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

Abstract

To provide improved compositions of 3-substituted 1,2,4-oxadiazole compounds, and improved methods for preparing and formulating 3-substituted 1,2,4-oxadiazole compounds.SOLUTION: The present invention provides a crystalline compound having a structure of formula (I).SELECTED DRAWING: Figure 1

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 content of which is hereby incorporated herein by reference in its entirety.

Background Art

[0002] In mammals, the immune system controls the activation and inactivation of lymphocytes by various mechanisms during and after an immune response. Among these mechanisms, there are mechanisms that specifically regulate the immune response as needed and when necessary.

[0003] 3 - substituted 1,2,4 - oxadiazole compounds act as immunomodulatory agents. Thus, 3 - substituted 1,2,4 - oxadiazole compounds can be used in the treatment of cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and graft rejection.

[0004] Considering the therapeutic effects associated with 3 - substituted 1,2,4 - oxadiazole compounds, improved compositions of these compounds are needed. Further, improved methods for preparing and formulating 3 - substituted 1,2,4 - oxadiazole compounds are needed.

Summary of the Invention

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

Chemical formula

[0006] Another aspect of the present invention relates to a method for preparing a 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 pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation may be used for the treatment or prevention of any medical condition or disease described herein. [Brief explanation of the drawing]

[0008] [Figure 1] Formula (I) shows the XRPD pattern of form 1. [Figure 2] The superimposed XRPD patterns of Form 2 of Equation (I) from Examples 2D and 2E are shown. [Figure 3] The thermogravimetric analysis and differential scanning calorimetry thermograms of Form 1 are shown. [Figure 4] The thermogravimetric analysis and differential scanning calorimetry thermograms of form 2 are shown. [Figure 5] The following shows a comparison of the XRPD patterns of Equation (I) Form 2 at 7-8 days, at 25°C, 60% relative humidity (RH); 40°C, 75% RH; and 30°C, 56% RH, compared with a solid-state Form 2 reference sample. [Figure 6] This shows a comparison of the XRPD patterns of Equation (I) Form 2 in water at 20°C, in water at 30°C, and Form 2 after solubility testing. [Figure 7A] Equation (I) shows the asymmetric unit of a form 2 single crystal. [Figure 7B] Formula (I) shows the proposed proton transfer for forming zwitterions in the form 2 crystal. [Figure 8] The amorphous (I) XRPD pattern is shown. [Modes for carrying out the invention]

[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 a crystalline compound having a structure of formula (I) that can be depicted by showing all of the atoms

Chemical formula

[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 medical condition disclosed herein.

[0013] In certain embodiments, the compounds of the present invention can have more than one crystal form. 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 understood herein as "polymorphs".

[0014] In certain embodiments, the polymorphs of the crystalline compound 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 twice the diffraction angle θ. Thus, in certain embodiments, the diffraction patterns described herein show the X-ray intensity measured against 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 further additional 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, 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 ±0.2 listed in Table 1.

Table 1

[0018] In certain embodiments, the crystalline hydrate of the compound of formula (I) has a substantially XRD pattern shown in FIG. 1 and is designated as Form 1.

[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 further 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 another embodiment, 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 ±0.2 listed in Table 2. [Table 2]

[0020] In certain embodiments, the crystalline hydrate of the compound of formula (I) has substantially the XRD pattern shown in Figure 2 and is referred to as form 2.

[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 endothermic reactions before melting / decomposition, according to 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 endothermic reactions before melting / decomposition, with a peak temperature within 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 endothermic reactions before melting / decomposition according to DSC, with peak temperatures within a range selected from approximately 120°C to approximately 140°C, approximately 125°C to approximately 135°C, and approximately 126°C to approximately 133°C. Refer to Figure 3, which is indicated as Embodiment 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 endothermic reactions before melting / decomposition, according to differential scanning calorimetry (DSC), with the peak temperature of the first endothermic reaction 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 endothermic reaction 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. Refer to Figure 4, which is indicated as Embodiment 2.

[0023] In some embodiments, the crystalline hydrate of the compound of formula (I) exhibits melting / decomposition according to DSC, with an onset temperature within a range selected from approximately 178°C to approximately 190°C, approximately 182°C to approximately 186°C, and approximately 183°C to approximately 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 pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition is selected from tablets, capsules, and suspensions.

[0025] In certain embodiments, the pharmaceutical composition comprises a salt of the compound of formula (I) and one or more pharmaceutically acceptable excipients.

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

[0027] In this specification, the term "hydrate" refers to a complex formed by combining the compound of formula (I) with water. The term includes both stoichiometric and non-stoichiometric hydrates.

[0028] In this specification, the term "solvate" refers to a complex formed by combining the compound of formula (I) with a solvent.

[0029] In this specification, “therapeutic effective dose” refers to an amount sufficient to achieve treatment when administered to a mammal in need of such treatment. The therapeutic effective dose varies depending on the subject being treated, the subject’s weight and age, the severity of the disease, the method of administration, etc., which can be readily determined by those skilled in the art.

[0030] The term "substantially pure" as used herein means exhibiting a crystalline polymorph with more than 90% purity and containing less than 10% of any other compound or another polymorph of crystalline form. Preferably, the crystalline polymorph is more than 95% pure and more than 98% pure.

[0031] The phrase "substantially as shown in the figure" indicates 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 the peaks are present in the figure.

[0032] In this specification, the term "approximately" means that, when referring to a number or range of numbers, the number or range referred to is an approximation within experimental variability (or statistical experimental error), and therefore the number or range of numbers may vary, for example, from 1% to 15% of the stated number or range.

[0033] Method for producing the crystalline form of the compound of formula (I) In certain embodiments, the present invention relates to a method for preparing a crystalline compound having the structure of formula (I), and includes the following: a) To provide a mixture containing a compound of formula (I) and a solvent; and b) Crystallizing the compound of formula (I) from a mixture containing the compound of formula (I).

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

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

[0037] In certain embodiments of the solutions, slurries, and suspensions disclosed herein, the crude solid material containing 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 containing 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 contains 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, the compound of formula (I) is substantially pure after crystallization. In some embodiments, the crystalline form of the compound of formula (I) is more 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 compound produced by the method of the invention is a solvate, for example, a hydrate.

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

[0041] In certain embodiments, the crystalline compound produced by the method 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, for example, to achieve Embodiment 2, the solid sample is Embodiment 1 and the solvent is water.

[0043] In certain embodiments, crystalline form 1 of the compound of formula (I) may substantially not include other crystalline forms of the compound of formula (I). In certain embodiments, crystalline form 1 of the compound of formula (I) may substantially not include crystalline form 2 of the compound of formula (I).

[0044] In certain embodiments, crystalline form 2 of the compound of formula (I) may substantially not include other crystalline forms of the compound of formula (I). In certain embodiments, crystalline form 2 of the compound of formula (I) may substantially not include crystalline form 1 of the compound of formula (I).

[0045] In certain embodiments, the mixture containing the compound of formula (I) is a solution, and the step of crystallizing the compound from the mixture includes supersaturating the solution and precipitating the compound of formula (I) from the solution.

[0046] In certain embodiments, supersaturating a mixture containing the compound of formula (I) includes the slow addition of an antisolvent, such as heptane, hexane, ethanol, or another polar or nonpolar 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. In certain embodiments, supersaturating a mixture containing the compound of formula (I) includes adding an antisolvent, cooling the solution 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., leaving the solution at ambient temperature) or active (e.g., cooling the solution in an ice bath or freezer).

[0047] In certain embodiments, the preparation method further includes 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 includes washing the crystals.

[0048] In certain embodiments, the preparation method further includes inducing crystallization. The method may also include drying the crystals, for example, under reduced pressure. In certain embodiments, the induction of precipitation or crystallization includes secondary nucleation, which occurs in the presence of a seed crystal or interaction with the environment (crystallizer wall, agitator impeller, sonication, etc.).

[0049] In other embodiments, the solvent is acetonitrile, diethyl ether, N,N-dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (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 Embodiment 1, the solvent is tetrahydrofuran.

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

[0051] In some embodiments, the antisolvent is selected from tetrahydrofuran, methanol, isopropanol, 1,4-dioxane, acetonitrile, and acetone. In some embodiments, the antisolvent is gradually diffused into an aqueous solution containing the compound of formula (I). In certain preferred embodiments, for example, to achieve Form 2, an aqueous solution containing Form 1 is diffused using an antisolvent 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 before the solid was isolated. In some embodiments, the solid was isolated 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, the slurry comprising 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, the 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 Embodiment 2, the solvent is a mixture containing water and tetrahydrofuran. In other embodiments, the solvent is a mixture containing water, as well as other solvents 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 (H2O / THF), water / methanol (H2O / MeOH), water / isopropanol (H2O / IPA), water / ethanol (H2O / EtOH), water / 1,4-dioxane (H2O / 1,4-dioxane), water / acetonitrile (H2O / ACN), or water / acetone (H2O / acetone).

[0057] In some embodiments, the solvent is a mixture containing 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 containing ethanol and water, to which additional ethanol or a mixture of ethanol and water is added. In some embodiments, the mixture contains the compound of formula (I) and a solvent of 2:1 EtOH:H2O (v / v), to which a mixture of 19:2 EtOH:H2O is then added for crystallization.

[0058] In some embodiments, crystallization is assisted by seeding or seed addition, which involves adding seed crystals to the mixture. In some embodiments, seed crystals are added in 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, seed crystals are added in 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, seed crystals are added in a weight percentage of the total mixture selected from 3 wt%, 4 wt%, and 5 wt%.

[0059] In some embodiments, the seed crystal is a seed crystal of form (I). In certain embodiments, the seed crystal is crushed.

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

[0061] In this specification, “antisolvent” means a solvent in which compound crystals are insoluble, minimally soluble, or partially soluble. In practice, 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 involves 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 before washing.

[0063] In certain embodiments, a method for producing the crystalline form of the compound of formula (I) is used to remove one or more impurities from a sample of the compound of formula (I). In certain embodiments, the crystallization method described herein is used, for example, to purify the compound of formula (I) as a final purification step in the production 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 involve high-performance liquid chromatography (HPLC), including preparative HPLC. In some embodiments, the purification of the compound of formula (I) by crystallization is scalable. Advantages of purification by crystallization include, but are not limited to, the removal of soluble impurities, the ease of the purification process, applicability to large-scale synthesis, acceptable yield, and high product purity.

[0065] In some embodiments, crystalline form (I) 2 was a more stable form. In some embodiments, crystalline form (I) 2 is more stable than crystalline form (I) 1 in water. 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 form (I) form 2 was completed in approximately 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the conversion to crystalline form (I) form 2 was completed in approximately 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, or 26 hours.

[0067] Use of the crystalline form of the compound of formula (I) The compound of formula (I) is a 3-substituted 1,2,4-oxadiazole compound having the following structure. [ka]

[0068] Functional “depletion” (immunodeficiency) between T and B cell subsets is a well-described feature of chronic viral infections, such as hepatitis B and C, and HIV virus. T cell depletion 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 T cell antigen receptors drives the sustained expression of T cell suppressor 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] Therefore, for example, but not limited to, cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and diseases modulated by graft rejection immune responses can be treated by administering immunomodulators, such as compounds of formula (I), and compositions disclosed herein. 3-substituted 1,2,4-oxadiazole compounds act as immunomodulators.

[0070] In certain embodiments, compounds of formula (I) modulate the immune response in cells.

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

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

[0073] According to any of the embodiments described above, in certain embodiments, cell contact occurs in the subject in need, thereby treating a disease or disorder selected from cancer, immune disorders, immunodeficiency disorders, inflammatory disorders, infectious diseases, and graft rejection.

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

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

[0076] Typical tumor cells include, but are not limited to, cancer cells such as: blastoma (e.g., glioblastoma), breast cancer (e.g., breast cancer, primary ductal carcinoma, trinegative breast cancer, estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and / or human epidermal growth factor receptor 2-positive (HER2+)), epithelial carcinoma (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., prostate adenocarcinoma), kidney cancer (e.g., renal cell carcinoma (RCC) and kidney cancer), 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 cancer), colorectal cancer (e.g., colorectal cancer and colorectal adenocarcinoma with high microsatellite instability), rectal cancer, anal cancer, peritoneal cancer, gastric cancer (e.g., gastric cancer and gastrointestinal cancer), testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer (e.g., cervical carcinoma), vaginal cancer (e.g., (e.g., vaginal cancer), vulvar cancer (e.g., vulvar carcinoma), esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer (e.g., thyroid cancer), parathyroid cancer, adrenal gland cancer, sarcoma (e.g., soft tissue sarcoma and Kaposi's sarcoma), urethral cancer, penile cancer, chronic or acute leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and chronic myeloblastic leukemia), pediatric solid tumors, Hodgkin lymphoma (HL) (e.g., lymphocyte-rich (LRCHL), nodular sclerosis (NSHL), mixed cell type (MCHL) and Lymphocyte depletion (LDHL), B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), non-Hodgkin lymphoma (NHL) (e.g., low-grade / follicular non-Hodgkin lymphoma, small lymphocytic (SL) NHL, intermediate-grade / follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-incisional cell NHL, giant tumor NHL, Burkitt lymphoma, mantle cell lymphoma), AIDS-associated lymphoma, cutaneous T-cell lymphoma (e.g., mycosis fungoides)Fundoids)) and Waldenström macroglobulinemia, post-transplant lymphoproliferative disorders (PTLD), lymphocytic lymphoma, primary CNS lymphoma, and T-cell lymphoma), mesothelioma, thymic carcinoma, myeloma (e.g., multiple myeloma), bladder cancer (e.g., bladder cancer), ureteral cancer, renal pelvis carcinoma, liver cancer (e.g., hepatocellular carcinoma, liver cancer, hepatocellular carcinoma), pancreatic cancer, post-transplant lymphoproliferative disorders (PTLD), neoplasms of the central nervous system (CNS), tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, epidermal carcinoma, salivary gland cancer, squamous cell carcinoma, abnormal angiogenesis associated with nevus, edema (e.g., associated with brain tumors), Meggs syndrome, Merkel cell carcinoma, environmentally induced cancers (including those induced by asbestos), and combinations of the said cancers.

[0077] In other embodiments, for example, tumor cells may include cancer cells selected from the following: prostate cancer, melanoma, breast cancer, colon cancer, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, stomach 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, tumor cells may include cancer cells selected from the following: melanoma, trinegative breast cancer, non-small cell lung cancer, renal cell carcinoma, pancreatic cancer, gastric cancer, bladder cancer, mesothelioma, Hodgkin lymphoma, cervical cancer, ovarian cancer, and head and neck squamous cell carcinoma.

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

[0080] In other embodiments, tumor cells are cancer cells selected from: endometrial cancer, ovarian cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and chronic or acute leukemia, such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphocytic lymphoma, and multiple myeloma.

[0081] In some embodiments, tumor cells are cancer cells selected from: prostate adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, breast cancer, and colorectal adenocarcinoma. In certain embodiments, tumor cells are derived from breast cancer. In some embodiments, tumor cells are derived from breast cancer selected from trinegative breast cancer, estrogen receptor positive (ER+), progesterone receptor positive (PR+), and / or human epidermal growth factor receptor 2 (HER2+). In other embodiments, tumor cells are derived from breast cancer selected from the 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 cells are cancer cells selected from the following: trinegative breast cancer, colorectal cancer with high microsatellite instability, gastric cancer, mesothelioma, pancreatic cancer, and cervical cancer.

[0083] In some embodiments, tumor cells and / or subjects are naive to immuno-oncological therapy. Immuno-oncology uses the subject's immune system to help fight cancer. For example, immuno-oncological therapies include 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 known as lambrolizumab), Examples include, but are not limited to, human monoclonal antibodies targeting PD-L1, tremelimumab (human monoclonal antibody targeting CTLA-4), CT-011 (antibody targeting PD-1), MDX-1106 (antibody targeting PD-1), MK-3475 (antibody targeting PD-1), YW243.55.S70 (antibody targeting PD-L1), MPDL3280A (antibody targeting PD-L1), MDX-1105 (antibody targeting PD-L1), and MEDI4736 (antibody targeting PD-L1). In some embodiments, immuno-oncological therapy is selected from anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, and anti-TIGIT antibodies (e.g., antibodies disclosed in WO2015 / 009856).

[0084] In other embodiments, tumor cells and / or subjects are responsive to immune checkpoint therapy. In some embodiments, cancers exhibit a response to anti-PD1 therapy. Examples of cancers include non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), bladder cancer, Hodgkin lymphoma, and head and neck squamous cell carcinoma.

[0085] Other embodiments of this disclosure provide methods for treating infections.

[0086] Further embodiments of the present disclosure provide a method for treating an infection, comprising administering a therapeutically effective amount of a composition comprising a crystalline form of the compound of formula (I) to a subject in need.

[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 drug for the treatment of an infectious disease, and a method for administering a therapeutically effective amount of a composition comprising the 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, viral, fungal, or parasitic infection, and the method of administering a composition comprising a therapeutically effective amount of a compound of formula (I) in crystalline form is for the treatment of a bacterial, viral, fungal, or parasitic infection.

[0089] In some embodiments, for example, a bacterial infection may be caused by at least one bacterium selected from the following: anthrax, bacilli, Bordetella, Borrelia, botulinum, brucellosis, Burkholderia, Campylobacter, Chlamydia, cholera, Clostridium, Conococcus, Corynebacterium, diphtheria, Enterobacter, Enterococcus, Erwinia, Escherichia, Francisella, Haemophilus, Helicobacter Heliobacter, Klebsiella, Legionella, Leptospirosis, Listeria, Lyme disease, Neisseria meningitidis, Mycobacteria, Mycoplasma, Neisseria, Pasteurella, Perobacter, Plague, Pneumonococcus, Proteus, Pseudomonas, Rickettsia, Salmonella, Serratia, Sigella, Staphylococcus, Streptococcus, Tetanus, Treponema, Vibrio, Yersinia, and Xanthomonas.

[0090] In other embodiments, for example, a viral infection may be caused by at least one virus selected from the following: adenovirus, papillomavirus, polyomavirus, herpesvirus, poxvirus, hepadnavirus, parvovirus, astrovirus, calicivirus, picornavirus, coronavirus (Coronoviridae), flavivirus, retrovirus, togavirus, arenavirus, bunyavirus, filovirus, orthomyxovirus, paramyxovirus, rhabdovirus, and reovirus. In certain embodiments, the viruses include arbovirus encephalitis virus, adenovirus, herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, herpesvirus 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, and West Nile virus. It may include rus, rubella, hepatitis E, human immunodeficiency virus (HIV), human T lymphotropic virus (HTLV), influenza, guanalitovirus, Junin virus, lassa virus, Machupo virus, Sabia virus, Crimean-Congo hemorrhagic fever virus, Ebola virus, Marburg virus, measles virus, molluscum contagiosum virus, mumps virus, parainfluenza, polynuclear respiratory virus, human metapneumovirus, Hendra virus, Nipah virus, rabies, hepatitis D, rotavirus, orbivirus, cortivirus, vaccinia virus, and vannavirus.

[0091] In other embodiments, for example, fungal infections may be selected from: thrush, Aspergillus (Fumigatus, Aspergillus niger, etc.), Blastomyces dermatichidis, Candida (Albicans, Crusey, Glabrata, Tropicalis, etc.), Coccidioides imitis, Cryptococcus (Neoformans, etc.), Histoplasma capsulatum, Mucorals (Mucor, Absidia, Rhizophus), South American spore spores, Sporotrichosis, Sporotrichus schenkyi, Zygomycosis, Chromoblastomycosis, Lobomycosis, Mycomas, Onychomycosis, Tinea versicolor, Tinea folliculitis, Tinea capitis, Tinea corporis, Tinea cruris, Tinea jaundice, Tinea melanosis, Tinea pedis, Otomycosis, Phenophytomycosis, and Rhinosporidium.

[0092] In some embodiments, for example, the parasitic infection may be caused by at least one parasite selected from the following: Acanthamoeba, Babesia japonica, Balantidium colonis, Entamoeba hystolytica, Giardia lamblia, Cryptosporidium muris, Trypanosomatida gambiense, Trypanosomatida rodesiens rhodesiense), Trypanosoma bursei, Trypanosoma cruzi, Mexican leishmania, Brazilian leishmania, tropical leishmania, Donovan leishmania, Toxoplasma gondii, Plasmodium vivax, ovale malaria parasite, Plasmodium quartanum, Plasmodium falciparum, Pneumocystis carinii, Trichomonas vaginalis, Histomonas meleagridis, Secementea, whipworm, roundworm, pinworm, hookworm, Naegleria fowleri, American hookworm, Brazilian hookworm, Strongyloides, Bancroftian filaria, Guinea worm, schistosoma, liver fluke, canine fluke, lung fluke, Schistosoma mansoni, Schistosoma halcionis, Japanese schistosoma, liver fluke, giant liver fluke, Egyptian fluke, and westermani lung fluke.

[0093] The term "subject" includes mammals (especially humans) and other animals, such as domesticated animals (e.g., household pets including cats and dogs) and non-domesticated animals (e.g., wild animals).

[0094] In this specification, a therapeutic agent that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the incidence or frequency of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in the treated population compared to an untreated control population (e.g., by only a statistically and / or clinically significant amount). Infection prevention includes, for example, reducing the number of infection diagnoses in the treated population compared to an untreated control population, and / or delaying the onset of symptoms of infection in the treated population compared to an untreated control population. Pain prevention includes, for example, reducing, or instead delaying, the magnitude of pain experienced by subjects in the treated population compared to an untreated control population.

[0095] The term “to treat” includes prophylactic and / or therapeutic measures. The term “prophylactic or therapeutic” measure is approved in the art and includes the administration of one or more subject compositions to a host. If administered before the clinical manifestations of an undesirable condition (e.g., a disease or other undesirable state in a host animal), the treatment is prophylactic (i.e., it protects the host from the onset of the undesirable condition), whereas if administered after the signs of an undesirable condition, the treatment is therapeutic (i.e., it is intended to reduce, alleviate, or stabilize an existing undesirable condition or its side effects).

[0096] Pharmaceutical composition In certain embodiments, the Disclosure provides pharmaceutical compositions comprising a crystalline form of a compound of formula (I) disclosed herein, mixed with an optionally pharmaceutically acceptable carrier or diluent.

[0097] This disclosure also provides a method for formulating a disclosed crystalline form of the compound of formula (I) for drug administration.

[0098] The compositions and methods of this disclosure may be used to treat individuals in need. In certain embodiments, the individuals may be mammals such as humans or non-human mammals. When administered to animals such as humans, the compositions or compounds are preferably administered as pharmaceutical compositions comprising, for example, a crystalline form of the compound of formula (I) of this 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 physiologically buffered saline, or other solvents or vehicles, such as glycols, glycerols, oils such as olive oil, or injectable organic esters. In preferred embodiments, if such pharmaceutical compositions are for human administration, particularly for invasive administration routes (i.e., routes such as injection or implantation that avoid transport or diffusion across the epithelial barrier), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients may be selected, for example, to perform delayed release of the active ingredient or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in the form of a single dose unit, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized products for reconstitution, powders, solutions, syrups, suppositories, or injections. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

[0099] A pharmaceutically acceptable carrier may include, for example, a physiologically acceptable active substance that acts to stabilize, increase the solubility of, or increase the absorption of a compound, such as the crystalline form of the compound of formula (I) of this disclosure. Examples of such physiologically acceptable active substances include 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 selection of a pharmaceutically acceptable carrier containing a physiologically acceptable active substance depends, for example, on the route of administration of the composition. Preparations of pharmaceutical compositions may be self-emulsifying drug delivery systems or self-microemulsifying drug delivery systems. Pharmaceutical compositions (preparations) may also be liposomes or other polymer matrices, which may incorporate, for example, the crystalline form of the compound of formula (I) of this disclosure. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively easy to manufacture and administer.

[0100] The phrase "pharmaceutically acceptable" is used herein to indicate a compound, material, composition, and / or dosage form that is within reasonable medical judgment, suitable for use in contact with human and animal tissues, free from excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0101] The phrase “pharmaceutically acceptable carrier” in this specification means a pharmaceutically 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 that it is compatible with the other material components of the formulation and is not harmful to the patient. Some examples of materials that can function as a pharmaceutically acceptable carrier include: (1) sugars, e.g., lactose, glucose and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, etc. (10) Sorghum oil and soybean oil; (11) Glycols, e.g., propylene glycol; (12) Polyols, e.g., glycerin, sorbitol, mannitol and polyethylene glycol; (13) Esters, e.g., ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers, e.g., magnesium hydroxide and aluminum hydroxide; (16) Alginic acid; (17) Pyrogen-free water; (18) Isotonic saline solution; (19) Ringer's solution; (16) Ethyl alcohol; (20) Phosphate buffer solution; and (21) Other non-toxic and suitable substances used in pharmaceutical formulations.

[0102] Pharmaceutical compositions (preparations) can be administered to subjects by any of many routes of administration, including, for example: orally (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorbed through the oral mucosa (e.g., sublingual); anally, rectally or transvaginally (e.g., as pessaries, creams or foams); parenterally (e.g., intramuscular, intravenous, subcutaneous or subarachnoid, as sterile solutions or suspensions); nasally; 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). Compounds can also be formulated for inhalation. In certain embodiments, compounds can be simply dissolved or suspended in sterile water. Details of suitable administration routes and compositions suitable therefor can be found, for example, in U.S. Patents 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] For convenience, formulations may be provided in unit dosage forms and may be prepared by any method well known in the field of pharmaceutical technology. The amount of active material component that, together with the carrier material, can produce a single dosage form varies depending on the host being treated and the specific method of administration. The amount of active material component that, together with the carrier material, can produce a single dosage form is generally the amount of compound that produces the therapeutic effect. Generally, out of 100 percent, this amount is in the range of about 1 percent to about 99 percent of the active material component, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent.

[0104] Methods for preparing these formulations or compositions include the step of combining an active compound, for example, a crystalline form of the compound of formula (I) of the present disclosure, with a carrier and optionally one or more minor components. Generally, formulations are prepared by uniformly and closely combining the compound of the present disclosure with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, shaping the product.

[0105] Formulations of the present disclosure suitable for oral administration may exist in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using flavored main ingredients, usually sucrose and gum arabic or tragacanth), lyophilized products, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using inert bases, e.g., gelatin and glycerin, or sucrose and gum arabic), and / or as mouthwashes, each containing a predetermined amount of the compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as boluses, licks, or pastes.

[0106] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.), the active material component is mixed with one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, arginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) water-retaining agents, e.g., glycerol; 4) Disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) Dissolution retarders, e.g., paraffin; (6) Absorption enhancers, e.g., quaternary ammonium compounds; (7) Wetting agents, e.g., cetyl alcohol and glycerol monostearate; (8) Absorbents, e.g., kaolin and bentonite clay; (9) Lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) Complexing agents, e.g., modified and unmodified cyclodextrins; and (11) Colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may 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 glycol, etc.

[0107] Tablets may be manufactured by compression or molding, using one or more adjuncts as optional. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surface-active or dispersant. Wet tablets may be manufactured by molding a mixture of powder compounds moistened with an inert liquid diluent in a suitable machine.

[0108] Tablets and other solid dosage forms of pharmaceutical compositions, such as sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may also be formulated using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile, for example, to provide a sustained or controlled release of the active material components therein. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injection medium immediately before use. These compositions may also optionally contain an opacifier and may be compositions that release only, or preferentially, the active material components in a delayed manner in a certain portion of the gastrointestinal tract. Examples of embedding compositions that can be used include polymer substances and waxes. The active material component can be encapsulated in microencapsulation form using one or more of the above excipients, if appropriate.

[0109] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophilized products for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active material component, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof.

[0110] In addition to inert diluents, oral compositions may also contain adjuvants, such as humectants, emulsifiers and suspending agents, sweeteners, flavorings, colorants, fragrances and preservatives.

[0111] In addition to the active compound, the suspension may contain a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyl, bentonite, agar and tragacanth, and mixtures thereof.

[0112] Pharmaceutical compositions for rectal, vaginal, or urethral administration may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylate, and may be provided as suppositories that are solid at room temperature but become liquid at body temperature, and thus melt in the rectum or vaginal cavity to release the active compound.

[0113] Formulations of pharmaceutical compositions for oral administration may be provided as oral rinses, oral sprays, or oral ointments.

[0114] Alternatively, or in addition, the composition may be formulated for delivery by catheters, stents, wires, or other intracavitary devices. Delivery via such devices may be particularly useful for delivery to the bladder, urethra, ureters, rectum, or intestines.

[0115] Suitable formulations for intravaginal administration include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be appropriate in the art.

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

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

[0118] The powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. The sprays may also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

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

[0120] Ophthalmic preparations, ophthalmic ointments, powders, solutions, etc., are also intended to be within the scope of this disclosure. Exemplary ophthalmic preparations are described in U.S. Patent Publications 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and U.S. Patent No. 6,583,124 (their contents incorporated herein by reference as a whole). If desired, liquid ophthalmic preparations have properties similar to or compatible with such fluids as tears, aqueous humor, or vitreous humor. The preferred route of administration is topical administration (e.g., topical administration, e.g., via eye drops or implantable tablets).

[0121] Suppositories are also intended to be within the scope of this disclosure.

[0122] The phrases “parenteral administration” and “administered parenterally” in this specification mean methods of administration other than enteral and local administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intra-articular, intra-orbital, intra-cardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0123] Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may include antioxidants, buffers, bacteriostatic agents, solutes or suspensions or thickeners that make the formulation isotonic with the blood of the target recipient.

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

[0125] These compositions may also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the composition. In addition, long-term absorption of injectable dosage forms can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin.

[0126] In some cases, slowing down the absorption of a drug from subcutaneous or intramuscular injection is desirable to prolong its effects. This can be achieved by using a liquid suspension of an insufficiently water-soluble crystalline or amorphous material. The absorption rate of the drug then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delaying the absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0127] Injectable depot formulations are prepared by forming a microencapsulation matrix of the target compound in a biodegradable polymer, such as polylactide-polyglycolides. The rate of drug release can be controlled by the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by trapping 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 either by itself or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active material component together with a pharmaceutically acceptable carrier.

[0129] The delivery method may also be provided by refillable or biodegradable devices. Various slow-release polymer devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including protein-based biologics. Various biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers, can be used to form implantable tablets for the sustained release of compounds at specific target sites.

[0130] The actual dosage level of the active material component in a pharmaceutical composition can be varied to obtain an amount of the active material component that is effective in achieving the desired therapeutic response for a particular patient, composition, and method of administration, without being harmful to the patient.

[0131] The selected dosage level depends on a variety of factors, including the activity of the specific compound or combination of compounds used, or its ester, salt, or amide; the route of administration; the timing of administration; the rate of excretion of the specific compound(s) used; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound(s) used; the age, sex, weight, condition, overall health, and prior medical history of the patient being treated; and similar factors well known in the medical field.

[0132] A physician or veterinarian with ordinary art in the art can readily determine and prescribe the therapeutically effective dose of a required pharmaceutical composition. For example, a physician or veterinarian can start administration of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. “Therapeutically effective dose” means a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective dose of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors influencing the effective dose 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 with the crystalline form of the compound of formula (I) of this disclosure. Larger total doses may be delivered by multiple administrations of the active ingredient. Methods for determining efficacy and dosage are known to those skilled in the art (incorporated herein by reference to Isselbacher et al. (1996) Harrison's Principles of Internal Medicine, 13th edition, 1814–1882).

[0133] Generally, the preferred daily dose of the active compound used in the compositions and methods of this disclosure is the minimum amount of the compound that is effective in producing a therapeutic effect. Such an effective dose generally depends on the factors described above.

[0134] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more subdoses, either in unit dosage form, separately at appropriate intervals throughout the day. In certain embodiments of this disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound is administered once daily.

[0135] Patients receiving this treatment are any animals in need, including primates, especially humans, and other mammals such as horses, cattle, pigs, and sheep; as well as poultry and pets in general.

[0136] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings, and fragrances, preservatives, and antioxidants may also be present in the composition.

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

[0138] The invention is described in general terms here, but will be more easily understood by referring to the following examples. The examples are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

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

[0140] Table 3 summarizes the details of the data collection: [Table 3]

[0141] HPLC Purity analysis was performed using an Agilent HP1100 series system equipped with a diode array detector, with ChemStation software vB.04.03, and the method detailed in Table 4 below. [Table 4]

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

[0143] PXRD determination of formula (I) reported in WO2015 / 033299 The PXRD of the compound of formula (I) was determined using the procedure described in Example 4 of WO2015 / 033299 (which describes an amorphous compound). The PXRD is shown in Figure 8. The entire contents of WO2015 / 033299 are thus incorporated by reference.

[0144] Example 1: Synthesis of Form 1 A. Crystallization from tetrahydrofuran Form (I) 1 exists under ambient conditions for short-term storage (i.e., less than 8 days). A mixture of Forms (I) 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 permeation mode, and it was confirmed to be crystallographic form (I) 1 as indicated by the XRPD analysis (Figure 1).

[0145] B. Crystallization from ethanol / water mixture 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 to obtain 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 its form 1 of formula (I) was confirmed by XRPD analysis.

[0146] Example 2: Synthesis of Form 2 A. Solid vapor diffusion Form (I) 1 (approximately 15.3 mg) was weighed into a 3 mL vial, and then placed in a 20 mL vial with 4.0 mL of water. The 20 mL vial was sealed with a cap and maintained under RT for 1 week, allowing solvent vapor to interact with the sample. The resulting solid was shown to be crystallographic form (I) 2 by XRPD analysis.

[0147] B. Addition of antisulfen Approximately 15.0 mg of the formula (I) form 1 sample was dissolved in 0.3 mL of H2O 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 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 H2O in a 3 mL glass vial of 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 capped and maintained in 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 (mentioned in Table 6 below), the solid was isolated by centrifugation, and its form was confirmed to be Formula (I) Form 2 by XRPD analysis (Figure 2). [Table 8] v:v=vol / vol;aw=water activity at 25℃

[0150] E. Addition of antisolvent using a water / acetonitrile mixture The compound was dissolved in 1 volume of water, 10 vol of acetonitrile was added, and the mixture was stirred for 12 hours. A white solid precipitated. The precipitate was filtered and washed with acetonitrile (2 vol) containing 1% H2O, and then 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 form 2 of formula (I) by XRPD analysis (Figure 2).

[0151] F. Liquid vapor diffusion Approximately 15.0 mg of Form 1 of Formula (I) was weighed into a 3 mL glass vial containing 0.3 mL of H2O (solvent). 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 open vial, without a cap, was then placed in 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 using formula (I). Thermogravimetric analysis (TGA) of Equation (I) Form 1 showed a 5.2% weight loss by 80°C, which is consistent with the monohydrate form. Differential scanning calorimetry (DSC) showed two overlapping endothermic reactions at 125.6°C and 133.1°C (peak temperatures), before melting / decomposition which began at 184.1°C (Figure 3).

[0153] The TGA of formula (I) form 2 showed a two-step weight loss of 9.6% up to 80°C, which is consistent with the dihydrate form. The DSC showed two endothermic reactions before melting / decomposition, starting at 184.3°C, and at 47.2°C and 72.9°C (peak temperature) (Figure 4).

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

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

[0156] Example 5: Solubility measurement for crystal 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 the temperature for 6 hours, and the solubility of the supernatant was measured by HPLC, while the solid was identified by XRPD. (See Table 9.) [Table 9]

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

[0158] Example 6: Determination of single crystal structure 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 crystal formula (I) form 2 is 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 with two oxygen atoms (O5 and O7) intramolecularly on one formula (I) molecule, and two hydrogen bonds with each N1 atom on two different formula (I) molecules between molecules. This water molecule bridges the negatively charged and positively charged groups of the zwitterion. The two additional water molecules form an intermolecular bridge between two N2 atoms. The CO / C=O bond distances from the carboxyl group were similar. Three residual electron density peaks were present, assigned as hydrogen atoms around the N1 atom. Therefore, it is suggested that the formula (I) molecule was a zwitterion in the form 2 crystal (Figure 7B).

[0160] Citation by reference All publications and patents referenced herein are incorporated by reference as collectively, as if each individual publication or patent were specifically and individually incorporated by reference. In case of any conflict, this application, including all definitions herein, shall prevail.

[0161] Equivalents While specific embodiments of the invention have been described, the above specification is merely descriptive and not limiting. Many modifications of the invention will become apparent to those skilled in the art upon reviewing this specification and the claims below. The complete scope of the invention should be determined by referring to the claims, along with the complete scope of their equivalents, and the specification, along with such modifications.

Claims

1. A crystalline compound having the structure of formula (I), wherein said crystalline compound is a monohydrate. 【Chemistry 1】

2. The crystalline compound of claim 1, wherein the X-ray powder diffraction pattern of the crystalline compound 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.

3. The crystalline compound of claim 2, wherein the X-ray powder diffraction pattern of the crystalline compound 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.

4. The crystalline compound of claim 3, wherein the X-ray powder diffraction pattern of the crystalline compound has 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.

5. The crystalline compound of claim 4, wherein the X-ray powder diffraction pattern of the crystalline compound 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.

6. The X-ray powder diffraction pattern of the crystalline compound is 6.8±0.2, 8.4±0.2, 10.6±0.2, 11.5±0.2, 13.6±0.2, 2, 16.5±0.2, 16.8±0.2, 17.6±0.2, 18.8±0.2, 19.3±0.2, 19.9±0.2, 20.4±0.2, 20.6±0.2, 21.0±0.2, 21.4±0.2, 21.8±0.2, 22.6±0.2, 23.6±0.2, 24.5±0.2, 24.

6. The crystalline compound of claim 5 having 2θ values ​​of 0.8±0.2, 25.3±0.2, 26.5±0.2, 27.1±0.2, 27.5±0.2, 28.0±0.2, 28.4±0.2, 29.3±0.2, 30.1±0.2, 30.8±0.2, 31.5±0.2, 32.4±0.2, 33.0±0.2, 33.5±0.2, 35.3±0.2, 36.5±0.2, 37.6±0.2, 38.1±0.2, and 38.7±0.

2.

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

8. A pharmaceutical composition for the treatment of cancer, immune disorders, immune deficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection comprising a crystalline compound according to any one of claims 1-6.

9. The pharmaceutical composition described in claim 8, wherein the pharmaceutical composition is a pharmaceutical composition for treating cancer.

10. 10. Use of the crystalline compound of any one of claims 1 to 6 for the manufacture of a medicament for the treatment of cancer, immune disorders, immune deficiency disorders, inflammatory disorders, infectious diseases, and transplant rejection.

11. The use according to claim 10, wherein the medicament is a medicament for treating cancer.

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