Crystalline form of deoxycytidine kinase inhibitors and their use

Abstract

This invention provides a composition containing a crystalline form of a compound that is a deoxycytidine kinase inhibitor (dCK). [Solution] A composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof in a crystalline form. JPEG2026143454000026.jpg73106

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Application No. 63 / 108,803, filed on 2 November 2020, and U.S. Provisional Application No. 63 / 190,107, filed on 18 May 2021, both of which are incorporated in their entirety by reference. [Background technology]

[0002] Deoxycytidine kinase (dCK) is an enzyme that plays a crucial role in cell division and functions in the phosphorylation of several deoxyribonucleosides and their nucleoside analogs. Deoxycytidine kinase is the rate-limiting enzyme in the salvage pathway of nucleoside synthesis, is primarily expressed in hematopoietic tissues, and has been observed to be upregulated in certain solid tumors. dCK deletion is further associated with specific forms of resistance to antiviral and anticancer chemotherapy agents. Due to its role in DNA synthesis and cell division, for example, and its association with drug resistance and / or drug sensitivity, dCK is a clinically important polypeptide target. Compounds and compositions that bind to dCK in vivo and inhibit its activity are desirable for the treatment of diseases and disorders involving dCK activity. [Overview of the project]

[0003] In one aspect of this specification, Formula I:

[0004] [ka] A composition is provided comprising a compound or a pharmaceutically acceptable salt thereof in a crystalline form.

[0005] In some embodiments, the crystalline form is polymorph I of the maleate of the compound of formula I.

[0006] In some embodiments, Polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic heating in the range of about 135 to about 160°C. In some embodiments, the melting point of Polymorph I is about 139°C. In some embodiments, the melting point of Polymorph I is about 148°C. In some embodiments, Polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram essentially as shown in Figure 1.

[0007] In some embodiments, polymorph I is dry, non-solvated, and / or non-hydrated.

[0008] In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern that includes peaks at 8.2±0.2°²-θ, 12.7±0.2°²-θ, and 16.4±0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from 16.9±0.2°²-θ, 17.6±0.2°²-θ, and 22.9±0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from 20.6±0.2°²-θ, 24.9±0.2°²-θ, and 19.9±0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern essentially as shown in Figure 2.

[0009] In some embodiments, Polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 1% to about 5% over a temperature range of about 25 to about 125°C. In some embodiments, Polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of less than about 4% over a temperature range of about 25 to about 125°C. In some embodiments, Polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of less than about 2% over a temperature range of about 25 to about 125°C. In some embodiments, Polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 4% over a temperature range of about 25 to about 125°C. In some embodiments, Polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 5% to about 15% over a temperature range of about 125 to about 200°C. In some embodiments, polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of approximately 10.3% over a temperature range of approximately 125 to approximately 200°C. In some embodiments, polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram essentially as shown in Figure 3.

[0010] In some embodiments, polymorph I contains less than 5% water. In some embodiments, polymorph I contains about 0.5% water. In some embodiments, polymorph I contains about 1.5% water. In some embodiments, polymorph I contains about 2.5% water.

[0011] In some embodiments, the crystalline form is polymorph II of the maleate of the compound of formula I.

[0012] In some embodiments, Polymorph II is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic temperatures in the range of about 150 to about 170°C. In some embodiments, the differential scanning calorimetry (DSC) thermogram further includes endothermic temperatures in the range of about 25 to about 60°C. In some embodiments, the melting point of Polymorph II is in the range of about 150 to about 155°C. In some embodiments, Polymorph II is characterized by a differential scanning calorimetry (DSC) thermogram essentially as shown in Figure 4.

[0013] In some embodiments, polymorph II includes small needle-like particles. In some embodiments, the size of the needles ranges from about 1 μm to about 50 μm.

[0014] In some embodiments, polymorph II is solvated or hydrated.

[0015] In some embodiments, polymorph II is characterized by an X-ray powder diffraction pattern that includes peaks at 7.6±0.2°²–θ, 8.7±0.2°²–θ, and 16.0±0.2°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from 12.2±0.2°²–θ, 17.6±0.2°²–θ, and 19.5±0.2°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern further includes at least one peak selected from 21.7±0.2°²–θ, 10.8±0.2°²–θ, and 13.4±0.2°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, polymorph II is essentially characterized by an X-ray powder diffraction pattern as shown in Figure 5.

[0016] In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of from about 1% to about 5% over a temperature range of from about 25°C to about 80°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of from about 2.0% to about 2.5% over a temperature range of from about 25°C to about 80°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of about 1.8% over a temperature range of from about 25°C to about 80°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of about 2.9% over a temperature range of from about 25°C to about 70°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of from about 0% to about 1% over a temperature range of from about 70°C to about 130°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of about 0.5% over a temperature range of from about 70°C to about 130°C. In some embodiments, polymorphic Form II is characterized by a thermogravimetric analysis (TGA) thermogram comprising a mass loss of about 0.5% over a temperature range of from about 80°C to about 130°C.

[0017] In some embodiments, polymorphic Form II comprises less than 5% water. In some embodiments, polymorphic Form II comprises from about 1.5% to about 2.5% water. In some embodiments, polymorphic Form II comprises about 3.78% water. In some embodiments, polymorphic Form II comprises about 2.65% water. In some embodiments, polymorphic Form II comprises about 0.8% water.

[0018] In some embodiments, more than 90% by weight of the composition is a crystalline form of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the composition comprises less than about 2% by weight of impurities.

[0020] In another embodiment, provided herein is a pharmaceutical composition comprising a composition described herein, and a pharmaceutically acceptable excipient.

[0021] In other embodiments, this specification provides a method for treating a control disease or disorder requiring treatment, the method comprising administering a composition described herein, or a pharmaceutical composition described herein, to the control in a therapeutically effective amount.

[0022] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, melanoma, stomach cancer, bladder cancer, endometrial cancer, kidney cancer, leukemia, liver cancer, lymphoma, pancreatic cancer, and thyroid cancer.

[0023] In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from fibromyalgia, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, ulcerative colitis, and type 1 diabetes.

[0024] In other embodiments, Formula I:

[0025] [ka] A method is provided for preparing a first crystalline form of the maleate of the compound, the method comprising: (i) dissolving the compound of formula I and an acid in a first solvent mixture at a first temperature; (ii) adding a second solvent at a second temperature; (iii) cooling the resulting solution to a third temperature; and (iv) filtering the solution and drying the resulting solid at a fourth temperature.

[0026] In some embodiments, the acid is maleic acid. In some embodiments, the first crystalline form is polymorph I. In some embodiments, the first solvent mixture is EtOH / siRNA, and the first temperature is about 50 to about 60°C. In some embodiments, the second solvent mixture is siRNA, and the second temperature is about 20 to about 25°C. In some embodiments, the third temperature is about -5 to about 5°C. In some embodiments, the fourth temperature is about 50 to 55°C.

[0027] In other aspects, this specification states that Formula I:

[0028] [ka] A method is provided for preparing a second crystalline form of the maleate of the compound of formula I, the method comprising drying the first crystalline form of the maleate of the compound of formula I at a temperature of about 70°C.

[0029] In some embodiments, the second crystalline form is polymorph II. In some embodiments, the first crystalline form is polymorph I.

[0030] In other embodiments, Formula I:

[0031] [ka] A method is provided for preparing a second crystalline form of a maleate of the compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising the step of slurring a first crystalline form of the maleate of the compound of formula I, or a mixture of crystalline forms of the maleate of the compound of formula I, in water.

[0032] In some embodiments, the second crystalline form is polymorph II. In some embodiments, the first crystalline form is polymorph I.

[0033] In another aspect, this specification provides a method for treating acute disseminated encephalomyelitis (ADEM) in a subject requiring treatment, the method comprising Formula I:

[0034] [ka] The process includes administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the compound of formula I is administered once daily. In some embodiments, the compound of formula I is administered twice daily. In some embodiments, the compound of formula I is administered at 12-hour intervals.

[0036] In some embodiments, the compound of formula I is administered in a unit dosage form. In some embodiments, the unit dosage form contains about 0.5 to about 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 25 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 75 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 100 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 150 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 320 mg / kg of the compound of formula I.

[0037] In some embodiments, the total amount of compound I administered per day is about 0.5 to about 350 mg / kg. In some embodiments, the total amount of compound I administered per day is about 50 mg / kg. In some embodiments, the total amount of compound I administered per day is about 100 mg / kg. In some embodiments, the total amount of compound I administered per day is about 150 mg / kg. In some embodiments, the total amount of compound I administered per day is about 320 mg / kg. In some embodiments, the total amount of compound I administered per day is about 5 to about 350 mg.

[0038] In some embodiments, the compound of formula I is formulated for oral administration. The compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, solution, suppository, or aerosol. In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution contains about 1 to about 50 mg / mL of the compound of formula I. In some embodiments, the solution contains about 5 mg / mL of the compound of formula I. In some embodiments, the solution contains about 15 mg / mL of the compound of formula I. In some embodiments, the solution contains about 20 mg / mL of the compound of formula I.

[0039] In some embodiments, administration of the compound of formula I results in a decrease in interferon-γ (IFNγ) levels in the subject.

[0040] In another aspect, this specification provides a method for treating an autoimmune disease or disorder of an object requiring treatment, the method comprising Formula I:

[0041] [ka] The procedure includes administering a therapeutically effective dose of the compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is administered once daily.

[0042] In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is optic neuritis. In some embodiments, the disease or disorder is acute disseminated encephalomyelitis (ADEM).

[0043] In some embodiments, the compound of formula I is administered in a unit dosage form. In some embodiments, the unit dosage form contains about 0.5 to about 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 25 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 75 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 100 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 150 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 320 mg / kg of the compound of formula I.

[0044] In some embodiments, the total amount of compound I administered per day is about 0.5 to about 350 mg / kg. In some embodiments, the total amount of compound I administered per day is about 50 mg / kg. In some embodiments, the total amount of compound I administered per day is about 100 mg / kg. In some embodiments, the total amount of compound I administered per day is about 150 mg / kg. In some embodiments, the total amount of compound I administered per day is about 320 mg / kg. In some embodiments, the total amount of compound I administered per day is about 5 to about 350 mg.

[0045] In some embodiments, the compound of formula I is formulated for oral administration. In some embodiments, the compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, solution, suppository, or aerosol. In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution contains about 1 to about 50 mg / mL of the compound of formula I. In some embodiments, the solution contains about 5 mg / mL of the compound of formula I. In some embodiments, the solution contains about 15 mg / mL of the compound of formula I. In some embodiments, the solution contains about 20 mg / mL of the compound of formula I.

[0046] In some embodiments, administration of the compound of formula I results in a decrease in interferon-γ (IFNγ) levels in the subject.

[0047] Embedding by citation All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawing]

[0048] The novel features of the present invention will be described in detail along with the appended claims. For a better understanding of the features and advantages of the present invention, please refer to the following detailed description and accompanying drawings illustrating exemplary embodiments in which the principles of the present invention are used. [Figure 1] The differential scanning calorimetry (DSC) thermogram of polymorph I of the compound of formula I is shown. [Figure 2] The X-ray powder diffraction (XRPD) patterns of polymorph I of the compound of formula I are shown. [Figure 3] The thermogravimetric analysis (TGA) thermogram of polymorph I of the compound of formula I is shown. [Figure 4] The differential scanning calorimetry (DSC) thermogram of polymorphic form II of the compound of formula I is shown. [Figure 5] The X-ray powder diffraction (XRPD) patterns of polymorph II of the compound of formula I are shown. [Figure 6] The thermogravimetric analysis (TGA) thermograms of polymorphic form II of the compound of formula I are shown. [Figure 7] This shows the changes in mouse body weight observed in different experimental groups over the course of a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 8] This shows the area under the curve for the percentage change in body weight compared to baseline observed in different experimental groups in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 9] This shows the changes in EAE scores observed across different experimental groups in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 10] This shows the area under the curve of clinical EAE scores observed for different experimental groups in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 11]This shows the cumulative disease scores observed for different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 12] In a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), the disease profile progression is shown for all animals exhibiting disease scores up to day 25, for different experimental groups. [Figure 13] This shows the area under the curve for progression of lesions observed in different experimental groups in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 14] This shows the proportion of asymptomatic animals observed in different experimental groups over the course of a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) experiments. [Figure 15] This shows the spleen weights observed in different experimental groups in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 16] This shows the levels of IFN-γ observed in different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 17] This shows the levels of interleukin-6 (IL-6) observed in different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 18] This shows the levels of interleukin-10 (IL-10) observed in different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 19]This shows the levels of interleukin-17a (IL-17a) observed in different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 20] This shows the levels of tumor necrosis factor-α (TNF-α) observed in different experimental groups in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). [Figure 21] This shows the changes in mouse body weight observed in different experimental groups over the course of a variable-dose mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) experiments. [Figure 22] This shows the percentage change in body weight observed across different experimental groups in a variable-dose mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) experiment. [Figure 23] This shows the physical condition scoring scale used in a variable-dose mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 24] This shows the mean physical status scores observed for different experimental groups over the course of a variable-dose mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) experiments. [Figure 25] This shows the mean disease scores observed for different experimental groups over the course of a variable-dose mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) experiments. [Figure 26] This shows the proportion of disease-free animals observed in different experimental groups over the course of a variable-dose mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Figure 27]This shows the spleen weights observed in different experimental groups in a variable-dose mouse model of experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG). [Modes for carrying out the invention]

[0049] (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy))phenyl)-5-methylthiazol-4-yl)ethyl)thio)pyrimidine-4,6-diamine (compound of formula I) is a potent and selective deoxycytidine kinase (dCK) inhibitor. dCK inhibitors are useful in treating a variety of diseases, disorders, and conditions in which abnormal dCK activity plays a role, such as cancer and autoimmune diseases.

[0050] The preparation and use of compounds of formula I have been previously described (see US9,598,404, US9,981,961, US9,688,673, WO2016 / 130581, US10,570,124, and WO2016 / 130562).

[0051] As used herein, the compound of formula I or "compound 1" refers to (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine)) having the chemical structure shown below:

[0052] [ka]

[0053] In some embodiments, the compound of formula I is crystalline.

[0054] As used herein, “crystalline form,” “polymorph,” “form,” and “form” may be used interchangeably herein and, unless a specific crystalline or amorphous form is mentioned, means all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, non-solvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, as well as mixtures thereof. The compounds of this disclosure include, for example, crystalline and amorphous forms of those compounds, including polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid form, e.g., polymorph I.

[0055] definition A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the target. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives, such as those known in the art as described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0056] As used herein, “treatment” or “treating” preferably refers to an approach to obtain a beneficial or desired outcome, including a clinical outcome. Beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: a reduction in symptoms caused by the disease, an improvement in the quality of life of persons affected by the disease, a reduction in the dosage of other medicines required to treat the disease, a delay in the progression of the disease, and / or an extension of the individual’s survival.

[0057] As used herein, “delay the onset of disease” means delaying, preventing, slowing, interfering with, stabilizing, and / or postponing the onset of a disease (such as cancer). This delay may be of varying lengths depending on the disease being treated and / or the individual’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay may encompass prevention in that the individual does not develop the disease in effect. For example, late-stage cancers, such as the onset of metastasis, can be delayed.

[0058] As used herein, “effective dose” or “effective amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to produce a beneficial or desired outcome. With respect to prophylactic use, beneficial or desired outcomes include outcomes such as elimination or reduction of the risk of disease, reduction of severity, or delay of onset, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the onset of the disease. With respect to therapeutic use, beneficial or desired outcomes include clinical outcomes such as a reduction in one or more symptoms caused by the disease, an improvement in the quality of life of people affected by the disease, a reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug such as by targeted enhancement, delay in disease progression, and / or extension of survival. In the case of cancer or tumors, an effective dose of a drug may be effective in reducing the number of cancer cells, shrinking tumor size, inhibiting (i.e., slowing, preferably stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., slowing, preferably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating, to some extent, one or more symptoms associated with the disorder. An effective dose may be administered in one or more doses. For the purposes of the present invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a prophylactic or therapeutic measure, either directly or indirectly. As understood in a clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, “effective dose” may be considered in the context of administering one or more therapeutic agents, and if the desired result can be achieved in combination with one or more other agents, or if it can be achieved, it may be considered that a single agent is given in an effective dose.

[0059] As defined herein, with respect to interactions with protein inhibitors, the terms “inhibition,” “to inhibit,” and “to suppress” mean that the inhibitor negatively affects (e.g., reduces) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. Inhibition may refer to a reduction in a disease or the symptoms of a disease. Inhibition may refer to a decrease in the activity of a particular protein or nucleic acid target. The protein may be a deoxycytidine kinase. Therefore, inhibition includes, at least partially, partially, or completely, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling, enzyme activity, or the amount of a protein.

[0060] The term "modulator" refers to a composition that increases or decreases the level, function, or target physical state of a target molecule.

[0061] The term "modulate" is used according to its simple, ordinary meaning, referring to the action of changing or altering one or more properties. "Modification" refers to the process of changing or altering one or more properties. For example, a modulator of a target protein alters the properties or function of the target molecule, or increases or decreases the amount of the target molecule. A modulator of a disease reduces the symptoms, causes, or properties of the target disease.

[0062] The terms "selective" or "selectivity" of a compound refer to its ability to identify molecular targets. The terms "specific," "individually," or "specific" of a compound refer to its ability to cause specific effects, such as inhibition, on a particular molecular target, with minimal or no effect on other proteins within the cell.

[0063] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that can be included in the composition of the present invention without causing significantly harmful toxicological effects to the patient, while assisting in the administration and absorption of the activator to the subject. Non-limiting examples of pharmacopoeia-acceptable excipients include water, NaCl, physiological saline, Ringer's lactate solution, standard sucrose, standard glucose, binders, excipients, disintegrants, lubricants, coatings, sweeteners, flavorings, salines (such as Ringer's solution), alcohols, oils, gelatin, lactose, amylose, or carbohydrates such as starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone (polyvinyl pyrrolidine), and colorants. Such preparations may be sterilized and, if desired, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or fragrances that do not react harmfully with the compounds of the present invention. Those skilled in the art will recognize that other pharmaceutical excipients are useful for the present invention.

[0064] The term “preparation” is intended to include formulations of an active compound comprising an encapsulating material as a carrier, which provides a capsule, in which the active ingredient, with or without other carriers, is surrounded by a carrier and thus acts in conjunction with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be used as solid dosage forms suitable for oral administration.

[0065] As used herein, the term “administer” means to a subject by oral administration, suppository administration, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intra-injured, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained-release device (e.g., a mini osmotic pump). Administration is by any route including parenteral and oral mucosa (e.g., buccal, sublingual, palate, gingiva, nose, vagina, rectum, or percutaneous). Parenteral administration includes, for example, intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other methods of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, and percutaneous patches.

[0066] "Concurrent administration" means that the compounds described herein are administered simultaneously with, immediately before, or immediately after, the administration of one or more additional therapies, such as anticancer agents described herein. The compounds described herein may be administered to a patient alone or concurrently. Concurrent administration is intended to include concurrent or sequential administration of the compounds individually or in combination (one or more compounds or drugs). Thus, the preparations may be combined with other active substances (e.g., anticancer agents) if desired.

[0067] Co-administration involves administering one active agent (e.g., a complex as described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administration of a second active agent (e.g., an anticancer agent). Embodiments are also contemplated herein in which co-administration involves administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours after administration of the second active agent. Co-administration involves administering two active agents simultaneously, substantially simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes from each other), or sequentially in any order. Co-administration can be achieved by co-formulation, i.e., by preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents may be formulated separately. In some embodiments, the activators and / or adjuvants are linked or conjugated to each other. In some embodiments, the compounds described herein are used in combination with cancer treatments such as chemotherapy or radiotherapy.

[0068] In the context of a substance or the activity or function of a substance related to a disease, the terms “related” or “associated” mean that a disease is caused (whole or in part) by the symptoms of the disease, or that the symptoms of a disease are caused (whole or in part) by a substance or the activity or function of a substance, or that the side effects of a compound (e.g., toxicity) are caused (whole or in part) by a substance or the activity or function of a substance.

[0069] "Patient," "Subject," "Patient requiring treatment," or "Subject requiring treatment" are interchangeable terms used herein and refer to a living organism that suffers from or is susceptible to a disease or illness that can be treated by administration of a pharmaceutical composition such as those provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is human. "Cancer patient" is a patient who has cancer or is susceptible to developing cancer.

[0070] Unless otherwise specifically indicated, the term “individual” as used herein refers to mammals including, but not limited to, cattle, horses, cats, rabbits, dogs, rodents, or primates (e.g., humans). In some embodiments, the individual is a human. In some embodiments, the individual is a non-human primate such as a chimpanzee and other ape and monkey species. In some embodiments, the individual is livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; laboratory animals including rodents such as rats, mice, and guinea pigs. In some embodiments, the present invention finds applications in both human medical and veterinary contexts.

[0071] "Disease" or "illness" refers to a condition or health state of a patient or subject that can be treated with the compounds or methods provided herein. In some embodiments, the disease used herein refers to cancer.

[0072] The terms "chemotherapeutic" or "chemotherapeutic agent" are used in their ordinary and common sense to refer to a chemical composition or compound that has antitumor properties or the ability to inhibit cell growth or proliferation.

[0073] Where used herein, "cancer model organism" refers to an organism that exhibits a phenotype resembling cancer within the organism, or the activity of a cancer-causing element. The term cancer is defined above. A wide variety of organisms can serve as cancer model organisms, including, for example, cancer cells, as well as mammalian organisms such as rodents (e.g., mice or rats) and primates (e.g., humans). Cancer cell lines are widely understood by those skilled in the art as cells that exhibit a phenotype or genotype similar to in vivo cancer. Cancer cell lines as used herein include cell lines derived from animals (e.g., mice) and humans.

[0074] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise.

[0075] It is understood that the embodiments and variations of the invention described herein include embodiments and variations that "consist of" and / or "essentially consist of".

[0076] Crystalline form of compound I Polymorphs produced according to the method of the present invention may be characterized by any methodology in the art. For example, polymorphs produced according to the method of the present invention may be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy, and / or spectroscopy (e.g., Raman, solid-state nuclear magnetic resonance (ssNMR), and infrared (IR)). In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD).

[0077] XRPD: Polymorphs according to the present invention may be characterized by XRPD analysis. The relative intensity of the XRPD peaks may vary depending on the particle size used, sample preparation technique, sample mounting procedure, and specific instrument. Furthermore, instrument variations and other factors may affect the 2-θ value. Thus, the XRPD peak position may vary, for example, by approximately plus or minus 0.2 degrees.

[0078] DSC: The polymorphs according to the present invention can be further identified by their characteristic DSC thermograms, as shown in Figures 1, 4, and the like. For DSCs, it is known that the observed temperature depends on the rate of temperature change, as well as the sample preparation technique and specific equipment used. Therefore, the values ​​reported herein with respect to DSC thermograms may vary, for example, by approximately plus or minus 4°C.

[0079] TGA: The polymorphs of the present invention may also exhibit thermal behavior different from that of amorphous materials or other polymorphs. Thermal behavior may be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphs from others. In one embodiment, polymorphs may be characterized by thermogravimetric analysis.

[0080] The polymorphs of the compound of formula I are useful in the manufacture of pharmaceutical formulations and can be obtained by crystallization processes to produce crystalline and semicrystalline forms or by solidification processes to obtain amorphous forms. In some embodiments, crystallization is carried out either by generating the desired compound (e.g., the compound of formula I) in a reaction mixture and isolating the desired polymorph from the reaction mixture, or by dissolving the raw compound in a solvent, optionally using heat, and then crystallizing / solidifying the product by cooling (including active cooling) and / or adding a reverse solvent for a period of time. In some embodiments, crystallization involves adding a seed form of the desired polymorph. After crystallization or solidification, drying can be carried out under controlled conditions until the desired water content is reached in the final polymorph.

[0081] Polymorph I of the compound of formula I Figure 1 shows the differential scanning calorimetry (DSC) thermogram of polymorph I of the compound of formula I.

[0082] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of polymorph I of the compound of formula I.

[0083] Figure 3 shows the thermogravimetric analysis (TGA) thermogram of polymorph I of the compound of formula I.

[0084] In one embodiment, polymorph I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine is provided herein. Several embodiments have provided compositions comprising polymorph I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine. In some embodiments, polymorph I of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine is (a) When measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern contains peaks at 8.2±0.2°²−θ, 12.7±0.2°²−θ, and 16.4±0.2°²−θ. (b) X-ray powder diffraction pattern substantially shown in Figure 2, (c) Differential scanning calorimetry (DSC) thermogram including endothermic activity in the range of approximately 135 to 160°C. (d) Differential scanning calorimetry (DSC) thermogram substantially shown in Figure 1, (e) A thermogravimetric analysis (TGA) thermogram substantially shown in Figure 3, or (f) Characterized by having a combination of those.

[0085] In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern substantially shown in Figure 2.

[0086] In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern with peaks at 8.2±0.2°²–θ, 12.7±0.2°²–θ, and 16.4±0.2°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern with peaks at 8.2±0.1°²–θ, 12.7±0.1°²–θ, and 16.4±0.1°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph I is characterized by an X-ray powder diffraction pattern with peaks at approximately 8.2°²–θ, approximately 12.7°²–θ, and approximately 16.4°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0087] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 16.9±0.2°²–θ, 17.6±0.2°²–θ, and 22.9±0.2°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 16.9±0.1°²–θ, 17.6±0.1°²–θ, and 22.9±0.1°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from approximately 16.9°²–θ, approximately 17.6°²–θ, and approximately 22.9°²–θ.

[0088] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 20.6±0.2°²–θ, 24.9±0.2°²–θ, and 19.9±0.2°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 20.6±0.1°²–θ, 24.9±0.1°²–θ, and 19.9±0.1°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from approximately 20.6°²–θ, approximately 24.9°²–θ, and approximately 19.9°²–θ.

[0089] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least one peak selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least two peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least three peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least four peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ.In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least six peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least seven peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least eight peaks selected from 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 8.2±0.2°²―θ, 12.7±0.2°²―θ, 16.4±0.2°²―θ, 16.9±0.2°²―θ, 17.6±0.2°²―θ, 22.9±0.2°²―θ, 20.6±0.2°²―θ, 24.9±0.2°²―θ, and 19.9±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 8.2±0.1°²―θ, 12.7±0.1°²―θ, 16.4±0.1°²―θ, 16.9±0.1°²―θ, 17.6±0.1°²―θ, 22.9±0.1°²―θ, 20.6±0.1°²―θ, 24.9±0.1°²―θ, and 19.9±0.1°²―θ.In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at approximately 8.2°²–θ, approximately 12.7°²–θ, approximately 16.4°²–θ, approximately 16.9°²–θ, approximately 17.6°²–θ, approximately 22.9°²–θ, approximately 20.6°²–θ, approximately 24.9°²–θ, and approximately 19.9°²–θ.

[0090] In some embodiments, Polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram substantially shown in Figure 1. In some embodiments, Polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic activity in the range of about 135 to about 160°C.

[0091] In some embodiments, polymorphic form I is approximately 135-160°C, 135-158°C, 135-156°C, 135-154°C, 135-152°C, 135-150°C, 135-148°C, 135-146°C, 135-144°C, 135-142°C, 135-140°C, 140-160°C, 140-158°C, 140-156°C, 140-154°C, 140-152°C °C, 140~150°C, 140~148°C, 140~146°C, 140~144°C, 140~142°C, 142~160°C, 142~158°C, 142~156°C, 142~154°C, 142~152°C, 142~150°C, 142~148°C, 142~146°C, 142~144°C, 144~160°C, 144~158°C, 144~156°C, 144~154 °C, 144~152°C, 144~150°C, 144~148°C, 144~146°C, 146~160°C, 146~158°C, 146~156°C, 146~154°C, 146~152°C, 146~150°C, 146~148°C, 148~160°C, 148~158°C, 148~156°C, 148~154°C, 148~152°C, 148~150°C, 150~160 The polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic heating at 150-158°C, 150-156°C, 150-154°C, 150-152°C, 152-160°C, 152-158°C, 152-156°C, 152-154°C, 154-160°C, 154-158°C, 154-156°C, 156-160°C, 156-158°C, or 158-160°C. In some embodiments, polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic heating at approximately 135-140°C, for example, approximately 135°C, 136°C, 137°C, 138°C, 139°C, or 140°C. In some embodiments, polymorph I has a melting point of approximately 139°C. In some embodiments, Polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic heating at approximately 145-150°C, for example, approximately 145°C, 146°C, 147°C, 148°C, 149°C, or 150°C. In some embodiments, Polymorph I has a melting point of approximately 148°C.

[0092] In some embodiments, polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram substantially shown in Figure 3. In some embodiments, polymorph I decomposes at temperatures of about 50°C, about 100°C, about 150°C, about 200°C, about 250°C, about 300°C, about 350°C, or about 400°C. In some embodiments, polymorph I decomposes at a temperature of about 150°C.

[0093] In some embodiments, polymorph I is stable at room temperature. In some embodiments, polymorph I can be stored at room temperature for extended periods without significant chemical degradation or changes in its crystalline form. In some embodiments, polymorph I can be stored at room temperature for at least about 1, 2, 3, or 7 days. In some embodiments, polymorph I can be stored at room temperature for about 7 days or more. In some embodiments, polymorph I can be stored at room temperature for 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some embodiments, polymorph I can be stored at room temperature for at least 1, 2, 3, or 7 days.

[0094] In some embodiments, polymorph I is stable at temperatures above room temperature and / or at high relative humidity (RH). In some embodiments, polymorph I can be stored for extended periods at about 40°C and about 75% RH without significant chemical degradation or changes in crystalline form. In some embodiments, polymorph I can be stored at about 40°C and about 75% RH for a period of at least about 1 day, 2 days, 3 days, or 7 days. In some embodiments, polymorph I can be stored at about 40°C and about 75% RH for a period of about 7 days or more. In some embodiments, polymorph I can be stored at approximately 40°C and approximately 75% RH for a period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some embodiments, polymorph I can be stored at approximately 40°C and approximately 75% RH for a period of approximately 1 day, 2 days, 3 days, or 7 days.

[0095] In some embodiments, polymorph I is stable at temperatures above room temperature and / or at high relative humidity (RH). In some embodiments, polymorph I can be stored for extended periods at about 60°C without significant chemical degradation or changes in crystalline form. In some embodiments, polymorph I can be stored at about 60°C for periods of at least about 1 day, 2 days, 3 days, or 7 days. In some embodiments, polymorph I can be stored at about 60°C for periods of about 7 days or more. In some embodiments, polymorph I can be stored at about 60°C for periods of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some embodiments, polymorph I can be stored at approximately 60°C for a period of approximately 1, 2, 3, or 7 days.

[0096] Compound polymorphism II of formula I Figure 4 shows the differential scanning calorimetry (DSC) thermogram of polymorph II of the compound of formula I.

[0097] Figure 5 shows the X-ray powder diffraction (XRPD) pattern of polymorph II of the compound of formula I.

[0098] Figure 6 shows the thermogravimetric analysis (TGA) thermogram of polymorph II of the compound of formula I.

[0099] In one embodiment, polymorph II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine is provided herein. Several embodiments have provided compositions comprising polymorph II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine. In some embodiments, polymorph II of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine is (a) When measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, the X-ray powder diffraction pattern contains peaks at 7.6±0.2°²−θ, 8.7±0.2°²−θ, and 16.0±0.2°²−θ. (b) X-ray powder diffraction pattern substantially shown in Figure 5, (c) Differential scanning calorimetry (DSC) thermogram including endothermic activity in the range of approximately 150 to 170°C. (d) Differential scanning calorimetry (DSC) thermogram, further including endothermic activity in the range of approximately 25 to approximately 60°C. (e) Differential scanning calorimetry (DSC) thermogram substantially shown in Figure 4, (f) A thermogravimetric analysis (TGA) thermogram substantially shown in Figure 6, or (g) Characterized by having a combination of those.

[0100] In some embodiments, polymorph II is characterized by an X-ray powder diffraction pattern substantially shown in Figure 5.

[0101] In some embodiments, polymorph II is characterized by an X-ray powder diffraction pattern with peaks at 7.6±0.2°²–θ, 8.7±0.2°²–θ, and 16.0±0.2°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph II is characterized by an X-ray powder diffraction pattern with peaks at 7.6±0.1°²–θ, 8.7±0.1°²–θ, and 16.0±0.1°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å. In some embodiments, polymorph II is characterized by an X-ray powder diffraction pattern with peaks at approximately 7.6°²–θ, approximately 8.7°²–θ, and approximately 16.0°²–θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

[0102] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 12.2±0.2°²–θ, 17.6±0.2°²–θ, and 19.5±0.2°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 12.2±0.1°²–θ, 17.6±0.1°²–θ, and 19.5±0.1°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from approximately 12.2°²–θ, approximately 17.6°²–θ, and approximately 19.5°²–θ.

[0103] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 21.7±0.2°²–θ, 10.8±0.2°²–θ, and 13.4±0.2°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from 21.7±0.1°²–θ, 10.8±0.1°²–θ, and 13.4±0.1°²–θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, further includes at least one peak selected from approximately 21.7°²–θ, approximately 10.8°²–θ, and approximately 13.4°²–θ.

[0104] In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least one peak selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least two peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least three peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least four peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ.In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least six peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least seven peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least eight peaks selected from 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 7.6±0.2°²―θ, 8.7±0.2°²―θ, 16.0±0.2°²―θ, 12.2±0.2°²―θ, 17.6±0.2°²―θ, 19.5±0.2°²―θ, 21.7±0.2°²―θ, 10.8±0.2°²―θ, and 13.4±0.2°²―θ. In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 7.6±0.1°²―θ, 8.7±0.1°²―θ, 16.0±0.1°²―θ, 12.2±0.1°²―θ, 17.6±0.1°²―θ, 19.5±0.1°²―θ, 21.7±0.1°²―θ, 10.8±0.1°²―θ, and 13.4±0.1°²―θ.In some embodiments, the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at approximately 7.6°²–θ, approximately 8.7°²–θ, approximately 16.0°²–θ, approximately 12.2°²–θ, approximately 17.6°²–θ, approximately 19.5°²–θ, approximately 21.7°²–θ, approximately 10.8°²–θ, and approximately 13.4°²–θ.

[0105] In some embodiments, Polymorph II features a differential scanning calorimetry (DSC) thermogram substantially shown in Figure 4. In some embodiments, Polymorph II features a differential scanning calorimetry (DSC) thermogram including endothermic activity in the range of about 150 to about 170°C.

[0106] In some embodiments, polymorph I is approximately 150-170°C, 150-168°C, 150-166°C, 150-164°C, 150-162°C, 150-160°C, 150-158°C, 150-156°C, 150-154°C, 150-152°C, 152-170°C, 152-168°C, 152-166°C, 152~164℃, 152~162℃, 152~160℃, 152~158℃, 152~156℃, 152~154℃, 154~170℃, 154~168℃, 154~166℃, 154~164℃, 154~162℃, 154~160℃, 154~158℃, 154~156℃, 156~170℃, 15 6~168℃, 156~166℃, 156~164℃, 156~162℃, 156~160℃, 156~158℃, 158~170℃, 158~168℃, 158~166℃, 158~164℃, 158~162℃, 158~160℃, 160~170℃, 160~168℃, 160~166℃, 160~ The differential scanning calorimetry (DSC) thermogram is characterized by endothermic heating at 164°C, 160-162°C, 162-170°C, 162-168°C, 162-166°C, 162-164°C, 164-170°C, 164-168°C, 164-166°C, 166-170°C, 166-168°C, or 168-170°C. In some embodiments, polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram that includes endothermic heating at approximately 150-155°C, for example, approximately 150°C, 151°C, 152°C, 153°C, 154°C, or 155°C. In some embodiments, polymorph I has a melting point of approximately 150-155°C.

[0107] In some embodiments, polymorphic form II is approximately 25-60°C, 25-58°C, 25-56°C, 25-54°C, 25-52°C, 25-50°C, 25-48°C, 25-46°C, 25-44°C, 25-42°C, 25-40°C, 25-38°C, 25-36°C, 25-34°C, 25-32°C, 25-30°C, 30-60°C, 30-58°C, 30-56°C, 30-54°C, 30-52°C, 30-50°C, 30-48°C, 30-46°C, 30-44°C, 30-42°C, 30-40°C, 30-38°C, 30-36°C, 30-34°C, 30-32°C, 32 ~60℃, 32~58℃, 32~56℃, 32~54℃, 32~52℃, 32~50℃, 32~48℃, 32~46℃, 32~44℃, 32~42℃, 32~40℃, 32~38℃, 32~36℃, 32~34℃, 34~60℃, 34~58℃, 34~56℃, 34~54℃, 34~52℃, 34~50℃, 34~48℃, 34~46℃, 34~44℃, 34~42℃, 34~40℃, 34~38℃, 34~36℃, 36~60℃, 36~58℃, 36~56℃, 36~54℃, 36~52℃, 36~50℃, 36~48℃, 36~46℃ 36~44℃, 36~42℃, 36~40℃, 36~38℃, 38~60℃, 38~58℃, 38~56℃, 38~54℃, 38~52℃, 38~50℃, 38~48℃, 38~46℃, 38~44℃, 38~42℃, 38~40℃, 40~60℃, 40~58℃, 40~56℃, 40~54℃, 40~52℃, 40~50℃, 40~48℃, 40~46℃, 40~44℃, 40~42℃, 42~60℃, 42~58℃, 42~56℃, 42~54℃, 42~52℃, 42~50℃, 42~48℃, 42~46℃, 42~44℃, 44~ 60℃, 44~58℃, 44~56℃, 44~54℃, 44~52℃, 44~50℃, 44~48℃, 44~46℃, 46~60℃, 46~58℃, 46~56℃, 46~54℃, 46~52℃, 46~50℃, 46~48℃, 48~60℃, 48~58℃, 48~56℃, 48~54℃, 48~52℃, 48~50℃, 50~60℃, 50~58℃, 50~56℃, 50~54℃, 50~52℃, 52~60℃, 52~58℃, 52~56℃, 52~54℃, 54~60℃, 54~58℃, 54~56℃, 56~60℃, 56~58℃,Alternatively, it features a differential scanning calorimetry (DSC) thermogram that includes further endothermic activity at 58-60°C.

[0108] In some embodiments, polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram substantially shown in Figure 6. In some embodiments, polymorph II decomposes at temperatures of about 50°C, about 100°C, about 150°C, about 200°C, about 250°C, about 300°C, about 350°C, or about 400°C. In some embodiments, polymorph II decomposes at a temperature of about 150°C.

[0109] In some embodiments, polymorph II is stable below room temperature. In some embodiments, polymorph II can be stored for long periods at approximately 2–8°C without significant chemical degradation or changes in crystalline form. In some embodiments, polymorph II can be stored at approximately 2–8°C for periods of at least approximately 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months. In some embodiments, polymorph II can be stored at approximately 2–8°C for periods of approximately 36 months or longer.In some specific examples, polymorph II occurs at approximately 2-8°C for 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, 6-7 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 2-3 weeks, 2-4 weeks, 3-4 weeks, 1-3 months, 1-6 months, 1-9 months, 1-12 months. 1-15 months, 1-18 months, 1-21 months, 1-24 months, 1-27 months, 1-30 months, 1-33 months, 1-36 months, 3-6 months, 3-9 months, 3-12 months, 3-15 months, 3-18 months, 3-21 months, 3-24 months, 3-27 months, 3-30 months, 3-33 months, 3-36 months, 6-9 months, 6-12 months, 6-15 months, 6-18 months, 6-21 months, 6-24 months, 6-27 months, 6-30 months, 6-3 3 months, 6-36 months, 9-12 months, 9-15 months, 9-18 months, 9-21 months, 9-24 months, 9-27 months, 9-30 months, 9-33 months, 9-36 months, 12-15 months, 12-18 months, 12-21 months, 12-24 months, 12-27 months, 12-30 months, 12-33 months, 12-36 months, 15-18 months, 15-21 months, 15-24 months, 15-27 months, 15-30 months, 15-33 months, 15- It can be stored for a period of 36 months, 18-21 months, 18-24 months, 18-27 months, 18-30 months, 18-33 months, 18-36 months, 21-24 months, 21-27 months, 21-30 months, 21-33 months, 21-36 months, 24-27 months, 24-30 months, 24-33 months, 24-36 months, 27-30 months, 27-33 months, 27-36 months, 30-33 months, 30-36 months, or 33-36 months. In some embodiments, polymorph II can be stored at approximately 2-8°C for a period of at least 1 day, 1 week, 1 month, 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, or 36 months.

[0110] In some embodiments, Polymorph II is stable at room temperature and relative humidity. In some embodiments, Polymorph II can be stored for extended periods at approximately 25°C and approximately 60% RH without significant chemical degradation or changes in crystalline form. In some embodiments, Polymorph II can be stored at approximately 25°C and approximately 60% RH for periods of at least approximately 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, Polymorph II can be stored at approximately 25°C and approximately 60% RH for periods of approximately 6 months or longer. In some embodiments, polymorph II can be stored at approximately 25°C and approximately 60% RH for a period of 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, 6-7 days, 1-2 weeks, 1-3 weeks, 1-4 weeks, 2-3 weeks, 2-4 weeks, 3-4 weeks, 1-2 months, 1-3 months, 1-4 months, 1-5 months, 1-6 months, 2-3 months, 2-4 months, 2-5 months, 2-6 months, 3-4 months, 3-5 months, 3-6 months, 4-5 months, 4-6 months, or 5-6 months. In some embodiments, polymorph II can be stored at approximately 25°C and approximately 60% RH for a period of at least 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months.

[0111] In some embodiments, polymorph II is stable at temperatures higher than room temperature and / or at high relative humidity (RH). In some examples, polymorph II can be stored for extended periods at about 40°C and about 75% RH without significant chemical decomposition or change of the crystalline form. In some examples, polymorph II can be stored at about 40°C and about 75% RH for periods of at least about 1, 2, 3, or 7 days. In some examples, polymorph II can be stored at about 40°C and about 75% RH for periods exceeding about 7 days. In some examples, polymorph II can be stored at about 40°C and about 75% RH for 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, or 2-6 days. 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some cases, polymorph II can be stored for 1, 2, 3, or 7 days at approximately 40°C and approximately 75% RH.

[0112] In some embodiments, polymorph II is stable at temperatures above room temperature and / or high relative humidity (RH). In some examples, polymorph II can be stored for extended periods at about 60°C without significant chemical decomposition or change of the crystalline form. In some examples, polymorph II can be stored at about 60°C for periods of at least about 1, 2, 3, or 7 days. In some examples, polymorph II can be stored at about 60°C for periods exceeding about 7 days. In some examples, polymorph II can be stored at 60°C for 1-2 days, 1-3 days, 1-4 days, 1-5 days, 1-6 days, 1-7 days, 2-3 days, 2-4 days, 2-5 days, 2-6 days, 2-7 days, 3-4 days, 3-5 days, 3-6 days, 3-7 days, 4-5 days, 4-6 days, 4-7 days, 5-6 days, 5-7 days, or 6-7 days. In some cases, polymorph II can be stored at approximately 60°C for a period of at least 1, 2, 3, or 7 days.

[0113] Method for producing the compound of formula I and its polymorphs The compounds used in the reactions described herein are prepared according to organic synthesis techniques, starting from commercially available chemicals and / or compounds described in the chemical literature."Commercially available chemicals" include Acros Organics (Geel, Belgium), Aldrich Chemicals (Milwaukee, Wisconsin, including Sigma and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, California), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, California), Fisher Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, UK), and Lancashire. It can be obtained from standard commercial sources including Synthesis (Windham, NH), Matrix Scientific (Columbia, South Carolina), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, Texas), Pierce Chemical (Rockford, Illinois), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech (Shanghai, China), TCI America (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and WuXi (Shanghai, China).

[0114] Appropriate references and papers that detail the synthesis of reactants useful for preparing the compounds described herein, or refer to articles describing the preparations, include, for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; SRSandler et al., “Organic Functional Group Preparations”, 2nd Ed., Academic Press, New York, 1983; HOHouse, “Modern Synthetic Reactions”, 2nd Ed., WABenjamin, Inc. Menlo Park, Calif. 1972; TLGilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992. For additional appropriate references and papers detailing the synthesis of reactants useful for the preparation of the compounds described herein, or referring to articles describing the preparation, see, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN:3-527-29074-5; Hoffman, RV. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN:0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai’s 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes, etc., may be mentioned..

[0115] Specific and similar reactants are also identified by indicators of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as by online databases (American Chemical Society, Washington, D.C.). Known chemicals that are not commercially available in catalogs are prepared by custom chemical synthesis houses, and many standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutically acceptable salts of pyrazole compounds described herein is PHStahl & CGWermuth, “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0116] isomer Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In other embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some situations, the compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all forms of diastereomers, enantiomers, and epimers and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomer salts). In some embodiments, the diastereomers have characteristic physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or, preferably, by separation / resolving techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical means that do not result in racemization.

[0117] labeled compound In some embodiments, the compounds described herein exist in isotope-labeled forms. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such isotope-labeled compounds. In some embodiments, the methods disclosed herein include methods for treating a disease by administering the isotope-labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotope-labeled compounds that are identical to those enumerated herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, respectively, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl. Compounds described herein containing the above-mentioned isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, hydrates, or derivatives, are within the scope of the present invention. Compounds labeled with specific isotopes, such as those incorporating radioactive isotopes like 3H or 14C, are useful in drug and / or substrate tissue distribution assays. Tritium-labeled (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detection. Furthermore, substitution with heavy isotopes such as deuterium, i.e., 2H, results in certain therapeutic benefits derived from greater metabolic stability, such as increased half-life in vivo or reduced required dose. In some embodiments, isotope-labeled compounds, their pharmaceutically acceptable salts, solvates, hydrates, or derivatives are prepared by any preferred method.

[0118] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0119] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0120] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with many inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in Insights during the final separation and purification of the compounds of the present invention, or by reacting the purified compounds in basic form separately with a suitable acid or base and separating the salts thus formed.

[0121] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates as a pharmaceutical composition.

[0122] Solvates are formed in stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during a crystallization process using a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein are suitably prepared or formed during the processes described herein. As just one example, hydrates of the compounds described herein are suitably prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in non-solvated forms as well as solvated forms. Generally, the solvated forms are considered equivalent to the non-solvated forms for the purposes of the compounds and methods provided herein.

[0123] This specification provides, in one embodiment, a method for producing one or more polymorphs of a compound of formula I.

[0124] [ka]

[0125] Compounds of formula I can be prepared as previously described in US9,598,404, US9,981,961, US9,688,673, WO2016 / 130581, US10,570,124, and WO2016 / 130562. In some embodiments, compounds of formula I are prepared according to the examples herein.

[0126] The polymorphs provided herein are not limited by the starting materials used to produce the compound of formula I.

[0127] This specification provides, in one embodiment, a method for preparing a compound of formula I, or polymorphs of pharmaceutically acceptable salts and / or solvates thereof, which are obtained by isolating the desired polymorph as a first solid form after synthesizing the compound of formula I, or by isolating the desired polymorph as a transition from a prior solid form of the compound of formula I. Transitions from one form to another are within the scope of this disclosure because they may serve as a substitute for methods for obtaining a desired form for the production of a pharmaceutical formulation.

[0128] The polymorphs of the compound of formula I obtained by the methods provided herein can be selected from polymorphic form I, polymorphic form II, and mixtures thereof.

[0129] The isolation and purification of the chemical entities and intermediates described herein may be carried out by any suitable separation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination thereof. Specific examples of suitable separation and isolation procedures can be obtained by referring to the following examples. However, other equivalent separation or isolation procedures may also be used. Prior to crystallization, the compounds of formula I may be isolated with a chemical purity of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, about 98%, or about 100%.

[0130] In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing a compound of formula I with a chemical purity of less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 94%, less than about 93%, less than about 92%, less than about 91%, less than about 90%, less than about 89%, less than about 88%, less than about 87%, less than about 86%, less than about 85%, less than about 84%, less than about 83%, less than about 82%, less than about 81%, less than about 80%, less than about 78%, less than about 76%, less than about 74%, less than about 72%, or less than about 70%. In some embodiments, the crystalline form is obtained by crystallizing the compound of formula I with a chemical purity in the range of about 70% to about 99%, 80% to about 96%, about 85% to about 96%, about 90% to about 96%, about 80% to about 98%, about 85% to about 98%, about 90% to about 98%, about 92% to about 98%, about 94% to 98%, or about 96% to about 98%.

[0131] Preparation of Polymorph I In one embodiment, the desired polymorph is polymorph I of the maleate of the compound of formula I, and the isolation step comprises recrystallization of the crude reaction product from a monosolvent system. In some embodiments, the desired polymorph is polymorph I of the maleate of the compound of formula I, and the isolation step comprises recrystallization of the crude product from a binary, tertiary, or higher solvent system, which is understood collectively as a polysolvent system. In some embodiments, the desired polymorph is polymorph I of the maleate of the compound of formula I, and the isolation step comprises crystallization from a monosolvent or polysolvent system, which comprises dissolving the compound of formula I and maleic acid in a monosolvent or polysolvent system at a temperature higher than ambient temperature. In some cases, the solubility of compounds of formula I and maleic acid in monosolvent or multisolvent systems is approximately 40-90°C, 45-90°C, 50-90°C, 55-90°C, 60-90°C, 65-90°C, 70-90°C, 75-90°C, 40-85°C, 45-85°C, 50-85°C, 55-85°C, 60-85°C, 65-85°C. 70-85℃, 75-85℃, 80-85℃, 40-80℃, 45-80℃, 50-80℃, 55-80℃, 60-80℃, 65-80℃, 70-80℃, 75-80℃, 40-75℃, 45-75℃, 50-75℃, 55-75℃, 60-75℃, 65-75℃, 70-75℃, 40-70℃, 45-70℃. The process is carried out at temperatures of 50-70°C, 55-70°C, 60-70°C, 65-70°C, 40-65°C, 45-65°C, 50-65°C, 55-65°C, 60-65°C, 40-60°C, 45-60°C, 50-60°C, 55-60°C, 40-55°C, 45-55°C, 50-55°C, 40-50°C, or 45-50°C. In some examples, the recrystallization solvent contains ethanol / ethyl acetate, and the dissolution of the compound of formula I and maleic acid in the solvent is carried out at a temperature of about 60°C. Any suitable amount of solvent can be used to dissolve the compound of formula I and maleic acid. In some embodiments, the amount of solvent used to dissolve the compound of formula I and maleic acid (e.g., 1:1 ethanol / ethyl acetate) is about 1-10 mL per gram of the compound of formula I. For example, in some embodiments, the amount of solvent used to dissolve the compound of formula I is 7.3 mL per gram of the compound of formula I.In some examples, the recrystallization solvent contains ethanol / ethyl acetate, and the dissolution of the compound of formula I and maleic acid in the solvent system is carried out at a temperature of approximately 60°C, with the amount of solvent used for dissolution being approximately 7.3 mL / g of the compound of formula I.

[0132] In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of, for example, about 0-40°C, 0-30°C, 0-20°C, 0-10°C, 10-40°C, 10-30°C, 10-20°C, 20-40°C, 20-30°C, 20-10°C, or 30-40°C. In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of about 25°C. In some embodiments, a solution containing a maleate of the compound of formula I is further maintained at this lower temperature for a certain period of time, for example, about 30 minutes, about 1 hour, 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, or about 24 hours or more.

[0133] In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of, for example, about 0-40°C, 0-30°C, 0-20°C, 0-10°C, 10-40°C, 10-30°C, 10-20°C, 20-40°C, 20-30°C, 20-10°C, or 30-40°C. In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of about 0°C. In some embodiments, a solution containing a maleate of the compound of formula I is further maintained at this lower temperature for a certain period of time, for example, about 30 minutes, about 1 hour, 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, or about 24 hours or more.

[0134] In some embodiments, crystallization further includes filtering a solution containing the obtained crystals of the maleate of the compound of formula I. In some embodiments, crystallization optionally includes washing the obtained crystals with a solvent, for example, a recrystallization solvent, one or more times. In some embodiments, crystallization optionally includes drying the obtained crystals under vacuum at a temperature of, for example, about 55°C.

[0135] In some embodiments, the chemical purity of polymorph I is higher than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of polymorph I is higher than approximately 90%. In some embodiments, the chemical purity of polymorph I is higher than approximately 95%. In some embodiments, the chemical purity of polymorph I is higher than approximately 99%. The chemical purity of polymorph I can be measured by any available analytical technique, for example, by HPLC analysis.

[0136] Preparation of Polymorphic Form II In one embodiment, the desired polymorph is polymorph II of the maleate of the compound of formula I, and the isolation step comprises recrystallization of the crude reaction product from a monosolvent system. In some embodiments, the desired polymorph is polymorph II of the maleate of the compound of formula I, and the isolation step comprises recrystallization of the crude product from a binary, tertiary, or higher solvent system, which are collectively understood as a polysolvent system. In some embodiments, the desired polymorph is polymorph II of the maleate of the compound of formula I, and the isolation step comprises crystallization from a monosolvent or polysolvent system, which comprises dissolving the maleate of the compound of formula I in a monosolvent or polysolvent system at a temperature higher than ambient temperature. In some cases, the solubility of the maleate of the compound of formula I in monosolvent or multisolvent systems is approximately 40-90°C, 45-90°C, 50-90°C, 55-90°C, 60-90°C, 65-90°C, 70-90°C, 75-90°C, 40-85°C, 45-85°C, 50-85°C, 55-85°C, 60-85°C, 65-85°C. 70-85℃, 75-85℃, 80-85℃, 40-80℃, 45-80℃, 50-80℃, 55-80℃, 60-80℃, 65-80℃, 70-80℃, 75-80℃, 40-75℃, 45-75℃, 50-75℃, 55-75℃, 60-75℃, 65-75℃, 70-75℃, 40-70℃, 45-70℃. The process is carried out at temperatures of 50-70°C, 55-70°C, 60-70°C, 65-70°C, 40-65°C, 45-65°C, 50-65°C, 55-65°C, 60-65°C, 40-60°C, 45-60°C, 50-60°C, 55-60°C, 40-55°C, 45-55°C, 50-55°C, 40-50°C, or 45-50°C. In some examples, the recrystallization solvent contains 1:1 DCM / methanol, and the dissolution of the maleate of the compound of formula I into the solvent is carried out at a temperature of about 45°C. Any suitable amount of solvent can be used to dissolve the maleate of the compound of formula I. In some embodiments, the amount of solvent used to dissolve the maleate of the compound (e.g., 1:1 DCM / methanol) is about 1-20 mL per gram of maleate of the compound of formula I. For example, in some embodiments, the amount of solvent used to dissolve the maleate of the compound of formula I is 7.4 mL per gram of the maleate of the compound of formula I.In some examples, the recrystallization solvent contains 1:1 DCM / methanol, the dissolution of the maleate of compound I in the solvent system is carried out at a temperature of approximately 45°C, and the amount of solvent used for dissolution is approximately 7.4 mL / g of the maleate of compound I.

[0137] In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of, for example, about 0-40°C, 0-30°C, 0-20°C, 0-10°C, 10-40°C, 10-30°C, 10-20°C, 20-40°C, 20-30°C, 20-10°C, or 30-40°C. In some embodiments, crystallization further includes actively cooling a heated solution containing the dissolved maleate of the compound of formula I to a temperature of about 5°C. In some embodiments, a solution containing a maleate of the compound of formula I is further maintained at this lower temperature for a certain period of time, for example, about 30 minutes, about 1 hour, 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 or more.

[0138] In some embodiments, crystallization further includes filtering a solution containing the obtained crystals of the maleate of the compound of formula I. In some embodiments, crystallization optionally includes washing the obtained crystals with a solvent, for example, a recrystallization solvent, one or more times. In some embodiments, crystallization optionally includes drying the obtained crystals under vacuum at a temperature of about 70°C.

[0139] In some embodiments, the chemical purity of polymorph II is higher than 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the chemical purity of polymorph II is higher than about 90%. In some embodiments, the chemical purity of polymorph II is higher than about 95%. In some embodiments, the chemical purity of polymorph II is higher than about 99%. The chemical purity of polymorph II can be measured by any available analytical technique, for example, by HPLC analysis.

[0140] In some embodiments, polymorph II is dry. In some embodiments, polymorph II is not solvated. In some embodiments, polymorph II is unhydrated. In some embodiments, polymorph II is anhydrous. In some embodiments, polymorph II is solvated. In some embodiments, polymorph II is hydrated.

[0141] Pharmaceutical composition This disclosure provides compositions comprising a pharmaceutical composition containing one or more crystalline forms of the present invention.

[0142] In some embodiments, the ratio of a desired crystalline form, such as polymorph I, to all other crystalline forms in the composition is approximately 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or higher w / w. In other embodiments, the ratio of polymorph II to all other polymorphs is approximately 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or higher w / w.

[0143] In some embodiments, one or more polymorphs of the compound of formula I are formulated into a pharmaceutical composition. In certain embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate the treatment of the active compound into a pharmaceutically usable formulation. The appropriate formulation depends on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable for formulating the pharmaceutical compositions described herein. Remington: The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,HAand Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0144] This specification provides pharmaceutical compositions comprising one or more polymorphs of a compound of formula I, and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, one or more polymorphs of a compound of formula I are administered as a pharmaceutical composition in which one or more polymorphs are mixed with other active ingredients, as in combination therapy. Included herein are all combinations of active molecules as described in the sections below and in the combination therapies throughout this disclosure. In specific embodiments, the pharmaceutical composition comprises one or more polymorphs of a compound of formula I.

[0145] When used herein, a pharmaceutical composition refers to a mixture of one or more polymorphs of a compound of formula I and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the administration of the polymorphs to a living organism. In some embodiments, in the implementation of the treatment or method of use provided herein, a therapeutically effective amount of one or more polymorphs of a compound of formula I is administered in the pharmaceutical composition to a mammal having the disease or condition being treated. In specific embodiments, the mammal is a human. In certain embodiments, the therapeutically effective amount varies depending on the severity of the disease, the age and relative health status of the subject, and other factors. One or more polymorphs of a compound of formula I described herein are used as components of a mixture, alone, or in combination with one or more therapeutic agents.

[0146] In one embodiment, one or more polymorphs of the compound of formula I are formulated in an aqueous solution. In a particular embodiment, the aqueous solution is selected from physiologically compatible buffers, such as Hanks' solution, Ringer's solution, or physiological saline, to name just a few examples. In another embodiment, one or more polymorphs of the compound of formula I are formulated for transmucosal administration. In a particular embodiment, the transmucosal formulation comprises a suitable penetrant for the barrier to be penetrated. In yet another embodiment in which one or more polymorphs described herein are formulated for other parenteral injections, the suitable formulation comprises an aqueous solution or a non-aqueous solution. In a particular embodiment, such a solution comprises a physiologically compatible buffer and / or excipients.

[0147] In another embodiment, the polymorphs described herein are formulated for oral administration. Polymorphs of the compound of formula I are formulated by combining the polymorph with, for example, a pharmaceutically acceptable carrier or excipient. In some embodiments, the polymorphs described herein are formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0148] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with one or more polymorphs described herein, optionally grinding the resulting mixture, adding suitable auxiliary agents as desired, and then processing the granular mixture to obtain tablets or sugar-coated tablet cores. Suitable excipients include, in particular, fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and other cellulose preparations; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrants may be optionally added. Disintegrants include, as just a few examples, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid, or salts thereof such as sodium alginate.

[0149] Dosage forms such as sugar-coated tablet cores and tablets are provided with one or more suitable coatings. In specific embodiments, a concentrated sugar solution is used to coat the dosage form. The sugar solution may optionally contain further components such as gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and suitable organic solvents or mixed solvents, but these are just a few examples. Dyes and / or pigments may also be optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments may optionally be used to characterize different combinations of dosages of the active compound.

[0150] In certain embodiments, at least one therapeutically effective amount of the polymorphs described herein is formulated into other oral dosage forms. The oral dosage forms include, in addition to compressible capsules made of gelatin, flexible, sealable capsules made of gelatin, and plasticizers such as glycerin or sorbitol. In specific embodiments, the compressible capsule contains the active ingredient in combination with one or more injectors. The injectors include, but are not limited to, binders such as lactose or starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In other embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, but are not limited to, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be optionally added.

[0151] In other embodiments, at least one therapeutically effective dose of the polymorphs described herein is formulated for buccal or sublingual administration. Formulations suitable for oral or sublingual administration include, but are not limited to, tablets, lozenges, or gels. In yet another embodiment, the polymorphs described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In a specific embodiment, the formulation for injection is provided in a unit dosage form (e.g., an ampoule) or a multi-dose container. Preservatives are optionally added to the infusion formulation. In yet another embodiment, the pharmaceutical composition of the polymorph of the compound of Formula I is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. The parenteral infusion formulation optionally includes a formulationy agent such as a suspending agent, stabilizer, and / or dispersing agent. In a particular embodiment, the pharmaceutical formulation for parenteral administration includes an aqueous solution of the active polymorph in a water-soluble form. In a further embodiment, the suspension of the active polymorph is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, but are not limited to, fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains a suitable stabilizer or agent that increases the solubility of the polymorphs, enabling the preparation of high-concentration solutions. Alternatively, in other embodiments, the active ingredient is in powder form for preparation with a suitable vehicle, e.g., sterile water free of pyrogens, before use.

[0152] In yet another embodiment, one or more polymorphs of the compound of formula I are administered topically. One or more polymorphs described herein are formulated into a variety of topically administered compositions such as solutions, suspensions, lotions, gels, pastes, medicinal sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally include solubilizers, stabilizers, isotonic enhancers, buffers, and preservatives.

[0153] In further embodiments, one or more polymorphs of the compound of formula I are formulated for transdermal administration. In specific embodiments, the transdermal formulation may be a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive, utilizing a transdermal delivery device and a transdermal delivery patch. In some embodiments, such patches are constructed for continuous, pulsed, or on-demand delivery of the therapeutic agent. In further embodiments, transdermal delivery of one or more polymorphs of the compound of formula I is achieved by means such as an iontophoresis patch. In certain embodiments, the transdermal patch provides controlled delivery of one or more polymorphs of the compound of formula I. In specific embodiments, the absorption rate is slowed by using a rate-limiting membrane or by trapping the compound within a polymer matrix or gel. In alternative embodiments, an absorption enhancer is used to increase absorption. The absorption enhancer or carrier comprises a pharmaceutically acceptable absorbable solvent that assists passage through the skin. For example, in one embodiment, the transdermal device takes the form of a bandage comprising a backing member, a reservoir containing a compound optionally having a carrier, a rate-controlling membrane for optionally being controlled over a long period of time and for delivering the compound to the host skin at a predetermined rate, and means for securing the device to the skin.

[0154] In other embodiments, one or more polymorphs of the compound of formula I are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of polymorphs of the compound of formula I are conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In specific embodiments, the dose unit of the pressurized aerosol is determined by providing a valve for delivering the measured amount. In certain embodiments, capsules and sachets, for use in inhalers or injectors, for example, made of gelatin, are formulated to include a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0155] In further embodiments, one or more polymorphs of the compound of formula I are formulated into rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retained enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. In the suppository form of the composition, but not limited to, low-melting-point waxes such as mixtures of fatty acid glycerides are optionally combined with cocoa butter to melt first.

[0156] In certain embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active polymorphs into pharmaceutically usable preparations. The appropriate formulation depends on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are used as optional as needed. Pharmaceutical compositions comprising one or more polymorphs of the compound of Formula I are produced, as merely an example, by conventional methods such as conventional mixing, dissolution, granulation, sugar-coated tablet preparation, powdering, emulsification, encapsulation, encapsulation, or compression processes.

[0157] A pharmaceutical composition comprises, as an active ingredient, at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one polymorph of a compound of formula I described herein. The active ingredient may be in the form of a free acid, a free base, or a pharmaceutically acceptable salt. All tautomers of the compounds described herein fall within the range of compounds shown herein. Furthermore, the compounds described herein include not only solvated forms with a pharmaceutically acceptable solvent such as water or ethanol, but also non-solvated forms. The solvated forms of the compounds presented herein are likewise considered to be disclosed herein. In addition, a pharmaceutical composition may optionally include other drugs or pharmaceuticals, carriers, preservatives, stabilizers, wetting agents, or emulsifiers such as adjuvants, solution promoters, salts for controlling osmotic pressure, buffers, and / or other therapeutically beneficial substances.

[0158] A method for preparing a composition comprising one or more polymorphs of a compound of formula I described herein comprises the step of formulating the polymorphs using one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions of the compound, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid before use, or emulsions. These compositions also optionally contain trace amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers and pH buffers.

[0159] In some embodiments, a pharmaceutical composition comprising at least one polymorph of a compound of formula I takes the form of a liquid, exemplary in which the drug exists in a solution, a suspension, or both. Generally, when the composition is administered as a solution or suspension, the first part of the drug is present in the solution, and the second part of the drug is present in particulate form in the suspension within the liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0160] In certain embodiments, a useful aqueous suspension contains one or more polymers as a suspending agent. Useful polymers include water-soluble polymers such as cellulopropyl polymers (e.g., hydroxypropyl methylcellulose) and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Specific pharmaceutical compositions described herein include, for example, mucosal-adhering polymers selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0161] Useful pharmaceutical compositions also optionally include solubilizers to enhance the solubility of polymorphs of the compound of formula I. The term “solubilizer” generally includes agents that result in a micelle or true solution of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, serve as solubilizers, as do ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0162] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusters or buffers, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0163] Furthermore, useful compositions also optionally include one or more salts in amounts necessary to bring the weight osmolality of the composition into an acceptable range. Such salts include sodium, potassium, or ammonium cations, as well as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0164] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stable chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridium chloride.

[0165] Further useful compositions may include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; as well as polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0166] Furthermore, other useful compositions may include one or more antioxidants to enhance chemical stability, if necessary. Suitable antioxidants include, but are not limited to, ascorbic acid and sodium disulfite.

[0167] In certain embodiments, the aqueous suspension composition is packaged in a single-dose, non-resealable container. Alternatively, a multi-dose, resealable container is used, in which case the composition typically contains a preservative.

[0168] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are utilized. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also utilized. In further embodiments, the polymorphs described herein are delivered using sustained-release systems such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. A variety of sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the polymorphs over a period of several weeks to over 100 days. Depending on the chemical properties and biological stability of the therapeutic agent, additional measures for protein stabilization are utilized.

[0169] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelating agents, thiol-containing compounds, and / or other common stabilizers. Examples of such stabilizers include, but are not limited to, (a) glycerol in approximately 0.5% to approximately 2% w / v, (b) methionine in approximately 0.1% to approximately 1% w / v, (c) monothioglycerol in approximately 0.1% to approximately 2% w / v, (d) EDTA in approximately 1 mM to approximately 10 mM, (e) ascorbic acid in approximately 0.01% to approximately 2% w / v, (f) polysorbate 80 in approximately 0.003% to approximately 0.02% w / v, (g) polysorbate 20 in approximately 0.001% to approximately 0.05% w / v, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[0170] Treatment method Disclosed herein are methods for inhibiting deoxycytidine kinase (dCK) activity, comprising contacting a compound or polymorph detailed herein with a deoxycytidine kinase either in vitro (e.g., in an enzyme or cell-based assay setting) or in vivo (e.g., in an animal model or in an individual subject requiring treatment). The compounds and polymorphs provided herein bind to a deoxycytidine kinase polypeptide and inhibit its activity. Thus, in another embodiment, methods are provided for inhibiting dCK activity and treating diseases and disorders in which dCK activity is involved.

[0171] In some embodiments, methods are provided for treating cancer in an individual, comprising administering to the individual an effective amount of a compound or polymorph described herein, or a pharmaceutically acceptable salt thereof.

[0172] As used herein, the term “cancer” refers to all types of cancer, neoplasms, or malignant or benign tumors found in mammals, including leukemia, carcinomas, and sarcomas. In some embodiments, cancer is a solid tumor carcinoma. In some embodiments, cancer is metastatic. In some embodiments, cancer is a humoral tumor carcinoma. In some embodiments, humoral tumor carcinoma is a hematological cancer. In some embodiments, cancer is refractory. Exemplary cancers include acute myeloid leukemia ("AML"), chronic myeloid leukemia ("CML"), as well as cancers of the brain, breast, pancreas, colon, liver, kidney, lung, non-small cell lung, melanoma, ovarian, sarcoma, and prostate. Further examples include cervical cancer, gastric cancer, head and neck cancer, uterine cancer, mesothelioma, metastatic bone cancer, medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, and endocrine and exocrine neoplasms.

[0173] The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs, generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually distinguished by (1) the duration and characteristics of the acute or chronic disease; (2) the type of cells involved: myeloid, lymphoid, or monocytic; and (3) the increase or absence of an increase in the number of abnormal cells in the blood: leukemia or leukemia (leukemic). Mouse leukemia models are widely accepted as predictors of in vivo antileukemia activity. Compounds that are positive in the P388 cell assay are generally considered to exhibit some level of antileukemia activity, regardless of the type of leukemia being treated. Therefore, the present invention relates to acute myeloid leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myeloid leukemia, leukemia, leukemia, leukemia, hematopoietic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukocyte leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, monocytic leukemia, megakaryocytic leukemia, and micromyelocytic leukemia. The invention includes methods for treating leukemia, including treating promyelocytic leukemia, lidar cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0174] The term "sarcoma" generally refers to a tumor composed of a substance similar to embryonic connective tissue, and generally consisting of densely packed cells embedded in a fibrillary or homogeneous material. Sarcomas that can be treated with a combination of anti-tumor thiol-binding mitochondrial oxidants and anticancer drugs include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemetii's sarcoma, liposarcoma, alveolar soft tissue sarcoma, dysplastic sarcoma, botulism sarcoma, chloroma sarcoma, choroidal carcinoma, embryonic sarcoma, Ewing's sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, myosarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, synovial sarcoma, reticular cell sarcoma, and Rouss's sarcoma.

[0175] The term "melanoma" is interpreted to mean tumors arising from the melanocyte system of the skin and other organs. Examples of melanomas that can be treated with a combination of anti-cancer thiol-binding mitochondrial oxidants and anticancer agents include keratotic melanoma, amoeboid melanoma, benign juvenile melanoma, Claudemann melanoma, S91 melanoma, Harding-Packey melanoma, juvenile melanoma, lentigo melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0176] The term "carcinoma" refers to a new malignant proliferation composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary carcinomas that can be treated with a combination of antitumor thiol-binding mitochondrial oxidants and anticancer drugs include, for example, adenocarcinoma, adenomatous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, bronchial squamous cell carcinoma, bronchoalveolar carcinoma, bronchial carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedone carcinoma, corpus carcinoma, cribriform carcinoma, curus carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, adenomatous carcinoma, dural carcinoma, embryonic carcinoma, cerebral carcinoma, epidermoid carcinoma, carcinoma epithelial adenoid, extrinsic carcinoma, vulvar carcinoma, fibroma, gelatinous adenocarcinoma, gelatinous carcinoma, giant cell carcinoma, and carcinoma. Granulosa cell carcinoma, pilaris carcinoma, hepatocellular carcinoma, hepatocellular carcinoma, Haasle cell carcinoma, vitreous carcinoma, hypermefloyd carcinoma, infant embryonic carcinoma, carcinoma in situ, carcinoma in situ, carcinoma in situ, Kronpecher carcinoma, Kruticky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticular, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma. Myxoid carcinoma, mucinous cell carcinoma, mucosal cell carcinoma, mucosal epidermal carcinoma, myxoid carcinoma, myxoid carcinoma, myxoid carcinoma, nasopharyngeal carcinoma, autocellular carcinoma, osphican carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, sickle cell carcinoma, lung carcinoma, renal cell carcinoma, kidney carcinoma, reservoir cell carcinoma, carcinoma, lymphatic carcinoma, scleral cell carcinoma, carcinoma, pseudocellular carcinoma. Examples include simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, filamentous carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, cavernous carcinoma, and choriocarcinoma.

[0177] In some embodiments, the cancer is a humoral tumor. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is characterized by high levels of replication stress, determined by measuring γH2A.X expression. In some embodiments, the cancer is ovarian cancer, pancreatic cancer, lung cancer, glioblastoma, hepatocellular carcinoma, breast cancer, prostate cancer, or head and neck cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is head and neck cancer.

[0178] In some embodiments of this section, methods are provided for treating an immunodeficiency in an individual in need, comprising administering to the individual an effective amount of a compound detailed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the immunodeficiency is an autoimmune disorder or transplant rejection. In some embodiments, the autoimmune disorder is a T-cell mediated autoimmune disorder. In some embodiments, the autoimmune disorder is selected from the group consisting of multiple sclerosis, lupus (including systemic lupus erythematosus), inflammatory bowel disease, rheumatoid arthritis, and type 1 diabetes.

[0179] In another aspect, this specification provides a method for treating a subject with acute disseminated encephalomyelitis (ADEM) requiring such treatment, the method comprising a therapeutically effective amount of a compound of formula I:

[0180] [ka] Alternatively, the process may include administering a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the compound of formula I is administered once daily. In some embodiments, the compound of formula I is administered twice daily. In some embodiments, the compound of formula I is administered 12 hours apart.

[0182] In some embodiments, the compound of formula I is administered in a unit dosage form. In some embodiments, the unit dosage form contains about 0.5 to about 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 25 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 50 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 75 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 100 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 125 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 150 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 175 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 200 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 225 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 250 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 275 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 300 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 320 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 325 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 0.5 to about 350 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 25 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 50 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 75 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 100 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 125 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 150 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 175 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains about 200 mg / subject of the compound of formula I.In some embodiments, the unit dosage form contains approximately 225 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 250 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 275 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 300 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 320 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 325 mg / subject of the compound of formula I. In some embodiments, the unit dosage form contains approximately 350 mg / subject of the compound of formula I.

[0183] In some embodiments, the total amount of compound I administered per day is about 0.5 to about 350 mg / kg. In some embodiments, the total amount of compound I administered per day is about 25 mg / kg. In some embodiments, the total amount of compound I administered per day is about 50 mg / kg. In some embodiments, the total amount of compound I administered per day is about 75 mg / kg. In some embodiments, the total amount of compound I administered per day is about 100 mg / kg. In some embodiments, the total amount of compound I administered per day is about 125 mg / kg. In some embodiments, the total amount of compound I administered per day is about 150 mg / kg. In some embodiments, the total amount of compound I administered per day is about 175 mg / kg. In some embodiments, the total amount of compound I administered per day is about 200 mg / kg. In some embodiments, the total amount of compound I administered per day is about 225 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 250 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 275 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 300 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 320 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 325 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 350 mg / kg.

[0184] In some embodiments, the total amount of compound I administered per day is about 0.5 to about 350 mg / subject. In some embodiments, the total amount of compound I administered per day is about 25 mg / subject. In some embodiments, the total amount of compound I administered per day is about 50 mg / subject. In some embodiments, the total amount of compound I administered per day is about 75 mg / subject. In some embodiments, the total amount of compound I administered per day is about 100 mg / subject. In some embodiments, the total amount of compound I administered per day is about 125 mg / subject. In some embodiments, the total amount of compound I administered per day is about 150 mg / subject. In some embodiments, the total amount of compound I administered per day is about 175 mg / subject. In some embodiments, the total amount of compound I administered per day is about 200 mg / subject. In some embodiments, the total amount of compound I administered per day is about 225 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 250 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 275 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 300 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 320 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 325 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 350 mg / subject.

[0185] In some embodiments, the total amount of compound I administered per day is about 5 to about 350 mg. In some embodiments, the total amount of compound I administered per day is about 25 mg. In some embodiments, the total amount of compound I administered per day is about 50 mg. In some embodiments, the total amount of compound I administered per day is about 75 mg. In some embodiments, the total amount of compound I administered per day is about 100 mg. In some embodiments, the total amount of compound I administered per day is about 125 mg. In some embodiments, the total amount of compound I administered per day is about 150 mg. In some embodiments, the total amount of compound I administered per day is about 175 mg. In some embodiments, the total amount of compound I administered per day is about 200 mg. In some embodiments, the total amount of compound I administered per day is about 225 mg. In some embodiments, the total amount of compound I administered per day is about 250 mg. In some embodiments, the total amount of compound I administered per day is approximately 275 mg. In some embodiments, the total amount of compound I administered per day is approximately 300 mg. In some embodiments, the total amount of compound I administered per day is approximately 320 mg. In some embodiments, the total amount of compound I administered per day is approximately 325 mg. In some embodiments, the total amount of compound I administered per day is approximately 350 mg.

[0186] In some embodiments, the compound of formula I is formulated for oral administration. In some embodiments, the compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, solution, suppository, or aerosol. In some embodiments, the compound of formula I is formulated as a tablet. In some embodiments, the compound of formula I is formulated as a pill. In some embodiments, the compound of formula I is formulated as a capsule. In some embodiments, the compound of formula I is formulated as a powder. In some embodiments, the compound of formula I is formulated as a liquid. In some embodiments, the compound of formula I is formulated as a suspension. In some embodiments, the compound of formula I is formulated as a suppository. In some embodiments, the compound of formula I is formulated as an aerosol.

[0187] In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution contains about 1 to about 50 mg / mL of the compound of formula I. In some embodiments, the solution contains about 5 mg / mL of the compound of formula I. In some embodiments, the solution contains about 10 mg / mL of the compound of formula I. In some embodiments, the solution contains about 15 mg / mL of the compound of formula I. In some embodiments, the solution contains about 20 mg / mL of the compound of formula I. In some embodiments, the solution contains about 25 mg / mL of the compound of formula I. In some embodiments, the solution contains about 30 mg / mL of the compound of formula I. In some embodiments, the solution contains about 35 mg / mL of the compound of formula I. In some embodiments, the solution contains about 40 mg / mL of the compound of formula I. In some embodiments, the solution contains about 45 mg / mL of the compound of formula I. In some embodiments, the solution contains about 50 mg / mL of the compound of formula I.

[0188] In some embodiments, administration of the compound of formula I results in a decrease in interferon-γ (IFNγ) levels in the subject.

[0189] This specification provides, in another embodiment, a method for treating an autoimmune disease or disorder of interest, wherein the method involves Formula I

[0190] [ka] The procedure includes administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is administered once daily.

[0191] In some embodiments, the disease or disorder is multiple sclerosis. In some embodiments, the disease or disorder is optic neuritis. In some embodiments, the disease or disorder is acute disseminated encephalomyelitis (ADEM).

[0192] In some embodiments, the compound of formula I is administered in unit dosage forms. In some embodiments, the unit dosage form contains about 0.5 to 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 25 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 50 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 75 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 100 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 125 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 150 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 175 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 200 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 225 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains about 250 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 275 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 300 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 320 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 325 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 350 mg / kg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 0.5 to approximately 350 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 25 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 50 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 75 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 100 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 125 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 150 mg / target of the compound of formula I. In some embodiments, the unit dosage form contains approximately 175 mg / compound of formula I. In some embodiments, the unit dosage form contains approximately 200 mg / compound of formula I. In some embodiments, the unit dosage form contains approximately 225 mg / compound of formula I.In some embodiments, the unit dosage form contains approximately 250 mg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 275 mg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 300 mg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 320 mg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 325 mg of the compound of formula I. In some embodiments, the unit dosage form contains approximately 350 mg of the compound of formula I.

[0193] In some embodiments, the total amount of compound I administered per day ranges from about 0.5 to about 350 mg / kg. In some embodiments, the total amount of compound I administered per day is about 25 mg / kg. In some embodiments, the total amount of compound I administered per day is about 50 mg / kg. In some embodiments, the total amount of compound I administered per day is about 75 mg / kg. In some embodiments, the total amount of compound I administered per day is about 100 mg / kg. In some embodiments, the total amount of compound I administered per day is about 125 mg / kg. In some embodiments, the total amount of compound I administered per day is about 150 mg / kg. In some embodiments, the total amount of compound I administered per day is about 175 mg / kg. In some embodiments, the total amount of compound I administered per day is about 200 mg / kg. In some embodiments, the total amount of compound I administered per day is about 225 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 250 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 275 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 300 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 320 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 325 mg / kg. In some embodiments, the total amount of compound I administered per day is approximately 350 mg / kg.

[0194] In some embodiments, the total amount of compound I administered per day ranges from about 0.5 to about 350 mg / subject. In some embodiments, the total amount of compound I administered per day is about 25 mg / subject. In some embodiments, the total amount of compound I administered per day is about 50 mg / subject. In some embodiments, the total amount of compound I administered per day is about 75 mg / subject. In some embodiments, the total amount of compound I administered per day is about 100 mg / subject. In some embodiments, the total amount of compound I administered per day is about 125 mg / subject. In some embodiments, the total amount of compound I administered per day is about 150 mg / subject. In some embodiments, the total amount of compound I administered per day is about 175 mg / subject. In some embodiments, the total amount of compound I administered per day is about 200 mg / subject. In some embodiments, the total amount of compound I administered per day is about 225 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 250 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 275 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 300 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 320 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 325 mg / subject. In some embodiments, the total amount of compound I administered per day is approximately 350 mg / subject.

[0195] In some embodiments, the total amount of compound I administered per day ranges from about 5 to about 350 mg. In some embodiments, the total amount of compound I administered per day is about 25 mg. In some embodiments, the total amount of compound I administered per day is about 50 mg. In some embodiments, the total amount of compound I administered per day is about 75 mg. In some embodiments, the total amount of compound I administered per day is about 100 mg. In some embodiments, the total amount of compound I administered per day is about 125 mg. In some embodiments, the total amount of compound I administered per day is about 150 mg. In some embodiments, the total amount of compound I administered per day is about 175 mg. In some embodiments, the total amount of compound I administered per day is about 200 mg. In some embodiments, the total amount of compound I administered per day is about 225 mg. In some embodiments, the total amount of compound I administered per day is about 250 mg. In some embodiments, the total amount of compound I administered per day is about 275 mg. In some embodiments, the total amount of compound I administered per day is about 300 mg. In some embodiments, the total amount of compound I administered per day is about 320 mg. In some embodiments, the total amount of compound I administered per day is about 325 mg. In some embodiments, the total amount of compound I administered per day is about 350 mg.

[0196] In some embodiments, the compound of formula I is formulated for oral administration. In some embodiments, the compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, suppository, or aerosol. In some embodiments, the compound of formula I is formulated as a tablet. In some embodiments, the compound of formula I is formulated as a pill. In some embodiments, the compound of formula I is formulated as a capsule. In some embodiments, the compound of formula I is formulated as a powder. In some embodiments, the compound of formula I is formulated as a liquid. In some embodiments, the compound of formula I is formulated as a suspension. In some embodiments, the compound of formula I is formulated as a suppository. In some embodiments, the compound of formula I is formulated as an aerosol.

[0197] In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution contains about 1 to about 50 mg / mL of the compound of formula I. In some embodiments, the solution contains about 5 mg / mL of the compound of formula I. In some embodiments, the solution contains about 10 mg / mL of the compound of formula I. In some embodiments, the solution contains about 15 mg / mL of the compound of formula I. In some embodiments, the solution contains about 20 mg / mL of the compound of formula I. In some embodiments, the solution contains about 25 mg / mL of the compound of formula I. In some embodiments, the solution contains about 30 mg / mL of the compound of formula I. In some embodiments, the solution contains about 35 mg / mL of the compound of formula I. In some embodiments, the solution contains about 40 mg / mL of the compound of formula I. In some embodiments, the solution contains about 45 mg / mL of the compound of formula I. In some embodiments, the solution contains about 50 mg / mL of the compound of formula I.

[0198] In some embodiments, administration of the compound of formula I results in a decrease in interferon-γ (IFNγ) levels in the subject.

[0199] Combination therapy In some embodiments, methods are provided for treating cancer in an individual, comprising administering an effective amount of the compound or polymorph described herein, or a pharmaceutically acceptable salt thereof, and thymidine to the individual. In some embodiments, the compound or polymorph is administered co-administered with thymidine. In some embodiments, the compound or polymorph is administered before, during, or after administration of thymidine. Examples of cancers to be treated include, but are not limited to, leukemia, lymphoma, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, melanoma, sarcoma, head and neck cancer, glioma, glioblastoma, and cancers unrelated to the tissue of origin characterized by genomic instability and / or activation of the DNA damage response. Inhibition of dCK by the compound or polymorph described herein, or a pharmaceutically acceptable salt thereof, synergistically with thymidine to induce cell cycle arrest in tumors.

[0200] In some embodiments, the compounds and polymorphs described herein are used together with other active drugs known to be useful in treating diseases (e.g., anticancer drugs) or with adjuvants that may not be effective on their own but may contribute to the effectiveness of the active drug. In some embodiments, the compounds and polymorphs described herein are administered together with other active drugs known to be useful in treating diseases.

[0201] The term "anticancer agent" is used in its simple and ordinary sense to refer to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) that has antitumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, an anticancer agent is a chemotherapeutic agent. In some embodiments, an anticancer agent is a drug approved by the FDA or a similar regulatory authority in a country other than the United States for the treatment of cancer.

[0202] SSR-250411 (Sanofi), steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin or leuprolide, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., dietristilbestrol, ethinylestradiol), anti-estrogens (e.g., tamoxifen), androgens (e.g., testosterone) (Teronpropionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., Calmette-Guerinbacillus (BCG), Levamisol), interleukin-2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., 1 Anti-CD20 monoclonal antibodies conjugated to 11In, 90Y, or 131I, etc.), triptolide, homohalingointin, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, epidermal growth factor receptor (EGFR) targeted therapies or treatments (e.g., gefitinib Iressa (trademark), Erlotinib (Tarceva (trademark)), Cetuximab (Erbitux (trademark)), Lapatinib (Tykerb (trademark)), Panitumumab (Vectibix (trademark)), Vandetanib (Caprelsa (trademark)), Afatinib / BIBW2992, CI-1033 / Canertinib, Neratinib / HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, Dacomitinib / PF299804, OSI-420 / Desmethylerlotinib,Examples include, but are not limited to, AZD8931, AEE788, peritinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, and dasatinib.

[0203] When polymorphs of the compound of formula I are administered to human subjects, the daily dose is generally determined by the prescribing physician and varies according to the age, weight, and response of the individual subject, as well as the severity of the subject's symptoms.

[0204] In one exemplary application, an appropriate amount of at least one polymorph of the compound of formula I is administered to a mammal undergoing treatment for cancer, e.g., breast cancer. The administration is typically in amounts of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day (administered as a single dose or in divided doses), e.g., at least about 0.1 mg / kg body weight / day. A specific therapeutic dose may include, for example, polymorphs of the compound of formula I ranging from about 0.01 mg to about 1000 mg, e.g., about 1 mg to about 1000 mg. The amount of at least one polymorph of the compound of formula I in a unit dose of a preparation may vary or be adjusted according to the specific application, ranging from about 0.1 mg to 1000 mg, e.g., from about 1 mg to 300 mg, e.g., from 10 mg to 200 mg. The amount administered depends on the specific IC of at least one polymorph of the compound of formula I used. 50 The effect will vary depending on the value and the judgment of the attending clinician, taking into account factors such as health status, weight, and age. In combination applications where at least one polymorph of the compound of formula I described herein is not the sole active ingredient, it may be possible to administer a smaller amount of at least one polymorph of the compound of formula I and still have a therapeutic or prophylactic effect.

[0205] In some embodiments, the pharmaceutical preparation is a unit dosage form. In such a form, the preparation is subdivided into unit doses containing an appropriate amount, for example, an amount of polymorph of the compound of formula I that is effective in achieving the desired objective.

[0206] The actual dosage used may vary depending on the subject's requirements and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the scope of the art. Generally, treatment is initiated with a lower dose than the optimal dose of at least one polymorph of the compound of formula I. The dose is then gradually increased until the optimal effect is achieved under the given conditions. For convenience, the total daily dose can be divided and administered in multiple portions throughout the day, if desired.

[0207] The dosage and frequency of administration of at least one polymorph of the compound of Formula I, as well as other chemotherapeutic agents and / or radiotherapy, where applicable, will be adjusted at the discretion of the attending clinician (physician), taking into account factors such as the age, condition, and size of the subject, and the severity of the disease being treated.

[0208] Chemotherapy agents and / or radiotherapy can be administered according to treatment protocols well known in the art. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents and / or radiotherapy may vary depending on the disease being treated and the known effects of chemotherapeutic agents and / or radiotherapy on that disease. Furthermore, according to the knowledge of a skilled clinician, treatment protocols (e.g., dosage and administration time) may be modified in consideration of the observed effects of the administered therapeutic agent (i.e., antitumor agent or radiation) on the subject and the observed response of the disease to the administered therapeutic agent.

[0209] Furthermore, generally, at least one polymorph of a compound of formula I does not need to be administered in the same pharmaceutical composition as the chemotherapeutic agent, and may be administered by different routes due to their different physical and chemical properties. For example, the polymorph / composition may be administered orally to obtain and maintain its good blood levels, while the chemotherapeutic agent may be administered intravenously. The mode of administration and the suitability of administration in the same pharmaceutical composition are, where possible, within the knowledge of a skilled clinician. The initial administration may be carried out according to established protocols known in the art, and then the dosage, mode of administration, and timing of administration may be modified by a skilled clinician based on the observed effects.

[0210] The specific selection of polymorphs (and, where appropriate, chemotherapy agents and / or radiation) depends on the attending physician's diagnosis, assessment of the patient's condition, and appropriate treatment protocols.

[0211] One or more polymorphs of the compound of formula I (and, where appropriate, chemotherapeutic agents and / or radiation) may be administered simultaneously (e.g., simultaneously, essentially simultaneously, or within the same treatment protocol) or sequentially, depending on the nature of the proliferative disorder, the condition of the subject, and the actual selection of chemotherapeutic agents and / or radiation administered in conjunction with the one or more polymorphs / composition (i.e., within a single treatment protocol).

[0212] In the application and use of combinations, one or more polymorphs / compositions and chemotherapeutic agents and / or radiation do not need to be administered simultaneously or essentially simultaneously, and the initial order of administration of one or more polymorphs / compositions and chemotherapeutic agents and / or radiation may not be important. Therefore, at least one polymorph of a compound of formula I may be administered first, followed by a chemotherapeutic agent and / or radiation, or the chemotherapeutic agent and / or radiation may be administered first, followed by at least one polymorph of a compound of formula I. This alternating administration may be repeated within a single treatment protocol. The determination of the order of administration and the number of repetitions of each therapeutic agent in the treatment protocol is made within the bounds of the knowledge of a skilled physician after evaluating the disease being treated and the condition of the subject. For example, the treatment may continue until the treatment protocol is completed, with the chemotherapeutic agent and / or radiation administered first, followed by at least one polymorph of a compound of formula I, and then, if deemed advantageous, the chemotherapeutic agent and / or radiation.

[0213] Therefore, according to experience and knowledge, the physician performing the procedure may modify each protocol for the administration of polymorphs of compound / composition of formula I for the procedure according to the needs of the individual patient as the procedure progresses.

[0214] The attending clinician will consider the patient's overall health status, as well as more concrete signs such as reduction of disease-related symptoms, inhibition of tumor growth, actual tumor shrinkage, or inhibition of metastasis, when determining whether the treatment is effective at the administered dose. Tumor size can be measured by standard radiological investigations, such as CAT or MRI scans, and continuous measurements may be used to determine whether tumor growth has slowed or even reversed. Reduction of disease-related symptoms such as pain, and overall improvement of the disease can also be used to help determine the effectiveness of the treatment.

[0215] Route of administration Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal, and topical administration. Furthermore, parenteral delivery includes, simply as an example, intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0216] In some embodiments, polymorphs of the compound of formula I are administered topically rather than systemically, for example, by direct injection of the polymorph into an organ, often in a depot preparation or sustained-release formulation. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target an organ and are selectively taken up by the organ. In yet another embodiment, polymorphs of the compound of formula I are provided in the form of a rapid-release formulation, a sustained-release formulation, or a medium-release formulation. In yet another embodiment, polymorphs of the compound of formula I are administered topically.

[0217] Kits and products Kits and products are also provided for use in the therapeutic applications described herein. In some embodiments, such a kit includes a carrier, package, or container partitioned to receive one or more containers such as vials, tubes, etc., each of which contains one of the distinct elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers are formed from a variety of materials such as glass or plastic.

[0218] The products provided herein include packaging materials. Examples of packaging materials for use in packaging pharmaceuticals are found in, for example, U.S. Patents 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging materials suitable for the selected formulation and the intended mode of administration and treatment. For example, a container may optionally contain one or more polymorphs described herein, either in the composition or in combination with another agent disclosed herein. The container may optionally have a sterile access port (for example, the container may be a vial with a stopper that can be pierced by an intravenous solution bag or a subcutaneous injection needle). Such a kit may optionally contain the compound, along with a description, label, or instructions for identification of its use in the method described herein.

[0219] For example, a kit typically includes one or more additional containers, each containing one or more materials (optionally concentrated forms, reagents, and / or devices, etc.) that are desirable from a commercial and user perspective for the use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tubes, labels and / or instructions for use listing the contents, and package inserts with instructions for use. A set of instructions is also typically included. Labels are optionally on the container or accompanying the container. For example, a label is on the container when the letters, numbers, or other characters forming the label are affixed, molded, or etched onto the container itself, and accompanying the container when they exist, for example, as accompanying documentation within the receptacle or carrier holding the container. Furthermore, labels are used to indicate that the contents are for use in a particular therapeutic application. In addition, labels provide instructions for the use of the contents, as in the methods described herein. In some embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms containing the compounds provided herein. The pack includes, for example, metal or plastic foil such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by a notice attached to the container in a form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, the notice reflecting agency approval of the form of the drug for human or veterinary administration. Such notice is, for example, a label or product insert approved by the U.S. Food and Drug Administration for a prescription drug. In some embodiments, a composition containing polymorphs of the compound of formula I formulated in a suitable pharmaceutical carrier is prepared, placed in a suitable container, and labeled with respect to the treatment of the indicated disease. [Examples]

[0220] Example 1 Preparation of 2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethylthio)pyrimidine-4,6-diamine(6)

[0221] [ka]

[0222] Step 1: Synthesis of 4-methoxy-3-(2-morpholinoethoxy)benzonitrile (1). A mixture of potassium carbonate (4.52 g, 32.7 mmol), 3-hydroxy-4-methoxybenzonitrile (2.44 g, 16.4 mmol), and 4-(2-chloroethyl)morpholine (2.45 g, 16.4 mmol) was heated to 100°C for 8 hours in a solvent mixture of DMF (40 mL) and acetone (25 mL). After cooling to room temperature (rt), the reaction mixture was diluted with aqueous HCl (0.1 M, 150 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic layer was removed under reduced pressure, and the crude residue was purified on silica gel using CH2Cl2:MeOH (40:1) as the eluent. The desired product 1 was obtained as a yellow oil in 85% yield. HRMS C 14 H 18 The calculated value for N2O3 was 263.1390, and the measured value was 263.1386.

[0223] Step 2: Synthesis of 4-methoxy-3-(2-morpholinoethoxy)benzothioamide (2). Compound 1 (2.46 g, 9.4 mmol) was dissolved in pyridine (5 mL, 61.8 mmol), Et3N (1.44 mL, 10.3 mmol) was added, followed by aqueous ammonium sulfide solution (20%, 12 mL, 35.2 mmol). The reaction mixture was stirred overnight and heated to 60°C. After cooling to rt, the solvent was removed under reduced pressure and mixed with SiO (50 mL) and saturated aqueous NH4Cl solution (200 mL). The mixture was extracted with SiO (2 × 20 mL). The combined organic solvent was removed under reduced pressure, and the residue was dried to obtain the desired product 2 as a yellow solid in 79% yield. HRMS C14 H 20 Calculated for N2O3S 297.1267, found 297.1266.

[0224] Step 3 Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethane-1-one (3). To a solution of compound 2 (1.40 g, 4.7 mmol) in EtOH (30 mL) was added 4-bromopentane-2,3-dione (0.84 g, 4.7 mmol). The reaction mixture was heated to 80°C for 3 hours. After cooling to rt, the solvent was removed under reduced pressure, and the residue was mixed with CH2Cl2 (20 mL) and water (100 mL). The mixture was extracted with CH2Cl2 (2×10 mL), and the combined organic solvents were removed under reduced pressure. Product 3 was obtained as a brown solid in 76% yield without further purification. HRMS C 19 H 24 Calculated for N2O4S 377.1530, found 377.1526.

[0225] Step 4 Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazol-4-yl)ethane-1-ol (4). A solution of 3 (1.35 g, 3.6 mmol) in CH2Cl2 (40 mL) was cooled to -78°C, and DIBAL-H (1 M in CH2Cl2, 14.3 mL, 14.3 mmol) was slowly added. The reaction mixture was allowed to warm to rt and stirred for 30 minutes. The solution was cooled to 0°C, saturated aqueous potassium sodium tartrate (10 mL) was added, and the mixture was stirred for 1 hour. The solution was extracted with CH2Cl2 (3×10 mL), and the combined organic solvents were removed under reduced pressure. The crude residue was purified on silica gel using 5-10% MeOH in CH2Cl2. Pure product 4 was obtained as a yellow oil in 40% yield. HRMS C 19 H 26 Calculated for N2O4S 379.1686, found 379.1684.

[0226] Step 5: Synthesis of 1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl 2,2,2-trifluoroacetate (5). A solution of compound 4 (47 mg, 0.12 mmol) in CH2Cl2 (5 mL) was cooled to 0°C, and trifluoroacetic anhydride (70 μL, 0.5 mmol) was added dropwise. The reaction mixture was heated to rt and stirred for 1 hour. The mixture was cooled to 0°C, and ice water (20 mL) was added. The mixture was extracted with CH2Cl2 (2 × 5 mL), and the combined organic layer was removed under reduced pressure to obtain the desired compound 5 in quantitative yield.

[0227] Step 6: Synthesis of 2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine(6). To a solution of 4,6-diaminopyrimidine-2-thiol (45 mg, 0.31 mmol) in DMF (1.5 mL), potassium carbonate (87 mg, 0.63 mmol), followed by compound 5 (75 mg, 0.16 mmol), was added. The solution was stirred overnight and heated to 80°C. After cooling to rt, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3 × 5 mL). The organic layers were combined and the solvent was removed under reduced pressure. The crude residue was purified on silica gel using 5-10% MeOH in CH2Cl2 to obtain the desired final compound 6 in 25% yield. HRMS C 23 H 30 The calculated value for N6O3S2 was 503.1894, and the measured value was 503.1876.

[0228] Example 2 Preparation of (R)-2-((1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl)thio)pyrimidine-4,6-diamine (compound of formula I)

[0229] [ka]

[0230] Step 1: Synthesis of (S)-1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethanol (7). To a stirred solution of (R)-(+)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene) in THF at -78°C under Ar, borane-tetrahydrofuran complex (1.0 M solution in THF) was added, followed by the addition of solution 3 in THF. After adding solution 3 using a syringe pump, the reaction mixture was stirred at -78°C for 6 hours, and then for a further 20 minutes. H2O and MeOH were added, and the mixture was warmed to room temperature. After concentration and removal of residual solvent, the resulting residue was washed with brine and extracted with ethyl acetate. The organic layer was washed three times with water, dried over anhydrous Na2SO4, concentrated under vacuum, and the crude residue was purified by flash column chromatography on silica gel to obtain alcohol 7 as a white solid. HRM C 19 H 26 The calculated value of N2O4S was 379.1686, and the measured value was 379.1684.

[0231] Step 2 Synthesis of (S)-1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethyl 2,2,2-trifluoroacetate (8). A solution of compound 7 (47 mg, 0.12 mmol) in CH2Cl2 (5 mL) was cooled to 0°C, and trifluoroacetic anhydride (70 μL, 0.5 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, and ice water (20 mL) was added. The mixture was extracted with CH2Cl2 (2 × 5 mL), and the combined organic layer was removed under reduced pressure to obtain the desired compound 8 in quantitative yield.

[0232] Step 3: Synthesis of (R)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethylthio)pyrimidine-4,6-diamine (9R) and (S)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethylthio)pyrimidine-4,6-diamine (9S). To a solution of 4,6-diaminopyrimidine-2-thiol (45 mg, 0.31 mmol) in DMF (1.5 mL), potassium carbonate (87 mg, 0.63 mmol), followed by 8 (75 mg, 0.16 mmol), was added. The solution was stirred overnight and heated to 80°C. After cooling to rt, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3 × 5 mL). The organic layers were combined and the solvent was removed under reduced pressure. The crude residue was purified on silica gel using 5-10% MeOH in CH2Cl2 to obtain pairs of enantiomers 9R and 9S as white solids. Recrystallization of the enantiomers using a MeOH / acetone solvent system yielded 9R with 93% ee. HRMS C 23 H 30 The calculated value for N6O3S2 was 503.1894, and the measured value was 503.1876.

[0233] Example 3: Preparation of compound polymorph I of formula I Maleic acid (66.05 g, 1.0 equivalent) was dissolved in ethanol (300 mL) at 40°C with stirring. In a separate container, (R)-2-(1-(2-(4-methoxy-3-(2-morpholinoethoxy)phenyl)-5-methylthiazole-4-yl)ethylthio)pyrimidine-4,6-diamine (314.95 g, 1.0 equivalent) was dissolved in ethanol (850 mL) and ethyl acetate (1.15 L) with stirring, and the mixture was stirred at 60°C for 1 hour. The maleic acid solution was slowly added, and the resulting reaction mixture was stirred at 60°C for 20 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5.8 L), and stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C, stirred at 0°C for 3 hours, and filtered. The filtered cake was dried at 55°C for 64 hours to obtain polymorph I of the compound of formula I (317.94 g, yield 82.0%, purity 97.6%).

[0234] Example 4: Preparation of compound polymorph II of formula I Polymorph Form I of the compound of Formula I (323.15 g) was dissolved in 1:1 DCM / methanol (2.4 L) at 45°C with stirring. The reaction mixture was cooled to 5°C over 1 hour and stirred at 5°C for 16 hours. The reaction mixture was diluted with methyl tert-butyl ether (2.4 L) over 2 hours, stirred at 5°C for 2 hours, and filtered. The filter cake was washed with methyl tert-butyl ether (700 mL) and dried at 70°C for 47 hours to obtain Polymorph Form I of the compound of Formula I (295.41 g, purity 98.4%).

[0235] Example 5 X-ray Powder Diffraction (XRPD) X-ray powder diffraction (XRPD) patterns were obtained with a Rigaku Miniflex. A CuK source (λ = 1.54056 Å) operating at 40 kV and 15 mA scans each sample for 2θ from 3° to 45°. The step size is 0.02° 2θ and the scanning speed is 2.5° / min.

[0236] The XRPD pattern obtained for Polymorph Form I of the compound of Formula I is summarized in Table 1 and Figure 2.

[0237]

Table 1

[0238] The XRPD pattern obtained for Polymorph Form II of the compound of Formula I is summarized in Table 2 and Figure 5.

[0239]

Table 2

[0240] Example 6 Thermogravimetric Analysis (TGA) Thermogravimetric analysis was performed using a TA Instruments Q5000 thermogravimetric analyzer. The sample was heated in an aluminum pan from ambient temperature to 250°C at a rate of 15°C / min, along with a nitrogen purge of 60 mL / min. The TGA thermogram obtained for polymorph I of the compound of formula I is summarized in Figure 3. The TGA thermogram obtained for polymorph II of the compound of formula I is summarized in Figure 6.

[0241] Example 7 Differential Scanning Calorimetry (DSC) Differential scanning calorimetry analysis was performed using a TA Instrument Discovery thermogravimetric analyzer. Samples were heated in a sealed aluminum pan from ambient temperature to 250°C at a rate of 10°C / min. The DSC thermogram obtained for polymorph I of the compound of formula I is summarized in Figure 1. The DSC thermogram obtained for polymorph II of the compound of formula I is summarized in Figure 4.

[0242] Example 8: High-performance liquid chromatography (HPLC) High-performance liquid chromatography (HPLC) was performed using the following equipment and / or conditions.

[0243] [Table 3]

[0244] Example 9: Stability test of polymorph II Table 3 shows the results for polymorphic form II in the accelerated stability test.

[0245] [Table 4]

[0246] Example 10 Efficacy of Compound 1 in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) Adult female C57BL / 6J mice were randomly assigned to the experimental group and acclimatized for one week before the start of the study. On days 0 and 7, the animals were administered an emulsion of MOG35-55 (200 μL / mouse) and complete Freund's adjuvant (CFA). MOG35-55 (300 μg / mouse) was purchased as powder and reconstituted with an initial concentration of 3 mg / mL of NaCl (0.9%). After reconstitution, an equivolute volume of CFA, prepared by reconstituting Mycobacterium tuberculosis H37Ra in an incomplete Freund's adjuvant, was mixed with the MOG35-55 solution at an initial concentration of 5 mg / mL to obtain a final concentration of 2.5 mg / mL. This was injected under gas (isoflurane) anesthesia into two lower quadrants of the back (100 μL each of the flanks) on day 0 and two upper quadrants of the back (100 μL each of the flanks) on day 7. On day 0 (immediately after MOG injection) and day 2, animals were administered parthioxidil toxin (PTx, 500 ng / mouse) prepared in phosphate-buffered saline (PBS, 100 μL / mouse) by intraperitoneal injection.

[0247] Treatment was administered according to the administration schedule shown in Table 4.

[0248] [Table 5]

[0249] Treatment was initiated prophylactically on day 1 for groups 1, 2, and 4, and therapeutically on day 8 for group 3, administered twice daily (BID). All experimental groups had n=12. The dosing interval was 12 hours, and the dose was 5 mL / kg.

[0250] Since weight loss is known to be an important feature of EAE that occurs in response to the appearance of the first symptom, animals were weighed daily from the day of immunization (day 0) until the end of the experiment. Changes in body weight observed throughout the experiment for different experimental groups are presented as mean ± SEM and summarized in Figure 7. As expected, significant weight loss was observed in a time-dependent manner in vehicle-treated animals (p<0.001). Initial MOG 35-55A marked weight loss was observed immediately after administration, and thereafter body weight gradually returned to normal. Similar effects on body weight were observed in the compound 1-treated group and the dexamethasone-treated group. Analysis of the two variables as being dependent on each other (time × treatment effect) revealed a significant overall effect (p=0.002), while suggesting that body weight increased over time similarly among all experimental groups.

[0251] Next, to evaluate the overall effect of the pharmacological treatment, analysis of the area under the curve (AUC) was performed. The area under the curve values for the percentage of body weight change relative to baseline for different experimental groups are presented as mean ± SEM and summarized in Figure 8. The AUC analysis confirmed the weight loss data and showed no significant difference between the group treated with compound 1 and the group treated with vehicle. Preventive treatment with compound 1 showed a small trend towards a reduction in AUC values indicating greater weight loss in this group compared with vehicle. However, this did not reach the significance threshold (p=0.72).

[0252] From day 0 until the end of the experiment, animals were scored daily for clinical signs of EAE, including paralysis affecting the tail and limbs. The following scale was used (0) No abnormality, the animal moves and behaves normally. (1) Limp tail, when the mouse is held by the base of the tail, the tail droops to the limb. (2) Partial hindlimb paralysis, spastic paralysis or paralysis affects one hindlimb. (3) Complete hindlimb paralysis, spastic paralysis or paralysis affects both hindlimbs. (4) Forelimb and hindlimb paralysis, spastic paralysis or paralysis affects one or both forelimbs. (5) Moribund. Changes in EAE scores observed throughout the experiment for different experimental groups are presented as mean ± SEM and summarized in Figure 9. Analysis of the clinical EAE profile revealed that the first clinical symptom appeared on day 7 post-immunization in almost all experimental groups. On day 8, treatment with compound 1 was initiated in group 3, which had received vehicle treatment up to that day. The vehicle-treated group showed a disease profile that steadily increased over time (p<0.0001). A similar disease course was observed in the group treated prophylactically with compound 1. In contrast, both administration of compound 1 after the therapeutic approach and prophylactic administration of dexamethasone as a positive control significantly improved the disease profile (p<0.0001).

[0253] Next, AUC analysis was performed to evaluate the overall effect of pharmacological treatment. The area under the curve for EAE clinical scores for different experimental groups is shown as mean ± SEM and summarized in Figure 10. The AUC analysis supported the changes in the disease profile observed over time. Therapeutic treatment with compound 1 reduced the calculated AUC, indicating symptom improvement. However, despite showing a clear trend, it did not reach a significant threshold. The trend of decreasing AUC values ​​was also observed in the prophylactic group with compound 1. Treatment with dexamethasone significantly reduced the curve and therefore reduced the calculated AUC indicating symptom improvement (vehicle vs. dexamethasone: p<0.0001).

[0254] The overall effect of the treatment was analyzed by summing the disease scores for each animal in each experimental group from the day the first symptom appeared to the 25th day, dividing this value by the number of days the animal showed a clinical score, and calculating the resulting mean cumulative score. The cumulative disease scores for different experimental groups are shown as mean ± standard error of the mean (SEM) and are summarized in Figure 11. The Kruskal-Wallis test (Kruskal-Wallis statistic: 24.74) revealed a significant overall effect of the treatment, but Dunn's multiple comparison test confirmed only a significant difference in the dexamethasone treatment group (p<0.0001 vs. vehicle).

[0255] Further parameters considered for EAE analysis are the plotting and analysis of "extended data." The graph shown in Figure 9 includes the disease scores of animals that terminated before the scheduled termination date up to their respective termination date (e.g., if an animal terminated on day 20, the next time point in the graph will contain fewer animals), while the graph shown in Figure 12 shows the disease profile progression resulting from all animals showing disease scores up to day 25 (e.g., animals that terminated early maintain the score they had on the termination date up to day 25). This is a common method for representing EAE disease profiles that can be used to assess group effects.

[0256] In Figure 9, under scenarios similar to those described above, the vehicle-treated group showed a disease profile that steadily increased over time (p<0.0001). A similar disease course was observed in the group prophylactically treated with compound 1. In contrast, both administration of compound 1 after a therapeutic approach and prophylactic administration of dexamethasone as a positive control significantly improved the disease profile (p<0.0001).

[0257] Next, to evaluate the overall effect of pharmacological treatment, AUC analysis was performed on long-term disease scores. The area under the curve of the extended disease scores for different experimental groups is shown as mean ± SEM and summarized in Figure 13. The AUC analysis supported the changes in the disease profile observed over time. Therapeutic treatment with compound 1 reduced the calculated AUC, indicating symptom improvement. However, despite showing a clear trend, it did not reach a significant threshold. Treatment with dexamethasone significantly reduced the curve and therefore reduced the calculated AUC indicating symptom improvement (vehicle vs. dexamethasone: p<0.0001).

[0258] In the analysis of incidence in the vehicle-treated group and the groups treated therapeutically and prophylactically with compound 1, the proportion of asymptomatic animals at any of the time points analyzed was considered. It was revealed that in the groups treated therapeutically with compound 1, a higher percentage of animals did not show disease symptoms at any of the time points analyzed compared to each vehicle-treated group (Figure 14, upper panel). Furthermore, the therapeutic treatment group never reached a 100% incidence (approximately 92% at day 19), while the vehicle-treated group reached a 100% incidence at day 13. Animals treated therapeutically with compound 1 not only showed significant remission reflected by improvement in symptoms after day 20 (Figures 9 and 12), but approximately 27% of the animals showed no symptoms at all, suggesting complete remission in these animals after day 20 (Figure 14, upper panel). In the group treated prophylactically with compound 1 (Figure 14, lower panel), no difference was observed in the proportion of asymptomatic animals, even if the animals remaining in the group showed improvement in symptoms compared to the vehicle-treated group (Figures 9 and 12).

[0259] The spleen was removed and weighed at the end of the experiment. The spleen weights observed for the different experimental groups are shown as mean ± SEM and summarized in Figure 15. No difference was observed between the recorded spleen sizes in both the vehicle-treated group and the group treated with compound 1. Animals treated with dexamethasone showed significantly lower spleen weights compared to the vehicle-treated group.

[0260] Analysis of plasma cytokine levels using Luminex showed that all measured cytokines (IFN-γ, IL-6, IL-10, IL-17a, and TNF-α) were at low levels, with most samples reporting values ​​close to or below the functional limit of quantification (LLOQ) for each cytokine assay (Figures 16-20).

[0261] The IFN-γ levels observed for the different experimental groups are presented as mean ± SEM and summarized in Figure 16. Overall, no statistically significant changes in IFN-γ were observed (p=0.096), but there was a decreasing trend from vehicle to dexamethasone, thus reflecting the in vivo clinical score data. The decrease in IFN-γ was observed for both prophylactic and therapeutic compound 1 treatments, and the therapeutic treatment was in close agreement with that of the dexamethasone group.

[0262] The interleukin-6 (IL-6) levels observed for different experimental groups are presented as mean ± SEM and summarized in Figure 17. IL-6 was present at low or subdetectable levels in the plasma from all samples, and no significant differences were observed between groups.

[0263] The interleukin-10 (IL-10) levels observed in different experimental groups are presented as mean ± SEM and summarized in Figure 18. No significant changes were observed in IL-10 levels.

[0264] The interleukin-17a (IL-17a) levels observed in different experimental groups are presented as mean ± SEM and summarized in Figure 19. IL-17a showed a similar trend to IFN-γ, with decreases and slight decreases in both treatment groups compared to the dexamethasone group. However, overall, none of these changes were statistically significant.

[0265] The tumor necrosis factor α (TNF-α) levels observed in different experimental groups are presented as mean ± SEM and summarized in Figure 20. Prophylactic compound 1 and dexamethasone induced a very slight decrease in TNF-α. However, none of the changes were statistically significant.

[0266] In this study, all animals were MOG 35-55Patients developed signs of EAE 7 days after disease induction by immunization. The efficacy of compound 1 was tested in the model using a prophylactic approach (group 2, treatment initiated on day 1) and a therapeutic approach (group 3, treatment initiated on day 8). Prophylactic treatment with compound 1 did not prevent or improve the clinical EAE profile when the effect was analyzed over time or when the overall effect was investigated using AUC analysis. On the contrary, therapeutic administration of compound 1 statistically significantly improved the disease profile at earlier time points (days 13 and 14) and again at later stages (days 22-25), which is usually associated with more neurodegenerative mechanisms. Therapeutic treatment with compound 1 also showed a tendency toward decreased AUC values ​​compared to vehicle AUC. As expected, treatment with the positive control dexamethasone statistically significantly reduced the EAE score (days 8-25) and clinical profile compared to vehicle, as assessed by AUC. This corticosteroid was used as a positive control based on validation data for this model and several independent studies demonstrating the efficacy of dexamethasone treatment in EAE. In particular, animals treated therapeutically with compound 1 showed significant symptom remission, with approximately 27% of animals recovering to zero. Plasma cytokine levels did not show any significant differences between the vehicle and treatment groups, although there was a general tendency for some cytokines, such as IFN-γ, IL-17a, and TNF-α, to decrease in the treatment group.

[0267] Example 11: Efficacy of various doses of compound 1 in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). Sixty female C57BL / 6 mice were housed for a one-week acclimatization period. Fifty-three mice were randomized at a body weight of 18.3–22.3 g and then enrolled in the study, with an average body weight of 19.7 g per group on day one less than the study day.

[0268] For the induction of MOG-EAE, MOG 35-55Peptides were administered in phosphate-buffered saline (PBS) and total Freund's adjuvant (CFA). MOG in PBS 35-55 The peptide was emulsified in a 1:1 (v:v) mixture with CFA by homogenizing it in an Omni BeadRuptor Elite using a 7 mL tube pre-filled with 2.8 mm ceramic beads. In short, MOG 35-55 The peptide was diluted to 1 mg / mL in cold PBS, and 1.75 mL was dispensed into each homogenization tube. Then, an equal volume (1.75 mL) of CFA was added on ice to a total volume of 3.5 mL. Homogenization was performed at a rate of 3.5 m / s for two rounds of 45-second cycles with a 30-second stay at 4°C, followed by a third round of two cycles with 45-second and 30-second stays at 4°C. Between each round, the samples were left on ice for approximately 15 minutes. The tubes were spun down at 300 g for 1 minute at 4°C. Mice were anesthetized under isoflurane anesthesia. Then, 100 μL (50 μg of MOG) was added. 35-55 ) was subcutaneously injected into the flank of each leg (a total of two injections and 100 μg of MOG). 35-55 On days 0 and 2 of the study, parthith toxin was formulated in PBS at a concentration of 2 ng / μL, and 100 μL (200 ng) was injected into each animal by intraperitoneal injection.

[0269] Treatment was administered according to the administration schedule shown in Table 5.

[0270] [Table 6]

[0271] For groups 2, 3, and 4, the treatment was initiated on day 1 with BID (Bio-Induced Dosage), while for group 5, it was initiated on day 1 with once-daily (QD) administration. All experimental groups had n=12. The dosing interval was 12 hours, and the dose was 5 mL / kg.

[0272] Weight measurements were taken daily for all animals in the control group (naive mice), except for days 5, 6, 8, 9, 11, and 27 of the experiment, when weight was not recorded. The weight changes observed throughout the experiment for different experimental groups are presented as mean ± SD and summarized in Figure 21. The percentage change in weight relative to baseline observed throughout the experiment for different experimental groups is presented as mean ± SD and summarized in Figure 22. Compared to group 2 (vehicle), group 5 (compound 1, 100 mg / kg, QD) showed significantly less weight loss from days 19-20 of the experiment to the end of the experiment, and then from days 22 to 28, the end of the experiment. Group 2 had significantly lower body weight compared to Group 1 (naive animals) on days 2 and 3 (p<0.05), 17 (p<0.01), 18 (p<0.001), and 19-28 (p<0.0001).

[0273] The physical condition scores of all animals were monitored on day 0, day 7, day 10 of the experiment, and then every other day. Physical condition scoring was performed according to the scale shown in Figure 23. The mean body condition scores observed throughout the experiment for different experimental groups are shown as mean ± SD and are summarized in Figure 24. Group 5 was at its best on day 22 ( ** p<0.01), day 24 ( **** p<0.0001), day 26 and day 28 ( *** Group 4 showed a statistically significant improvement compared to animals from Group 2 (p<0.001). Group 4 showed a statistically significant improvement on days 24 and 26 ( * p<0.05), and on day 28 ( ** Group 3 showed a statistically significant effect compared to Group 2 (p<0.01). Only Group 3 showed a statistically significant decrease in physical condition scores on day 28 of the study. ** p<0.01). Group 2 was on day 22 ( *** p<0.001) and days 24-28 ( **** In group p<0.0001), the physical condition scores were significantly lower than in group 1.

[0274] Disease severity was scored every two days for all groups, starting on day 0, day 7, and from day 10 onward. The following scale was used: (0) Normal (1) Loss of tail tension (2) Loss of tension in the tail and weakness of the hind limbs (3) Severe weakness or paralysis of both limbs / one limb (4) Paralysis of two or more limbs (5) Death.

[0275] The mean disease scores observed throughout the experiment for different experimental groups are shown as mean ± SD and are summarized in Figure 25. The mean disease score per group was calculated by averaging the individual disease scores in each group. Starting from days 14–18, disease severity increased in all groups. Disease severity was statistically significantly lower in group 5, administered 100 mg / kg of compound 1, compared to the vehicle group, from day 18 to day 28 of the study.

[0276] Disease incidence was calculated as the percentage of total animals per group from day 0 to day 28 of the study. The percentage of disease-free mice observed throughout the experiment for different experimental groups is summarized in Figure 26. Group 5 showed a lower incidence and a later onset of disease. Log-rank (Mantel-Cox) tests comparing vehicle BID, compound 175 mg / kg BID, compound 125 mg / kg BID, and compound 1100 mg / kg QD gave p-values ​​of 0.039 for median time to disease at 18, 19, 18, and 20 days, respectively.

[0277] Spleen weight was determined for all mice and all groups on day 28 of the study during autopsy. The observed spleen weights for different experimental groups are shown as mean ± SEM and summarized in Figure 27. Group 5 showed a significantly higher spleen weight compared to group 2.

[0278] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Numerous variations, modifications, and substitutions will be conceivable to those skilled in the art without departing from the present invention. It should be understood that various alternative forms of the embodiments of the present invention described herein may be employed when carrying out the present invention. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

1. Formula I: 【Chemistry 1】 A composition comprising a compound or a pharmaceutically acceptable salt thereof in a crystalline form.

2. The composition according to claim 1, wherein the crystalline form is polymorph I of the maleate of the compound of formula I.

3. The composition according to claim 2, wherein the polymorph I is characterized by a differential scanning calorimetry (DSC) thermogram including endothermic temperatures in the range of about 135 to about 160°C.

4. The composition according to claim 2 or 3, wherein the melting point of the polymorph I is about 139°C.

5. The composition according to claim 2 or 3, wherein the melting point of the polymorph I is about 148°C.

6. The composition according to any one of claims 2 to 5, wherein the polymorph I is substantially characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 1.

7. The composition according to any one of claims 2 to 6, wherein the polymorph I is dry, non-solvated, and / or non-hydrated.

8. The composition according to any one of claims 2 to 7, wherein the polymorph I is characterized by an X-ray powder diffraction pattern that includes peaks at 8.2 ± 0.2°²-θ, 12.7 ± 0.2°²-θ, and 16.4 ± 0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

9. The composition according to claim 8, wherein the X-ray powder diffraction pattern further includes at least one peak selected from 16.9 ± 0.2°²-θ, 17.6 ± 0.2°²-θ, and 22.9 ± 0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

10. The composition according to claim 8 or 9, wherein the X-ray powder diffraction pattern further includes at least one peak selected from 20.6 ± 0.2°²-θ, 24.9 ± 0.2°²-θ, and 19.9 ± 0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

11. The composition according to any one of claims 8 to 10, wherein the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 8.2±0.2°²-θ, 12.7±0.2°²-θ, 16.4±0.2°²-θ, 16.9±0.2°²-θ, 17.6±0.2°²-θ, 22.9±0.2°²-θ, 20.6±0.2°²-θ, 24.9±0.2°²-θ, and 19.9±0.2°²-θ.

12. The composition according to any one of claims 8 to 11, wherein the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 8.2±0.2°²-θ, 12.7±0.2°²-θ, 16.4±0.2°²-θ, 16.9±0.2°²-θ, 17.6±0.2°²-θ, 22.9±0.2°²-θ, 20.6±0.2°²-θ, 24.9±0.2°²-θ, and 19.9±0.2°²-θ.

13. The composition according to any one of claims 2 to 12, wherein the polymorph I is substantially characterized by an X-ray powder diffraction pattern as shown in Figure 2.

14. The composition according to any one of claims 2 to 13, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 1% to about 5% over a temperature range of about 25 to about 125°C.

15. The composition according to any one of claims 2 to 14, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing less than 4% mass loss over a temperature range of about 25 to about 125°C.

16. The composition according to any one of claims 2 to 15, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing less than 2% mass loss over a temperature range of about 25 to about 125°C.

17. The composition according to any one of claims 2 to 14, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 4% over a temperature range of about 25 to about 125°C.

18. The composition according to any one of claims 2 to 17, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 5% to about 15% over a temperature range of about 125 to about 200°C.

19. The composition according to any one of claims 2 to 18, wherein the polymorph I is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 10.3% over a temperature range of about 125 to about 200°C.

20. The composition according to any one of claims 2 to 19, wherein the polymorph I is substantially characterized by a thermogravimetric analysis (TGA) thermogram as shown in Figure 3.

21. The composition according to any one of claims 2 to 20, wherein the polymorph I contains less than 5% water.

22. The composition according to any one of claims 2 to 21, wherein the polymorph I contains about 0.5% water.

23. The composition according to any one of claims 2 to 21, wherein the polymorph I contains about 1.5% water.

24. The composition according to any one of claims 2 to 21, wherein the polymorph I contains about 2.5% water.

25. The composition according to claim 1, wherein the crystalline form is polymorph II of the maleate of the compound of formula I.

26. The composition according to claim 25, wherein the polymorphic form II is characterized by a differential scanning calorimetry (DSC) thermogram including endothermic temperatures in the range of about 150 to about 170°C.

27. The composition according to claim 25 or 26, wherein the differential scanning calorimetry (DSC) thermogram further comprises endothermic activity in the range of about 25 to about 60°C.

28. The composition according to claims 25 to 27, wherein the melting point of the polymorph II is in the range of about 150 to about 155°C.

29. The composition according to claims 25 to 28, wherein the earlier polymorphic form II is substantially characterized by a differential scanning calorimetry (DSC) thermogram as shown in Figure 4.

30. The composition according to claims 25 to 29, wherein the polymorph II comprises small needle-shaped particles.

31. The composition according to claim 30, wherein the needle size is in the range of about 1 μm to about 50 μm.

32. The composition according to any one of claims 25 to 31, wherein the polymorph II is solvated or hydrated.

33. The composition according to any one of claims 25 to 32, wherein the polymorph II is characterized by an X-ray powder diffraction pattern that includes peaks at 7.6 ± 0.2°² - θ, 8.7 ± 0.2°² - θ, and 16.0 ± 0.2°² - θ, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

34. The composition according to claim 33, wherein the X-ray powder diffraction pattern further includes at least one peak selected from 12.2 ± 0.2°²-θ, 17.6 ± 0.2°²-θ, and 19.5 ± 0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

35. The composition according to claim 33 or 34, wherein the X-ray powder diffraction pattern further includes at least one peak selected from 21.7 ± 0.2°²-θ, 10.8 ± 0.2°²-θ, and 13.4 ± 0.2°²-θ when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å.

36. The composition according to any one of claims 33 to 35, wherein the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes at least five peaks selected from 7.6±0.2°²-θ, 8.7±0.2°²-θ, 16.0±0.2°²-θ, 12.2±0.2°²-θ, 17.6±0.2°²-θ, 19.5±0.2°²-θ, 21.7±0.2°²-θ, 10.8±0.2°²-θ, and 13.4±0.2°²-θ.

37. The composition according to any one of claims 33 to 36, wherein the X-ray powder diffraction pattern, when measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 Å, includes peaks at 7.6±0.2°²-θ, 8.7±0.2°²-θ, 16.0±0.2°²-θ, 12.2±0.2°²-θ, 17.6±0.2°²-θ, 19.5±0.2°²-θ, 21.7±0.2°²-θ, 10.8±0.2°²-θ, and 13.4±0.2°²-θ.

38. The composition according to any one of claims 25 to 37, wherein the polymorph II is substantially characterized by an X-ray powder diffraction pattern as shown in Figure 5.

39. The composition according to any one of claims 25 to 38, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 1% to about 5% over a temperature range of about 25 to about 80°C.

40. The composition according to any one of claims 25 to 39, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 2.0% to about 2.5% over a temperature range of about 25 to about 80°C.

41. The composition according to any one of claims 25 to 40, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 1.8% over a temperature range of about 25 to about 80°C.

42. The composition according to any one of claims 25 to 39, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 2.9% over a temperature range of about 25 to about 70°C.

43. The composition according to any one of claims 25 to 42, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0% to about 1% over a temperature range of about 70 to about 130°C.

44. The composition according to any one of claims 25 to 43, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.5% over a temperature range of about 70 to about 130°C.

45. The composition according to any one of claims 25 to 44, wherein the polymorph II is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.5% over a temperature range of about 80 to about 130°C.

46. The composition according to any one of claims 25 to 45, wherein the polymorph II contains less than 5% water.

47. The composition according to any one of claims 25 to 46, wherein the polymorph II contains about 1.5% to about 2.5% water.

48. The composition according to any one of claims 25 to 46, wherein the polymorph II contains about 3.78% water.

49. The composition according to any one of claims 25 to 46, wherein the polymorph II contains about 2.65% water.

50. The composition according to any one of claims 25 to 46, wherein the polymorph II contains about 0.8% water.

51. The composition according to claims 1 to 50, wherein more than 90% by weight of the composition is a crystalline form of the compound of formula I or a pharmaceutically acceptable salt thereof.

52. The composition according to claims 1 to 51, comprising less than approximately 2% by weight of impurities.

53. A pharmaceutical composition comprising the composition according to any one of claims 1 to 52 and a pharmaceutically acceptable excipient.

54. A method for treating a disease or disorder requiring treatment, comprising the step of administering a therapeutically effective amount of a composition according to claims 1 to 52 or a pharmaceutical composition according to claim 53 to the subject.

55. The method according to claim 54, wherein the disease or disorder is cancer.

56. The method according to claim 55, wherein the cancer is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, melanoma, stomach cancer, bladder cancer, endometrial cancer, kidney cancer, leukemia, liver cancer, lymphoma, pancreatic cancer, and thyroid cancer.

57. The method according to claim 54, wherein the disease or disorder is an autoimmune disease.

58. The method according to claim 57, wherein the autoimmune disease is selected from fibromyalgia, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, ulcerative colitis, and type 1 diabetes.

59. Formula I: 【Chemistry 2】 A method for preparing a first crystalline form of the maleate of the compound, (i) A step of dissolving the compound of formula I and an acid in a first solvent mixture at a first temperature, (ii) A step of adding a second solvent at a second temperature, (iii) A step of cooling the obtained solution to a third temperature, (iv) A step of filtering the solution and drying the obtained solid at a fourth temperature. Methods that include...

60. The method according to claim 59, wherein the acid is maleic acid.

61. The method according to claim 59 or 60, wherein the first crystal form is polymorph I.

62. The method according to any one of claims 59 to 61, wherein the first solvent mixture is EtOH / EtOAc and the first temperature is about 50 to about 60°C.

63. The method according to any one of claims 59 to 62, wherein the second solvent mixture is EtOAc and the second temperature is about 20 to about 25°C.

64. The method according to any one of claims 59 to 63, wherein the third temperature is approximately -5 to approximately 5°C.

65. The method according to any one of claims 59 to 64, wherein the fourth temperature is approximately 50 to approximately 55°C.

66. Formula I: 【Transformation 3】 A method for preparing a second crystalline form of the maleate of a compound of formula I, comprising the step of drying a first crystalline form of the maleate of a compound of formula I at a temperature of about 70°C.

67. The method according to claim 66, wherein the second crystal form is polymorph II.

68. The method according to claim 66 or 67, wherein the first crystalline form is polymorph I.

69. Formula I: 【Chemistry 4】 A method for preparing a second crystalline form of a compound or a pharmaceutically acceptable salt of a compound of formula I or a maleate of the same compound, comprising the step of slurring a mixture of a first crystalline form of a maleate of a compound of formula I or a maleate of a compound of formula I in water.

70. The method according to claim 69, wherein the second crystal form is polymorph II.

71. The method according to claim 69 or 70, wherein the first crystal form is polymorph I.

72. A method for treating acute disseminated encephalomyelitis (ADEM) in patients requiring treatment, comprising formula I: 【Transformation 5】 A method comprising the step of administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

73. The method according to claim 72, wherein the compound of formula I is administered once daily.

74. The method according to claim 72, wherein the compound of formula I is administered twice a day.

75. The method according to claim 74, wherein the compound of formula I is administered at 12-hour intervals.

76. The method according to any one of claims 72 to 75, wherein the compound of formula I is administered in a unit dosage form.

77. The method according to claim 76, wherein the unit dosage form comprises about 0.5 to about 350 mg / kg of the compound of formula I.

78. The method according to claim 77, wherein the unit dosage form comprises about 25 mg / kg of the compound of formula I.

79. The method according to claim 77, wherein the unit dosage form comprises about 75 mg / kg of the compound of formula I.

80. The method according to claim 77, wherein the unit dosage form contains about 100 mg / kg of the compound of formula I.

81. The method according to claim 77, wherein the unit dosage form comprises about 150 mg / kg of the compound of formula I.

82. The method according to claim 77, wherein the unit dosage form comprises approximately 320 mg / kg of the compound of formula I.

83. The method according to any one of claims 72 to 82, wherein the total amount of the compound of formula I administered per day is about 0.5 to about 350 mg / kg.

84. The method according to claim 83, wherein the total amount of the compound of formula I administered per day is approximately 50 mg / kg.

85. The method according to claim 83, wherein the total amount of the compound of formula I administered per day is approximately 100 mg / kg.

86. The method according to claim 83, wherein the total amount of the compound of formula I administered per day is approximately 150 mg / kg.

87. The method according to claim 83, wherein the total amount of the compound of formula I administered per day is approximately 320 mg / kg.

88. The method according to any one of claims 72 to 87, wherein the total amount of the compound of formula I administered per day is about 5 to about 350 mg.

89. The method according to any one of claims 72 to 88, wherein the compound of formula I is formulated for oral administration.

90. The method according to any one of claims 72 to 89, wherein the compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, solution, suppository, or aerosol.

91. The method according to any one of claims 72 to 90, wherein the compound of formula I is formulated as a solution.

92. The method according to claim 91, wherein the solution contains about 1 to about 50 mg / mL of the compound of formula I.

93. The method according to claim 92, wherein the solution contains the compound of formula I in an amount of about 5 mg / mL.

94. The method according to claim 92, wherein the solution contains the compound of formula I in an amount of about 15 mg / mL.

95. The method according to claim 92, wherein the solution contains the compound of formula I in an amount of about 20 mg / mL.

96. The method according to any one of claims 72 to 95, wherein administration of the compound of formula I results in a decrease in interferon-gamma (IFNγ) levels in the subject.

97. A method for treating an autoimmune disease or disorder in a subject requiring treatment, wherein formula I: 【Transformation 6】 A method comprising the step of administering a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is administered once daily.

98. The method according to claim 97, wherein the disease or disorder is multiple sclerosis.

99. The method according to claim 97, wherein the disease or disorder is optic neuritis.

100. The method according to claim 97, wherein the disease or disorder is acute disseminated encephalomyelitis (ADEM).

101. The method according to any one of claims 97 to 100, wherein the compound of formula I is administered in a unit dosage form.

102. The method according to claim 101, wherein the unit dosage form contains about 0.5 to about 350 mg / kg of the compound of formula I.

103. The method according to claim 102, wherein the unit dosage form contains about 25 mg / kg of the compound of formula I.

104. The method according to claim 102, wherein the unit dosage form comprises about 75 mg / kg of the compound of formula I.

105. The method according to claim 102, wherein the unit dosage form contains about 100 mg / kg of the compound of formula I.

106. The method according to claim 102, wherein the unit dosage form contains about 150 mg / kg of the compound of formula I.

107. The method according to claim 102, wherein the unit dosage form contains approximately 320 mg / kg of the compound of formula I.

108. The method according to any one of claims 97 to 106, wherein the total amount of the compound of formula I administered per day is about 0.5 to about 350 mg / kg.

109. The method according to claim 108, wherein the total amount of the compound of formula I administered per day is approximately 50 mg / kg.

110. The method according to claim 108, wherein the total amount of the compound of formula I administered per day is about 100 mg / kg.

111. The method according to claim 108, wherein the total amount of the compound of formula I administered per day is approximately 150 mg / kg.

112. The method according to claim 108, wherein the total amount of the compound of formula I administered per day is approximately 320 mg / kg.

113. The method according to any one of claims 97 to 112, wherein the total amount of the compound of formula I administered per day is about 5 to about 350 mg.

114. The method according to any one of claims 97 to 113, wherein the compound of formula I is formulated for oral administration.

115. The method according to any one of claims 97 to 114, wherein the compound of formula I is formulated as a tablet, pill, capsule, powder, liquid, suspension, solution, suppository, or aerosol.

116. The method according to any one of claims 97 to 115, wherein the compound of formula I is formulated as a solution.

117. The method according to claim 116, wherein the solution contains about 1 to about 50 mg / mL of the compound of formula I.

118. The method according to claim 117, wherein the solution contains about 5 mg / mL of the compound of formula I.

119. The method according to claim 117, wherein the solution contains about 15 mg / mL of the compound of formula I.

120. The method according to claim 117, wherein the solution contains about 20 mg / mL of the compound of formula I.

121. The method according to any one of claims 97 to 120, wherein administration of the compound of formula I results in a decrease in interferon-gamma (IFNγ) levels in the subject.

Images