiting an XRPD pattern having characteristic peaks expressed in degrees 2-theta (±0.2° 2-theta) of 6.46, 15.88, 19.44, and 5.

86.

21. 21. The method of claim 20, wherein the solvent is water or the solvent is a 1:4 (v / v) mixture of MIBK:n-heptane.

22. 21. The method of claim 20, wherein the step of stirring the slurry is carried out at a temperature of from about 50°C to about 70°C, optionally, the temperature is from about 55°C to about 65°C.

23. 12. The method of claim 11, further comprising adding seeds of the compound of claim 1 or 2 to the mixture.

24. The method of claim 15, further comprising adding seeds of the compound of claim 1 or 2 to the mixture.

25. The method of claim 20, further comprising adding seeds of the compound of claim 1 or 2 to the mixture.

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