Crystalline forms of 3-substituted 1,2,4-oxadiazoles

Abstract

The present invention relates to crystalline forms of 3-substituted 1,2,4-oxadiazole compounds, their preparation methods, and related pharmaceutical preparations. The invention also relates to preparations suitable for pharmaceutical, veterinary, and agricultural applications. [Selection diagram] None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to Indian Provisional Patent Application No. 201741036169, filed on October 11, 2017, the contents of which are hereby incorporated by reference in their entirety. [Background technology]

[0002] The immune system in mammals controls lymphocyte activation and inactivation during and after an immune response by various mechanisms. Among these mechanisms are those that specifically regulate the immune response when and where needed.

[0003] The 3-substituted 1,2,4-oxadiazole compounds act as immunomodulators and can therefore be used in the treatment of cancer, immune disorders, immune deficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.

[0004] Given the therapeutic benefits associated with 3-substituted 1,2,4-oxadiazole compounds, there is a need for improved compositions of these compounds. Additionally, there is a need for improved methods for preparing and formulating 3-substituted 1,2,4-oxadiazole compounds. Summary of the Invention

[0005] One aspect of the present invention relates to a crystalline compound having the structure of formula (I) [ka]

[0006] Another aspect of the present invention relates to a process for preparing the crystalline compound of formula (I).

[0007] In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising a crystalline compound of formula (I) and one or more pharma- ceutically acceptable excipients.In certain embodiments, the pharmaceutical preparation may be for use in treating or preventing a condition or disease described herein. [Brief description of the drawings]

[0008] [Figure 1] 1 shows the XRPD pattern of Formula (I) Form 1. [Diagram 2] 1 shows overlaid XRPD patterns of Formula (I) Form 2 from Example 2D and Example 2E. [Diagram 3] 1 shows the thermogravimetric analysis and differential scanning calorimetry thermograms of Form 1. [Figure 4] 1 shows the thermogravimetric analysis and differential scanning calorimetry thermograms of Form 2. [Diagram 5] FIG. 1 shows a comparison of the XRPD patterns of Formula (I) Form 2 compared to a solid form Form 2 reference sample after 7-8 days at 25° C., 60% relative humidity (RH); 40° C., 75% RH; and 30° C., 56% RH. [Figure 6] FIG. 1 shows a comparison of XRPD patterns of Formula (I) Form 2 in water at 20° C.; in water at 30° C.; and Form 2 after solubility testing. [Figure 7A] 1 shows the asymmetric unit of Formula (I) Form 2 single crystal. [Figure 7B] 1 shows the proposed proton transfer to form zwitterions in Formula (I) Form 2 crystals. [Figure 8] 1 shows the XRPD pattern of amorphous formula (I). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In certain embodiments, the present invention provides a crystalline compound having the structure of formula (I): [ka]

[0010] In some embodiments, the present invention provides crystalline compounds having a structure of formula (I) that can be drawn by showing all of the atoms. [ka]

[0011] In certain embodiments, the crystalline compound of formula (I) is solvated. In certain such embodiments, the crystalline compound of formula (I) is a hydrate (e.g., a monohydrate or a dihydrate). In certain particular embodiments, the crystalline compound of formula (I) is a monohydrate. In certain particular embodiments, the crystalline compound of formula (I) is a dihydrate.

[0012] Any of the crystalline compounds described herein can be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0013] In certain embodiments, the compounds of the present invention can be in more than one crystal configuration. In an exemplary embodiment, the crystalline compound having the structure of formula (I) exists as "Form 1", "Form 2", or a mixture thereof, as described in detail below. These different forms are known herein as "polymorphs".

[0014] In certain embodiments, the polymorphs of the crystalline compounds are characterized by powder X-ray diffraction (XRD). θ represents the diffraction angle measured in degrees. In certain embodiments, the diffractometer used in XRD measures the diffraction angle as two times the diffraction angle θ. Thus, in certain embodiments, the diffraction patterns described herein show the X-ray intensity measured versus the angle 2θ.

[0015] In certain embodiments, the crystalline compound of Formula (I) is solvated.

[0016] In some embodiments, the crystalline compound of formula (I) is solvated with water and is a hydrate. In certain embodiments, the crystalline hydrate of the compound of formula (I) is a monohydrate or a dihydrate. In other embodiments, the crystalline hydrate of the compound of formula (I) is a monohydrate. In other embodiments, the crystalline hydrate of the compound of formula (I) is a dihydrate.

[0017] In certain embodiments, the crystalline hydrate of the compound of Formula (I) has 2θ values ​​of 8.4±0.2, 13.6±0.2, 16.5±0.2, 16.8±0.2, 21.4±0.2, and 28.4±0.2. In further embodiments, the crystalline hydrate has 2θ values ​​of 8.4±0.2, 13.6±0.2, 16.5±0.2, 16.8±0.2, 19.3±0.2, 20.4±0.2, 21.4±0.2, and 28.4±0.2. In still additional embodiments, the crystalline hydrates have 2θ values ​​of 8.4±0.2, 13.6±0.2, 16.5±0.2, 16.8±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 21.4±0.2, 24.5±0.2, 26.5±0.2, and 28.4±0.2. In further embodiments, the crystalline hydrate has 2θ values ​​of 8.4±0.2, 11.5±0.2, 13.6±0.2, 16.5±0.2, 16.8±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 21.4±0.2, 21.8±0.2, 24.5±0.2, 26.5±0.2, 27.5±0.2, 28.0±0.2, 28.4±0.2, 30.0±0.2, and 32.4±0.2. In some embodiments, the crystalline hydrate has 2θ values ​​selected from the following peaks listed in Table 1 ±0.2: [Table 1] TIFF0007618445000005.tif55162

[0018] In certain embodiments, the crystalline hydrate of compound of formula (I) has an XRD pattern substantially as shown in FIG.

[0019] In some embodiments, the crystalline hydrate has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 29.7±0.2, and 33.7±0.2. In further embodiments, the crystalline hydrate has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 20.3±0.2, 28.9±0.2, 29.7±0.2, and 33.7±0.2. In still additional embodiments, the crystalline hydrates have 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 19.6±0.2, 20.3±0.2, 26.2±0.2, 28.9±0.2, 29.7±0.2, and 33.7±0.2. In yet other embodiments, the crystalline hydrate has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 19.1±0.2, 19.6±0.2, 20.3±0.2, 21.1±0.2, 21.4±0.2, 26.2±0.2, 27.2±0.2, 28.9±0.2, 29.7±0.2, 32.2±0.2, and 33.7±0.2. In some embodiments, the crystalline hydrate has 2θ values ​​selected from the following peaks listed in Table 2 ±0.2: [Table 2]

[0020] In certain embodiments, the crystalline hydrate of compound of formula (I) has an XRD pattern substantially as shown in FIG.

[0021] In certain embodiments, the crystalline hydrate of the compound of formula (I) is a monohydrate. In certain embodiments, the crystalline hydrate of the compound of formula (I) contains about 0.9, about 1.0, about 1.1, or about 1.2 molecules of water per molecule of the compound of formula (I). In certain embodiments, the crystalline hydrate of the compound of formula (I) exhibits one or two overlapping endotherms before melting / decomposition by differential scanning calorimetry (DSC), with a peak temperature of about 115°C to about 145°C. In some embodiments, the crystalline hydrate of the compound of formula (I) exhibits one or two overlapping endotherms before melting / decomposition, with a peak temperature in a range selected from about 116°C to about 140°C. In some embodiments, the crystalline hydrate of the compound of Formula (I) exhibits one or two overlapping endotherms by DSC prior to melting / decomposition with peak temperatures within a range selected from about 120° C. to about 140° C., about 125° C. to about 135° C., and about 126° C. to about 133° C. (see FIG. 3), labeled Form 1.

[0022] In certain embodiments, the crystalline hydrate of the compound of formula (I) is a dihydrate. In certain embodiments, the crystalline hydrate of the compound of formula (I) contains about 1.8, about 1.9, about 2.0, about 2.1, or about 2.2 molecules of water per molecule of the compound of formula (I). In certain embodiments, the crystalline hydrate of the compound of formula (I) exhibits two endotherms by differential scanning calorimetry (DSC) prior to melting / decomposition, with the peak temperature of the first endotherm being within a range selected from about 25°C to about 65°C, 30°C to about 60°C, about 40°C to about 55°C, and about 45°C to about 50°C; the peak temperature of the second endotherm being within a range selected from about 60°C to about 85°C, about 65°C to about 80°C, and about 70°C to about 75°C. See FIG. 4, labeled Form 2.

[0023] In some embodiments, the crystalline hydrate of the compound of Formula (I) exhibits melting / decomposition by DSC with an onset temperature within a range selected from about 178°C to about 190°C, about 182°C to about 186°C, and about 183°C to about 185°C.

[0024] In certain embodiments, the present invention relates to a pharmaceutical composition comprising a crystalline compound of formula (I) and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical composition is selected from a tablet, a capsule, and a suspension.

[0025] In certain embodiments, a pharmaceutical composition comprises a salt of a compound of Formula (I) and one or more pharma- ceutically acceptable excipients.

[0026] Definition: As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0027] As used herein, the term "hydrate" refers to the complex formed by combining a compound of formula (I) with water. The term includes stoichiometric as well as non-stoichiometric hydrates.

[0028] As used herein, the term "solvate" refers to a complex formed by combining a compound of Formula (I) with a solvent.

[0029] As used herein, a "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the subject being treated, the subject's weight and age, the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0030] The term "substantially pure" is used herein to refer to a crystalline polymorph that is greater than 90% pure and contains less than 10% of any other compound or other polymorph of the crystalline form. Preferably, the crystalline polymorph is greater than 95% pure, and even greater than 98% pure.

[0031] The phrase "substantially as shown in the figure" refers to an X-ray powder diffraction pattern in which at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of its peaks are apparent in the figure.

[0032] As used herein, the term "about," when referring to a number or numerical range, means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary, for example, by 1% to 15% of the stated number or numerical range.

[0033] Methods for preparing crystalline forms of the compound of formula (I) In certain embodiments, the present invention relates to a method for preparing a crystalline compound having a structure of formula (I), comprising: a) providing a mixture comprising a compound of formula (I) and a solvent; and b) crystallizing a compound of formula (I) from a mixture containing the compound of formula (I).

[0034] In certain embodiments, the mixture comprising a compound of Formula (I) and a solvent is a reaction mixture.

[0035] In certain embodiments, the mixture comprising the compound of formula (I) is a solution. In certain embodiments, the solution comprises the compound of formula (I) dissolved in a solvent. In some embodiments, the solution comprises a crude solid material comprising the compound of formula (I) dissolved in a solvent. In some embodiments, the solution comprises a reaction mixture.

[0036] In certain embodiments, the mixture is a slurry or suspension. In certain embodiments, the slurry or suspension comprises a crude solid material comprising the compound of formula (I).

[0037] In certain embodiments of the solutions, slurries, and suspensions disclosed herein, the crude solid material comprising the compound of formula (I) is less than 70% pure, less than 75% pure, less than 80% pure, less than 85% pure, or less than 90% pure with respect to the compound of formula (I). In certain embodiments, the crude solid material comprising the compound of formula (I) is less than 90% pure with respect to the compound of formula (I). In certain embodiments, the crude solid material comprises about 70% to about 90% of the compound of formula (I). In some embodiments, the purity of the crude solid material is about 70% to about 90% with respect to the compound of formula (I).

[0038] In certain embodiments, after crystallization, the compound of formula (I) is substantially pure. In some embodiments, the crystalline form of the compound of formula (I) is greater than 90% pure. In some embodiments, the purity of the crystalline form of the compound of formula (I) is selected from greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. In some embodiments, the purity of the crystalline form of the compound of formula (I) is greater than 95%. In some embodiments, the purity of the crystalline form of the compound of formula (I) is greater than 98%. In some embodiments, the purity of the crystalline form of the compound of formula (I) is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%.

[0039] In certain embodiments, the crystalline compounds produced by the methods of the invention are solvates, eg, hydrates.

[0040] In certain embodiments, the crystalline compound produced by the methods of the invention is a monohydrate.

[0041] In certain embodiments, the crystalline compound produced by the methods of the invention is a dihydrate.

[0042] In some embodiments, the solvent vapor gradually diffuses into the solid sample. In some embodiments, the solvent vapor is water vapor. In some embodiments, the solid sample is in Form 1 and the solvent is water, for example to achieve Form 2.

[0043] In certain embodiments, crystalline Form 1 of the compound of formula (I) can be substantially free of other crystalline forms of the compound of formula (I). In certain embodiments, crystalline Form 1 of the compound of formula (I) can be substantially free of crystalline Form 2 of the compound of formula (I).

[0044] In certain embodiments, crystalline Form 2 of the compound of formula (I) can be substantially free of other crystalline forms of the compound of formula (I). In certain embodiments, crystalline Form 2 of the compound of formula (I) can be substantially free of crystalline Form 1 of the compound of formula (I).

[0045] In certain embodiments, the mixture comprising the compound of formula (I) is a solution, and the step of crystallizing the compound from the mixture comprises supersaturating the solution and causing the compound of formula (I) to precipitate from the solution.

[0046] In certain embodiments, supersaturating the mixture containing the compound of formula (I) includes slowly adding an antisolvent, such as heptane, hexane, ethanol, or another polar or non-polar liquid miscible with the aqueous solution, cooling the solution (with or without seeding the solution), reducing the volume of the solution, or any combination thereof. In certain embodiments, the antisolvent is ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, methyl tert-butyl ether, isopropyl acetate, and acetone. In certain embodiments, the antisolvent is ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, and acetone. In certain embodiments, the antisolvent is ethanol. In certain embodiments, supersaturating the mixture containing the compound of formula (I) includes adding an antisolvent, cooling the solution to below ambient temperature, for example, reducing the volume of the solution by evaporating the solvent from the solution. In certain embodiments, cooling the solution can be passive (e.g., allowing the solution to stand at ambient temperature) or active (e.g., cooling the solution in an ice bath or freezer).

[0047] In certain embodiments, the preparation method further comprises isolating the crystals, for example, by filtering the crystals, by decanting the fluid from the crystals, or by any other suitable separation technique. In further embodiments, the preparation method further comprises washing the crystals.

[0048] In certain embodiments, the preparation method further comprises inducing crystallization. The method can also comprise drying the crystals, for example under reduced pressure. In certain embodiments, inducing precipitation or crystallization comprises secondary nucleation, where nucleation occurs in the presence of a seed crystal or interaction with the environment (crystallizer walls, stirring impeller, sonication, etc.).

[0049] In other embodiments, the solvent is acetonitrile, diethyl ether, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane, ethanol, ethyl acetate, heptane, hexane, isopropyl acetate, methanol, methyl ethyl ketone, N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, toluene, 2-propanol (isopropanol), 1-butanol, water, or any combination thereof. In some embodiments, the solvent is dichloromethane. In some preferred embodiments, for example to achieve Form 1, the solvent is tetrahydrofuran.

[0050] In some embodiments, the anti-solvent is selected from tetrahydrofuran, methanol, isopropanol, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, and acetone. In some embodiments, the anti-solvent is gradually added to the aqueous solution containing the compound of formula (I). In certain preferred embodiments, for example, to achieve Form 2, the aqueous solution containing Form 1 is combined with an anti-solvent selected from tetrahydrofuran, methanol, isopropanol, diethyl ether, ethanol, 1,4-dioxane, acetonitrile, and acetone.

[0051] In some embodiments, the anti-solvent is selected from tetrahydrofuran, methanol, isopropanol, 1,4-dioxane, acetonitrile, and acetone. In some embodiments, the anti-solvent is gradually diffused into the aqueous solution containing the compound of formula (I). In certain preferred embodiments, for example to achieve Form 2, the aqueous solution containing Form 1 is diffused with an anti-solvent selected from tetrahydrofuran, methanol, isopropanol, 1,4-dioxane, acetonitrile, and acetone.

[0052] In some embodiments, the slurry containing the compound of formula (I) and the solvent were mixed prior to isolating the solid. In some embodiments, isolation of the solid is by filtration or centrifugation. In some embodiments, to achieve Form 2, the slurry containing Form 1 was mixed with a solvent selected from acetonitrile, anisole, dichloromethane, ethanol, isopropyl acetate, methyl tert-butyl ether (MTBE), n-heptane, tetrahydrofuran, water, and mixtures thereof.

[0053] In some embodiments, to achieve Form 2, a slurry containing Form 1 was mixed with a solvent selected from acetonitrile, ethanol, methyl tert-butyl ether (MTBE), water, and mixtures thereof.

[0054] In some embodiments, to achieve Form 2, a slurry containing the compound was mixed with a solvent selected from acetonitrile, methyl tert-butyl ether (MTBE), water, and mixtures thereof.

[0055] In certain embodiments, the solvent is a mixture containing water. In some preferred embodiments, the solvent is a mixture containing water and ethanol, isopropanol, methanol, or tetrahydrofuran. In certain preferred embodiments, for example to achieve Form 2, the solvent is a mixture containing water and tetrahydrofuran. In other embodiments, the solvent is a mixture containing water and another solvent selected from ethanol, isopropanol, methanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, and acetone.

[0056] In certain preferred embodiments, the solvent mixture is selected from water / tetrahydrofuran (HO / THF), water / methanol (HO / MeOH), water / isopropanol (HO / IPA), water / ethanol (HO / EtOH), water / 1,4-dioxane (HO / 1,4-dioxane), water / acetonitrile (HO / ACN), or water / acetone (HO / acetone).

[0057] In some embodiments, the solvent is a mixture comprising EtOH:H2O in a volume to volume ratio selected from 19:2, 5:1, 2:1, 1:1, and 1:9. In some embodiments, the solvent is a mixture comprising ethanol and water, to which additional ethanol or a mixture of ethanol and water is added. In some embodiments, the mixture comprises the compound of formula (I) and a solvent of 2:1 EtOH:H2O (v / v), and then a mixture of 19:2 EtOH:H2O is added for crystallization.

[0058] In some embodiments, crystallization is assisted by seeding, which involves adding seed crystals to the mixture. In some embodiments, the seed crystals are added at a weight percentage of the total mixture selected from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, and about 10 wt%. In some embodiments, the seed crystals are added at a weight percentage of the total mixture selected from about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, and about 6 wt%. In some embodiments, the seed crystals are added at a weight percentage of the total mixture selected from 3 wt%, 4 wt%, and 5 wt%.

[0059] In some embodiments, the seed crystals are Formula (I) Form 2 seeds. In certain embodiments, the seed crystals are ground.

[0060] In certain embodiments, washing the crystals comprises washing with a liquid selected from an antisolvent, acetonitrile, ethanol, heptane, hexane, methanol, tetrahydrofuran, toluene, water, or a combination thereof.

[0061] As used herein, "antisolvent" refers to a solvent in which the compound crystals are insoluble, minimally soluble, or partially soluble. In effect, the addition of an antisolvent to a solution in which salt crystals are dissolved reduces the solubility of the salt crystals in the solution, thereby stimulating the precipitation of the salt. In certain embodiments, the crystals are washed with a combination of an antisolvent and an organic solvent. In certain embodiments, the antisolvent is water, while in other embodiments, it is an alkane solvent, such as hexane or pentane, or an aromatic hydrocarbon solvent, such as benzene, toluene, or xylene. In certain embodiments, the antisolvent is methanol.

[0062] In certain embodiments, washing the crystals comprises washing the crystalline compound of Formula (I) with a solvent or a mixture of one or more solvents described above. In certain embodiments, the solvent or mixture of solvents is cooled prior to washing.

[0063] In certain embodiments, the methods for preparing a crystalline form of the compound of formula (I) are used to remove one or more impurities from a sample of the compound of formula (I). In certain embodiments, the crystallization methods described herein are used to purify the compound of formula (I), for example, as a final purification step in the manufacture of the compound.

[0064] In certain embodiments, the compound of formula (I) is purified by crystallization. In some embodiments, the purification of the compound of formula (I) does not use high performance liquid chromatography (HPLC), including preparative HPLC. In some embodiments, the purification of the compound of formula (I) by crystallization is scalable. The advantages of purification by crystallization include, but are not limited to, removal of soluble impurities, ease of purification process, applicability to large-scale synthesis, acceptable yield, and high product purity.

[0065] In some embodiments, crystalline Formula (I) Form 2 was the form with greater stability. In some embodiments, crystalline Formula (I) Form 2 is more stable in water than crystalline Formula (I) Form 1. In some embodiments, the temperature was less than about 20°C, less than about 15°C, less than about 10°C, less than about 5°C, or less than about 0°C. In some embodiments, the temperature was about 20°C, about 15°C, about 10°C, about 5°C, or about 0°C. In some embodiments, the temperature was about 10°C, about 9°C, about 8°C, about 7°C, about 6°C, about 5°C, about 4°C, about 3°C, about 2°C, about 1°C, about 0°C, about -1°C, or about -2°C. In some embodiments, the temperature was about 10°C.

[0066] In some embodiments, the conversion to crystalline Formula (I) Form 2 was complete in about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days. In some embodiments, the conversion to crystalline Formula (I) Form 2 was complete in about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, or about 26 hours.

[0067] Use of the crystalline forms of the compound of formula (I) The compounds of formula (I) are 3-substituted 1,2,4-oxadiazole compounds having the structure [ka]

[0068] Functional "exhaustion" (immune dysfunction) among T and B cell subsets is a well-described feature of chronic viral infections, such as hepatitis B and C and HIV viruses. T cell exhaustion was first described for CD8 T cells in mice chronically infected with lymphocytic choriomeningitis virus clone 13. In the lymphocytic choriomeningitis virus mouse model, repeated antigen stimulation via the T cell antigen receptor drives sustained expression of T cell inhibitory receptors, including programmed cell death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3), on virus-specific CD8 T cells (J. Illingworth et al., J. Immunol. 2013, 190(3): 1038-1047).

[0069] Thus, for example, but not limited to, cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and diseases regulated by the immune response, such as transplant rejection, can be treated by administering an immunomodulator, such as a compound of Formula (I), and compositions disclosed herein. The 3-substituted 1,2,4-oxadiazole compounds act as immunomodulators.

[0070] In certain embodiments, the compounds of Formula (I) modulate the immune response in a cell.

[0071] In other embodiments, the disclosure provides a method of modulating an immune response in a cell, comprising contacting the cell with a composition comprising a crystalline form of a compound of formula (I) according to any of the above embodiments. In some embodiments, the disclosure provides a method of modulating an immune response in a cell, comprising contacting the cell with a composition comprising a crystalline form of a compound of formula (I) according to any of the above embodiments.

[0072] In certain embodiments, the disclosure provides for the use of a crystalline form of the compound of formula (I) for the preparation of a medicament for the treatment of, for example, cancer, immune disorders, immune deficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.

[0073] According to any of the foregoing embodiments, in certain embodiments, contacting of the cells occurs in a subject in need thereof to treat a disease or disorder selected from cancer, an immune disorder, an immunodeficiency disorder, an inflammatory disorder, an infectious disease, and transplant rejection.

[0074] In certain embodiments, the disclosure provides a method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of the compound of Formula (I).

[0075] In certain embodiments, the present disclosure provides methods for inhibiting tumor cell proliferation and / or metastasis by administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of the compound of Formula (I).

[0076] Representative tumor cells include, but are not limited to, cells of cancers such as blastoma (e.g., glioblastoma), breast cancer (e.g., breast carcinoma, primary ductal carcinoma, triple negative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (PR+), and / or human epidermal growth factor receptor 2 positive (HER2+)), epithelial cancer (e.g., carcinoma), colon cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), melanoma (e.g., cutaneous melanoma, intraocular melanoma, cutaneous or intraocular malignant melanoma, and lymph node associated melanoma), prostate cancer (e.g., prostatic adenocarcinoma), renal cancer (e.g., renal cell carcinoma (RCC) and renal cell carcinoma), bone cancer (e.g., osteosarcoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), skin cancer, head or neck cancer (e.g., head and neck squamous cell carcinoma), uterine cancer, ovarian cancer (e.g., ovarian carcinoma), colorectal cancer (e.g., microsatellite instability high colorectal carcinoma and colorectal adenocarcinoma), rectal cancer, cancer of the anal region, cancer of the peritoneum, gastric cancer (e.g., gastric and gastrointestinal cancer), testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer (e.g., cervical carcinoma), vaginal cancer (e.g., cancer of the vagina), vulva (e.g., vulvar carcinoma), esophagus, small intestine, endocrine system, thyroid (e.g., thyroid cancer), parathyroid, adrenal gland, sarcoma (e.g., soft tissue sarcoma and Kaposi's sarcoma), urethra, penis, chronic or acute leukemia (e.g., acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and chronic myeloblastic leukemia), childhood solid tumors, Hodgkin's lymphoma (HL) (e.g., lymphocyte-rich (LRCHL), nodular sclerosing type (NSHL), mixed cell type (MCHL), and lymphocytic depletion (LDHL)), B-cell lymphomas (e.g., diffuse large B-cell lymphoma (DLBCL)), non-Hodgkin's lymphomas (NHL) (e.g., low-grade / follicular non-Hodgkin's lymphoma, small lymphocytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small noncleaved cell NHL, bulky mass disease NHL, Burkitt's lymphoma, mantle cell lymphoma), AIDS-related lymphomas, cutaneous T-cell lymphomas (e.g., mycosis fungoides,fundoides) and Waldenstrom's macroglobulinemia, post-transplant lymphoproliferative disorder (PTLD), lymphocytic lymphoma, primary CNS lymphoma, and T-cell lymphoma), mesothelioma, thymic carcinoma, myeloma (e.g., multiple myeloma), cancer of the bladder (e.g., bladder carcinoma), cancer of the ureter, carcinoma of the renal pelvis, liver cancer (e.g., hepatocellular carcinoma, hepatoma, hepatoma), pancreatic cancer, post-transplant lymphoproliferative disorder (PTLD), neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, epidermoid carcinoma, salivary gland cancer, squamous cell carcinoma, abnormal blood vessel proliferation associated with nevus syndrome, edema (e.g., associated with brain tumors), Meigs syndrome, Merkel cell carcinoma, environmentally induced cancers (including those induced by asbestos), and combinations of the above cancers.

[0077] In other embodiments, for example, the tumor cells include cells of a cancer selected from: prostate cancer, melanoma, breast cancer, colon cancer, prostate cancer, lung cancer, renal cancer, pancreatic cancer, gastric cancer, bladder cancer, esophageal cancer, mesothelioma, thyroid cancer, thymic cancer, sarcoma, glioblastoma, chronic or acute leukemia, lymphoma, myeloma, Merkel cell carcinoma, epithelial carcinoma, colorectal cancer, vaginal cancer, cervical cancer, ovarian cancer, and head and neck cancer.

[0078] In other embodiments, for example, the tumor cells include cells of a cancer selected from: melanoma, triple-negative breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric cancer, bladder cancer, mesothelioma, Hodgkin's lymphoma, cervical cancer, ovarian cancer, and head and neck squamous cell carcinoma.

[0079] In some embodiments, the tumor cells are cells of a cancer selected from the following: small cell lung carcinoma, multiple myeloma, bladder cancer, primary ductal carcinoma, ovarian cancer, Hodgkin's lymphoma, gastric cancer, acute myeloid leukemia, and pancreatic cancer.

[0080] In other embodiments, the tumor cells are cells of a cancer selected from endometrial cancer, ovarian cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and chronic or acute leukemia, such as acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, and multiple myeloma.

[0081] In some embodiments, the tumor cells are from a cancer selected from the following: prostate adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, breast cancer, and colorectal adenocarcinoma. In certain embodiments, the tumor cells are from breast cancer. In some embodiments, the tumor cells are from breast cancer selected from triple negative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (PR+), and / or human epidermal growth factor receptor 2 (HER2+). In other embodiments, the tumor cells are from breast cancer selected from PAM50+ breast cancer assay panel (Parker, JS, et al., J. Clin. Oncol., 2009, 27(8): 1160-1167), luminal A, luminal B, HER2-rich, basal-like, and normal-like.

[0082] In some embodiments, the tumor cell is a cell of a cancer selected from: triple-negative breast cancer, microsatellite instability-high colorectal cancer, gastric cancer, mesothelioma, pancreatic cancer, and cervical cancer.

[0083] In some embodiments, the tumor cells and / or the subject are naive to immuno-oncology therapy. Immuno-oncology uses the subject's immune system to help fight cancer. For example, immuno-oncology therapy includes atezolizumab (a human monoclonal antibody targeting PD-L1), avelumab (a human monoclonal antibody targeting PD-L1), brentuximab vedotin (an antibody-drug conjugate targeting CD30), durvalamab (a human monoclonal antibody targeting PD-L1), ipilimumab (a human monoclonal antibody targeting CTLA-4), nivolumab (a human monoclonal antibody targeting PD-L1), pembrolizumab (also called lambrolizumab, Examples of immuno-oncology therapies include, but are not limited to, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-TIGIT antibodies (e.g., antibodies disclosed in WO2015 / 009856).

[0084] In other embodiments, the tumor cell and / or the subject is responsive to immune checkpoint therapy. In some embodiments, the cancer shows response to anti-PD1 therapy. For example, the cancer includes non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), bladder cancer, Hodgkin's lymphoma, and head and neck squamous cell carcinoma.

[0085] Another embodiment of the present disclosure provides a method of treating an infection.

[0086] Yet another embodiment of the present disclosure provides a method of treating an infection comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I).

[0087] In certain embodiments, the present disclosure provides the use of a crystalline form of the compound of formula (I) for the preparation of a medicament for the treatment of an infectious disease, as well as a method of administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) for the treatment of an infectious disease.

[0088] In some embodiments, the infectious disease is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection, and the method of administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of Formula (I) is for the treatment of a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.

[0089] In some embodiments, for example, the bacterial infection can be caused by at least one bacterium selected from the following: Anthrax, Bacillus, Bordetella, Borrelia, Botulinum, Brucella, Burkholderia, Campylobacter, Chlamydia, Cholera, Clostridium, Conococcus, Corynebacterium, Diptheria, Enterobacter, Enterococcus, Erwinia, Escherichia, Francisella, Haemophilus, Helicobacter Heliobacter, Klebsiella, Legionella, Leptospirosis, Listeria, Lyme Disease, Meningococcus, Mycobacteria, Mycoplasma, Neisseria, Pasteurella, Pelobacter, Plague, Pneumonococcus, Proteus, Pseudomonas, Rickettsia, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus, Tetanus, Treponema, Vibrio, Yersinia, and Xanthomonas.

[0090] In other embodiments, for example, the viral infection may be caused by at least one virus selected from the following: adenovirus, papillomavirus, polyomavirus, herpesvirus, poxvirus, hepadnavirus, parvovirus, astrovirus, calicivirus, picornavirus, coronoviridae, flavivirus, retrovirus, togavirus, arenavirus, bunyavirus, filovirus, orthomyxovirus, paramyxovirus, rhabdovirus, and reovirus. In certain embodiments, the virus is an arbovirus encephalitis virus, adenovirus, herpes simplex type I, herpes simplex type 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, herpes virus type 8, papillomavirus, BK virus, coronavirus, echovirus, JC virus, smallpox, hepatitis B, bocavirus, parvovirus B19, astrovirus, Norwalk virus, coxsackievirus, hepatitis A, poliovirus, rhinovirus, severe acute respiratory syndrome virus, hepatitis C, yellow fever, dengue virus, West Nile virus, The virus may be rabies, rubella, hepatitis E, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), influenza, Guanarito virus, Junin virus, Lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, measles virus, molluscum virus, mumps virus, parainfluenza, respiratory syncytial virus, human metapneumovirus, Hendra virus, Nipah virus, rabies, hepatitis D, rotavirus, orbivirus, Cortivirus, vaccinia virus, and Banna virus.

[0091] In other embodiments, for example, the fungal infection may be selected from thrush, Aspergillus (fumigatus, Aspergillus niger, etc.), Blastomyces dermatitidis, Candida (albicans, krusei, glabrata, tropicalis, etc.), Coccidioides immitis, Cryptococcus (neoformans, etc.), Histoplasma capsulatum, Mucorales (Mucor, abscidia, rhizophus), South American blastomycosis, Sporotrichosis, Sporotrichus schenckii, zygomycosis, chromoblastomycosis, lobomycosis, mycetoma, onychomycosis, psoriasis versicolor, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea nigricans, tinea pedis, otomycosis, brown fungal infection, and rhinosporidiosis.

[0092] In some embodiments, for example, the parasitic infection can be caused by at least one parasite selected from the following: Acanthamoeba, Babesia murine, Balantidium coli, Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rhodasiensis, Trypanosomatida rhodasiensis, and / or other parasites. rhodesiense), Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicanus, Leishmania braziliensis, Leishmania tropica, Leishmania donovani, Toxoplasma gondii, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Pneumocystis carinii, Trichomonas vaginalis, Histomonas meleagridis, Secementea, Trichuris trichiura, Ascaris lumbricoides, Pinworms, Ancylostoma dubini, Naegleria fowleri, Ancylostoma americanus, Ancylostoma braziliensis, Strongyloides stercoralis, Wuchereria bancrofti, Dracaena worm, Schistosoma blood fluke, Clonorchis fasciata, Intestinal fluke, Paragonimus spp., Schistosoma mansoni, Schistosoma haematobium, Schistosoma japonicum, Fasciola hepatica, Fasciola giantis, Fluke virulence, and Paragonimus westermani.

[0093] The term "subject" includes mammals, especially humans, and other animals, such as domestic animals (eg, household pets, including cats and dogs) and non-domestic animals (eg, wildlife).

[0094] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that reduces the occurrence or frequency of a disorder or condition in a statistical sample in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of a disorder or condition compared to an untreated control sample. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population compared to an untreated control population (e.g., by a statistically and / or clinically significant amount). Preventing infection includes, for example, reducing the number of diagnoses of infection in a treated population compared to an untreated control population, and / or delaying the onset of symptoms of infection in a treated population compared to an untreated control population. Preventing pain includes, for example, reducing or alternatively delaying the magnitude of pain sensations experienced by subjects in a treated population compared to an untreated control population.

[0095] The term "treat" includes preventive and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the subject compositions to a host. When administered prior to clinical symptoms of an unwanted condition (e.g., a disease or other unwanted condition of a host animal), the treatment is then preventive (i.e., it protects the host against the onset of the unwanted condition), whereas when administered after the onset of an unwanted condition, the treatment is therapeutic (i.e., intended to reduce, ameliorate, or stabilize an existing unwanted condition or its side effects).

[0096] Pharmaceutical Compositions In certain embodiments, the present disclosure provides pharmaceutical compositions comprising a crystalline form of a compound of formula (I) disclosed herein, optionally mixed with a pharma- ceutically acceptable carrier or diluent.

[0097] The present disclosure also provides methods for formulating the disclosed crystalline forms of the compound of formula (I) for pharmaceutical administration.

[0098] The compositions and methods of the present disclosure may be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising a crystalline form of the compound of formula (I) of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions such as water or physiological buffered saline, or other solvents or vehicles, such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be selected, for example, to effect delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilisates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as a skin patch. The composition can also be present in a solution suitable for topical administration, such as eye drops.

[0099] A pharma- ceutically acceptable carrier can include a physiologically acceptable agent that acts to stabilize, increase the solubility, or increase the absorption of a compound, such as, for example, a crystalline form of the compound of formula (I) of the present disclosure. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or dextran, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable carrier that includes a physiologically acceptable agent depends, for example, on the route of administration of the composition. The pharmaceutical composition preparation can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, which can incorporate, for example, a crystalline form of the compound of formula (I) of the present disclosure. For example, liposomes that include phospholipids or other lipids are non-toxic, physiologically acceptable metabolizable carriers, and are relatively simple to prepare and administer.

[0100] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit / risk ratio.

[0101] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, tocopherol, and the like. corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0102] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example: orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, as aqueous or non-aqueous solutions or suspensions); absorption through the oral mucosa (e.g., sublingually); anally, rectally, or vaginally (e.g., as pessaries, creams, or foams); parenterally (e.g., including intramuscularly, intravenously, subcutaneously, or intrathecally, as sterile solutions or suspensions); intranasally; intraperitoneally; subcutaneously; transdermally (e.g., as patches applied to the skin); and topically (e.g., as creams, ointments, or sprays applied to the skin, or as eye drops). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and in the patents cited therein.

[0103] The formulations may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form varies depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form is generally the amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0104] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a crystalline form of the compound of formula (I) of the present disclosure, with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0105] Formulations of the present disclosure suitable for oral administration can be present in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), lyophilisates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The composition or compound can also be administered as a bolus, electuary, or paste.

[0106] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) hydrates, such as glycerol; (5) hydrates, such as glycerol; (6) hydrates, such as glycerol; (7) hydrates, such as glycerol; (8) hydrates, such as glycerol; (9) hydrates, such as glycerol; (10) hydrates, such as glycerol; (11) hydrates, such as glycerol; (12) hydrates, such as glycerol; (13) hydrates, such as glycerol; (14) hydrates, such as glycerol; (15) hydrates, such as glycerol; (16) hydrates, such as glycerol; (17) hydrates, such as glycerol; (18) hydrates, such as glycerol; (19 ... (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions can also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0107] Tablets may be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active or dispersing agents. Molded tablets may be manufactured by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0108] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation field. They can also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide a desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0109] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsion, lyophilized matter for reconstitution, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0110] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0111] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0112] Formulations of pharmaceutical compositions for rectal, intravaginal, or urethral administration can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and can be provided as a suppository which is solid at room temperature but liquid at body temperature and will therefore melt in the rectal or vaginal cavity and release the active compound.

[0113] Formulations of a pharmaceutical composition for administration to the mouth may be presented as a mouthwash, or a mouth spray, or a mouth ointment.

[0114] Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be useful for delivery to the bladder, urethra, ureter, rectum, or intestine, among others.

[0115] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0116] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0117] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0118] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0119] Transdermal patch has the added advantage of providing controlled delivery of the compound of the present disclosure to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in appropriate medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate of such flux can be controlled by providing a rate-limiting membrane or dispersing compound in a polymer matrix or gel.

[0120] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated within the scope of this disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference in their entirety. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. The preferred route of administration is topical administration (e.g., topical administration, e.g., eye drops, or administration via an implant).

[0121] Suppositories are also contemplated as being within the scope of this disclosure.

[0122] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0123] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the formulation isotonic with the blood of the intended recipient.

[0124] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0125] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, prolonged absorption of the injectable formulation may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0126] In some cases, in order to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The rate of absorption of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0127] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0128] For use in the methods of this disclosure, the active compound can be provided per se or as a pharmaceutical composition comprising, for example, 0.1-99.5% (more preferably, 0.5-90%) of the active ingredient together with a pharma- ceutically acceptable carrier.

[0129] Methods of introduction can also be provided by rechargeable or biodegradable devices. A variety of slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biologics. A variety of biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0130] Actual dosage levels of the active ingredient in the pharmaceutical compositions can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and method of administration, without being harmful to the patient.

[0131] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, overall health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0132] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin administration of a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the crystalline form of the compound of formula (I) of the present disclosure. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th Edition, 1814-1882, incorporated herein by reference).

[0133] In general, the suitable daily dose of the active compound used in the compositions and methods of the present disclosure is the amount of the compound that is the lowest dose effective to produce a therapeutic effect.Such effective dose generally depends on the factors described above.

[0134] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more subdoses, which are administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments of the present disclosure, active compound can be administered 2 or 3 times a day.In a preferred embodiment, active compound is administered once a day.

[0135] The patient to receive this treatment may be any animal in need, including primates, particularly humans, and other mammals, such as horses, cattle, pigs and sheep; as well as poultry and pets in general.

[0136] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0137] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0138] Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0139] Working Example Analysis method X-ray powder diffraction X-ray powder diffraction patterns were collected on an Empyrean diffractometer or an X'Pert3 diffractometer using CuKα radiation (45 kV, 40 mA).

[0140] Data collection details are summarized in Table 3: [Table 3]

[0141] HPLC Purity analyses were performed on an Agilent HP1100 series system equipped with a diode array detector using ChemStation software vB.04.03, using the methods detailed in Table 4 below. [Table 4]

[0142] Thermogravimetry and Differential Scanning Calorimetry: Thermogravimetric analysis (TGA) data was collected using a TA Instruments TA Q500 / Q5000 TGA. Differential scanning calorimetry (DSC) was performed using a TA Instruments TA Q200 / Q2000 DSC. Method parameters are provided in Table 5 below. [Table 5]

[0143] PXRD determination of formula (I) as reported in WO2015 / 033299 PXRD determination of the compound of formula (I) was obtained using the procedure described in Example 4 of WO2015 / 033299 (depicting the compound as being amorphous). The PXRD is shown in Figure 8. The contents of WO2015 / 033299 are hereby incorporated by reference in their entirety.

[0144] Example 1: Synthesis of Form 1 A. Crystallization from tetrahydrofuran Formula (I) Form 1 exists at ambient conditions upon short-term storage (i.e., less than 8 days). A mixture of Formula (I) Forms 1 and 2 (16 mg) was weighed into a glass vial and tetrahydrofuran (THF, 0.5 mL) was added. The resulting slurry was stirred at room temperature for approximately 4 days. The wet solid was analyzed by XRPD in transmission mode and confirmed to be crystalline Formula (I) Form 1 as indicated by XRPD analysis (Figure 1).

[0145] B. Crystallization from Ethanol / Water Mixtures Approximately 68.0 g of the amorphous compound of formula (I) was dissolved in a minimum amount of water and ethanol was added to the solution, resulting in a white precipitate. The solid was isolated by filtration. The solid was washed with ethanol, followed by diethyl ether. The solid was dried under high vacuum and confirmed to be formula (I) Form 1 by XRPD analysis.

[0146] Example 2: Synthesis of Form 2 A. Solid Vapor Diffusion Formula (I) Form 1 (approximately 15.3 mg) was weighed into a 3 mL vial, which was then placed into a 20 mL vial with 4.0 mL of water. The 20 mL vial was sealed with a cap and kept at RT for 1 week to allow solvent vapor to interact with the sample. The resulting solid was shown to be crystalline Formula (I) Form 2 by XRPD analysis.

[0147] B. Antisolvent Addition Approximately 15.0 mg of Formula (I) Form 1 sample was dissolved in 0.3 mL of HO in a 20 mL glass vial and stirred at RT. The corresponding antisolvent (e.g., THF, MeOH, IPA, EtOH, 1,4-dioxane, ACN, or acetone) was added to the above aqueous solution until a precipitate appeared or the total volume reached 15.0 mL. The solid was isolated by centrifugation and confirmed to be Formula (I) Form 2 by XRPD analysis. [Table 6]

[0148] C. Solution Vapor Diffusion Approximately 15.0 mg of Formula (I) Form 1 was dissolved in 0.3 mL of HO in a 3 mL glass vial at RT. The clear solution in the open, uncapped vial was then placed in a 20 mL vial with 4.0 mL of antisolvent (e.g., THF, MeOH, IPA, EtOH, 1,4-dioxane, ACN, or acetone). The 20 mL vial was sealed with a cap and kept at RT to allow interaction between the vapor and the solution. The solid was confirmed to be Formula (I) Form 2 by XRPD analysis. [Table 7]

[0149] D. Slurry Approximately 20.0 mg of Formula (I) Form 1 was weighed into a glass vial and 0.5 mL of the corresponding solvent (shown in Table 8) was added. After slurrying for approximately 3 days at the assigned temperature (referenced in Table 6 below), the solid was isolated by centrifugation and confirmed to be Formula (I) Form 2 by XRPD analysis (Figure 2). [Table 8] v: v = vol / vol; aw = water activity at 25°C

[0150] E. Antisolvent addition using a water / acetonitrile mixture The compound was dissolved in 1 volume of water and 10 vol of acetonitrile was added to it and stirred for 12 hours. A white solid precipitated. The precipitate was filtered, washed with acetonitrile containing 1% HO (2 vol) and washed with acetonitrile (2 vol). The precipitate was finally washed with MTBE (10 vol) and dried under high vacuum for 10-15 hours. The solid was confirmed to be Formula (I) Form 2 by XRPD analysis (Figure 2).

[0151] F. Liquid Vapor Diffusion Approximately 15.0 mg of Formula (I) Form 1 was weighed into a 3 mL glass vial to which 0.3 mL of HO (solvent) was added. After vortexing, the suspension was filtered through a polytetrafluoroethylene (PTFE) filtration membrane and the solution was transferred to a new 3 mL glass vial. The uncapped, open vial was then placed into a 20 mL glass vial with 4 mL of 1,4-dioxane (antisolvent) and the system was maintained at room temperature for liquid vapor diffusion. After 70 days at room temperature, rod-shaped crystals suitable for single crystal X-ray diffraction were obtained.

[0152] Example 3: Thermogravimetric analysis and differential scanning calorimetry of formula (I) Thermogravimetric analysis (TGA) of Formula (I) Form 1 showed a weight loss of 5.2% by 80° C., consistent with a monohydrate form. Differential scanning calorimetry (DSC) showed two overlapping endotherms at 125.6° C. and 133.1° C. (peak temperatures) before melting / decomposition with an onset at 184.1° C. (FIG. 3).

[0153] TGA of Formula (I) Form 2 showed a two-step weight loss of 9.6% up to 80° C., consistent with a dihydrate form. DSC showed two endotherms at 47.2° C. and 72.9° C. (peak temperatures) before melting / decomposition with an onset at 184.3° C. (FIG. 4).

[0154] Example 4: Stability and forced decomposition studies for crystalline formula (I) solid state stability Samples of Formula (I) crystalline Form 2 were stored as solids at 25° C. / 60% relative humidity (RH), 30° C. / approximately 56%, and 40° C. / 75% RH for 7-8 days. Samples were prepared in duplicate with a 2 week offset. Each replicate was stored in a different container.

[0155] Crystalline Form 2 of Formula (I) remained unchanged in terms of solid and particulate morphology after storage for 7-8 days at 25° C. / 60% RH, 30° C. / approximately 56% RH, and 40° C. / 75% RH. See FIG. 5.

[0156] Example 5: Solubility Determination for Crystalline Formula (I) The equilibrium solubility of Formula (I) Form 2 was measured in water at 20° C. and 30° C. All samples were equilibrated at temperature for 6 hours and the solubility of the supernatant was measured by HPLC while the solid was confirmed by XRPD. (See Table 9) [Table 9]

[0157] No morphological changes were observed during the solubility studies for Form 2 (Figure 6).

[0158] Example 6: Single crystal structure determination Single crystals for X-ray diffraction were obtained from H2O / 1,4-dioxane by liquid vapor diffusion as described in Example 2F. X-ray diffraction data were collected using a PANalytical instrument. Structural information and refinement parameters are given in Table 10. [Table 10]

[0159] Single crystal structure analysis confirmed that crystalline Formula (I) Form 2 was a dihydrate with an asymmetric unit consisting of one Formula (I) molecule and two water molecules (Figure 7A). One water molecule forms two hydrogen bonds intramolecularly with two oxygen atoms (O5 and O7) on one Formula (I) molecule and two hydrogen bonds intermolecularly with each N1 atom on two different Formula (I) molecules. This water molecule bridges the negatively and positively charged groups of the zwitterion. Two additional water molecules form an intermolecular bridge between the two N2 atoms. The bond distances of C-O / C=O from the carboxyl groups were similar. There were three residual electron density peaks assigned as hydrogen atoms around the N1 atom. Therefore, it is suggested that the Formula (I) molecule was a zwitterion in the Form 2 crystals (Figure 7B).

[0160] Citation by reference All publications and patents mentioned in this specification are hereby incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including all definitions herein, will control.

[0161] Equivalent While specific embodiments of the subject invention have been described, the above specification is illustrative only and not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the patent specification, along with such variations.

Claims

1. A crystal of a dihydrate of the compound represented by formula (I), 【Chemistry 1】 The dihydrate crystal of the compound represented by formula (I), wherein the X-ray powder diffraction pattern of the dihydrate crystal of the compound represented by formula (I) has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 29.7±0.2, and 33.7±0.

2.

2. 2. The dihydrate crystal of the compound of claim 1, wherein the X-ray powder diffraction pattern of the dihydrate crystal of the compound has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 20.3±0.2, 28.9±0.2, 29.7±0.2, and 33.7±0.

2.

3. 2. The dihydrate crystal of the compound of claim 1, wherein the X-ray powder diffraction pattern of the dihydrate crystal of the compound has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 19.6±0.2, 20.3±0.2, 26.2±0.2, 28.9±0.2, 29.7±0.2, and 33.7±0.

2.

4. 2. The dihydrate crystal of the compound of claim 1, wherein the X-ray powder diffraction pattern of the dihydrate crystal of the compound has 2θ values ​​of 12.9±0.2, 13.5±0.2, 15.7±0.2, 17.0±0.2, 19.1±0.2, 19.6±0.2, 20.3±0.2, 21.1±0.2, 21.4±0.2, 26.2±0.2, 27.2±0.2, 28.9±0.2, 29.7±0.2, 32.2±0.2, and 33.7±0.

2.

5. The X-ray powder diffraction patterns of the dihydrate crystal of the compound were 10.9±0.2, 11.6±0.2, 12.9±0.2, 13.5±0.2, 15.7±0.2, 16.1±0.2, 17.0±0.2, 19.1±0.2, 19.6±0.2, 20.3±0.2, 21.1±0.2, 21.4±0.2, 22.2±0.2, 22.9±0.2, 24.2±0.2, 24.5±0.2, 24.8±0.2, 25.0 ... . A crystal of the dihydrate of the compound of claim 1 having 2θ values ​​of 1±0.2, 25.8±0.2, 26.2±0.2, 26.4±0.2, 27.2±0.2, 28.2±0.2, 28.9±0.2, 29.7±0.2, 30.2±0.2, 31.0±0.2, 32.2±0.2, 33.7±0.2, 34.2±0.2, 36.0±0.2, 37.0±0.2, 38.4±0.2 and 39.0±0.

2.

6. A pharmaceutical composition comprising a crystalline dihydrate of the compound of any one of claims 1 to 5, and one or more pharma- ceutically acceptable excipients.

7. 13. Use of the dihydrate crystal of the compound of claim 1 in the manufacture of a medicament for treating cancer, an immune disorder, an immunodeficiency disorder, an inflammatory disorder, an infectious disease, or a transplant rejection.

8. The use of claim 7, wherein the medicament is for treating cancer.

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