CN116723845A - Crystalline forms of deoxycytidine kinase inhibitors and uses thereof - Google Patents

Abstract

Described herein are crystalline forms of a compound that is a deoxycytidine kinase (dCK) inhibitor, methods of preparing such crystalline forms, pharmaceutical compositions and medicaments comprising such crystalline forms, and methods of using such crystalline forms to treat conditions, diseases, or disorders that would benefit from modulation of deoxycytidine kinase (dCK) activity.

Description

Crystalline forms of deoxycytidine kinase inhibitors and uses thereof

Cross reference

The present application claims the benefit of U.S. provisional application Ser. No. 63/108,803 filed 11/2/2020 and U.S. provisional application Ser. No. 63/190,107 filed 5/18 2021, both of which are incorporated by reference in their entireties.

Background

Deoxycytidine kinase (dCK) is an enzyme that plays a key role in cell division and in the phosphorylation of several deoxyribonucleosides and nucleoside analogues thereof. Deoxycytidine kinase, a rate-limiting enzyme in the salvage pathway of nucleoside synthesis, was observed to be expressed predominantly in hematopoietic tissues and up-regulated in certain solid tumors. dCK deficiency is also associated with certain forms of resistance to antiviral and anticancer chemotherapeutic agents. dCK is a clinically important polypeptide target because of its role in DNA synthesis and cell division, for example, and its association with drug resistance and/or drug sensitivity. Compounds and compositions that bind and inhibit dCK activity in vivo are expected to be useful in the treatment of diseases and conditions in which dCK activity is implicated.

Disclosure of Invention

In one aspect, provided herein is a composition comprising a crystalline form of a compound of formula I:

in some embodiments, the crystalline form is the polymorph form I of the maleate salt of the compound of formula I.

In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 ℃ to about 160 ℃. In some embodiments, polymorph form I has a melting point of about 139 ℃. In some embodiments, polymorph form I has a melting point of about 148 ℃. In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 1.

In some embodiments, polymorph form I is dry, unsolvated, and/or unhydrated.

In some embodiments, polymorph form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2- θ, 12.7±0.2° 2- θ, and 16.4±0.2° 2- θ, as usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises 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, e.g., using ± +. >Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 20.6±0.2° 2- θ, 24.9±0.2° 2- θ, and 19.9±0.2° 2- θ, e.g., using ± +.>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least five peaks selected from the group consisting of 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodimentsPolymorph form I is characterized by an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of about 1% to about 5% over a temperature range of about 25 ℃ to about 125 ℃. In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of less than about 4% over a temperature range of about 25 ℃ to about 125 ℃. In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of less than about 2% over a temperature range of about 25 ℃ to about 125 ℃. In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of about 4% over a temperature range of about 25 ℃ to about 125 ℃. In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of about 5% to about 15% over a temperature range of about 125 ℃ to about 200 ℃. In some embodiments, polymorph form I is characterized by a thermogram comprising a mass loss of about 10.3% over a temperature range of about 125 ℃ to about 200 ℃. In some embodiments, polymorph form I is characterized by a thermogram of thermogravimetric analysis (TGA) substantially as shown in figure 3.

In some embodiments, polymorph form I comprises less than 5% water. In some embodiments, polymorph form I comprises about 0.5% water. In some embodiments, polymorph form I comprises about 1.5% water. In some embodiments, polymorph form I comprises about 2.5% water.

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

In some embodiments, polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 ℃ to about 170 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) thermogram further comprises an endotherm in the range of about 25 ℃ to about 60 ℃. In some embodiments, polymorph form II has a melting point in the range of about 150 ℃ to about 155 ℃. In some embodiments, polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 4.

In some embodiments, polymorph form II comprises small needle-like particles. In some embodiments, the needle size is in the range of about 1 μm to about 50 μm.

In some embodiments, polymorph form II is solvated or hydrated.

In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.2° 2- θ, 8.7±0.2° 2- θ, and 16.0±0.2° 2- θ, as usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 12.2±0.2° 2- θ, 17.6±0.2° 2- θ, and 19.5±0.2° 2- θ, e.g., using ± ± 0.2 °2- θ>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises 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, as with ± using +.>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodiments of the present invention, in some embodiments, The X-ray powder diffraction pattern includes peaks at 7.6.+ -. 0.2.+ -. 2-theta, 8.7.+ -. 0.2.+ -. 2-theta, 16.0.+ -. 0.2.+ -. 2-theta, 12.2.+ -. 0.2.+ -. 2-theta, 17.6.+ -. 0.2.+ -. 2-theta, 19.5.+ -. 0.2.+ -. 2-theta, 21.7.+ -. 0.2.+ -. 2-theta, 10.8.+ -. 0.2.+ -. 2-theta and 13.4.+ -. 0.2.+ -. 2-theta, as used>Is measured by X-ray powder diffraction. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 1% to about 5% over a temperature range of about 25 ℃ to about 80 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 2.0% to about 2.5% over a temperature range of about 25 ℃ to about 80 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 1.8% over a temperature range of about 25 ℃ to about 80 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 2.9% over a temperature range of about 25 ℃ to about 70 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 0% to about 1% over a temperature range of about 70 ℃ to about 130 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 0.5% over a temperature range of about 70 ℃ to about 130 ℃. In some embodiments, polymorph form II is characterized by a thermogram comprising a mass loss of about 0.5% over a temperature range of about 80 ℃ to about 130 ℃.

In some embodiments, polymorph form II comprises less than 5% water. In some embodiments, polymorph form II comprises about 1.5% to about 2.5% water. In some embodiments, polymorph form II comprises about 3.78% water. In some embodiments, polymorph form II comprises about 2.65% water. In some embodiments, polymorph form II comprises about 0.8% water.

In some embodiments, greater than 90% by weight of the composition is a crystalline form of the compound of formula I or a pharmaceutically acceptable salt thereof.

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

In another aspect, provided herein is a pharmaceutical composition comprising a composition described herein and a pharmaceutically acceptable excipient.

In another aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition described herein or a pharmaceutical composition described herein.

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, gastric cancer, bladder cancer, endometrial cancer, renal cancer, leukemia, liver cancer, lymphoma, pancreatic cancer, and thyroid cancer.

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

In another aspect, provided herein is a method of preparing a first crystalline form of a maleate salt of a compound of formula I:

wherein the method comprises:

(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;

(iv) The solution was filtered and the resulting solid was dried at a fourth temperature.

In some embodiments, the acid is maleic acid. In some embodiments, the first crystalline form is polymorph form I. In some embodiments, the first solvent mixture is EtOH/EtOAc and the first temperature is from about 50 ℃ to about 60 ℃. In some embodiments, the second solvent is EtOAc and the second temperature is about 20 ℃ to about 25 ℃. In some embodiments, the third temperature is about-5 ℃ to about 5 ℃. In some embodiments, the fourth temperature is about 50 ℃ to 55 ℃.

In another aspect, provided herein is a method of preparing a second crystalline form of the maleate salt of the compound of formula I:

wherein the process comprises drying the first crystalline form of the maleate salt of the compound of formula I at a temperature of about 70 ℃.

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

In another aspect, provided herein is a method of preparing a second crystalline form of a maleate salt of a compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein the method comprises slurrying the first crystalline form of the maleate salt of the compound of formula I or the mixture of crystalline forms of the maleate salt of the compound of formula I in water.

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

In another aspect, provided herein is a method of treating Acute Disseminated Encephalomyelitis (ADEM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

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, administration of the compound of formula I is performed twelve hours apart.

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

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

In some embodiments, the compounds of formula I are formulated for oral administration. In some embodiments, the compounds of formula I are formulated as tablets, pills, capsules, powders, liquids, suspensions, solutions, suppositories, or aerosols. In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50mg/mL of the compound of formula I. In some embodiments, the solution comprises about 5mg/mL of the compound of formula I. In some embodiments, the solution comprises about 15mg/mL of the compound of formula I. In some embodiments, the solution comprises about 20mg/mL of the compound of formula I.

In some embodiments, administration of a compound of formula I results in a decrease in interferon gamma (ifnγ) levels in the subject.

In another aspect, provided herein is a method of treating an autoimmune disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is administered once daily.

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).

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

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

In some embodiments, the compounds of formula I are formulated for oral administration. In some embodiments, the compounds of formula I are formulated as tablets, pills, capsules, powders, liquids, suspensions, solutions, suppositories, or aerosols. In some embodiments, the compound of formula I is formulated as a solution. In some embodiments, the solution comprises from about 1 to about 50mg/mL of the compound of formula I. In some embodiments, the solution comprises about 5mg/mL of the compound of formula I. In some embodiments, the solution comprises about 15mg/mL of the compound of formula I. In some embodiments, the solution comprises about 20mg/mL of the compound of formula I.

In some embodiments, administration of a compound of formula I results in a decrease in interferon gamma (ifnγ) levels in the subject.

Incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the invention are set forth with particularity in the appended claims. The features and advantages of this invention will be better understood by reference to the following detailed description of illustrative embodiments in which the principles of the invention are utilized, and the accompanying drawings, in which:

Figure 1 shows a Differential Scanning Calorimetry (DSC) thermogram of polymorph form I of a compound of formula I.

Figure 2 shows an X-ray powder diffraction (XRPD) pattern of polymorph form I of a compound of formula I.

Figure 3 shows a thermogram of the polymorphic form I of the compound of formula I (TGA).

Figure 4 shows a Differential Scanning Calorimetry (DSC) thermogram of polymorph form II of a compound of formula I.

Fig. 5 shows an X-ray powder diffraction (XRPD) pattern of polymorph form II of a compound of formula I.

Figure 6 shows a thermogram of polymorphic form II of the compound of formula I (TGA).

Fig. 7 shows the changes in mouse body weight observed for different experimental groups during a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Figure 8 shows area under the curve values of the percentage of body weight change from baseline observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Fig. 9 shows the variation in EAE scores observed for different experimental groups during a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Figure 10 shows area under the curve values of EAE clinical scores observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 11 shows the cumulative disease scores observed for the different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Figure 12 shows the disease profile developed by all animals for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments, showing the disease scores up to day 25.

Figure 13 shows the area under the curve values of the extended disease scores observed for the different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Figure 14 shows the percentage of asymptomatic animals observed for different experimental groups during a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Fig. 15 shows spleen weights observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Fig. 16 shows IFN- γ levels observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 17 shows the levels of interleukin 6 (IL-6) observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Fig. 18 shows the interleukin 10 (IL-10) levels observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 19 shows the levels of interleukin 17a (IL-17 a) observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 20 shows tumor necrosis factor alpha (TNF-alpha) levels observed for different experimental groups in a mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 21 shows the changes in mouse body weight observed for different experimental groups during variable dose mouse models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 22 shows the percentage of body weight change observed for different experimental groups during variable dose mouse models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 23 shows the physical condition scoring scale used in a variable dose mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiment.

Figure 24 shows the average physical condition scores observed for different experimental groups during variable dose mouse models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 25 shows the average disease scores observed for different experimental groups during variable dose mouse models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Figure 26 shows the percentage of disease-free animals observed for different experimental groups during variable dose mouse models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Fig. 27 shows spleen weights observed for different experimental groups in a variable dose mouse model of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE) experiments.

Detailed Description

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

The preparation and use of compounds of formula I have been previously described (see, U.S. Pat. No. 5,172,242, U.S. Pat. No. 5,241, 10,570,124 and U.S. Pat. No. 5,2016,130562, each of which is incorporated by reference in its entirety).

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

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

As used herein, "crystalline Form," "polymorph," "Form," and "Form" are used interchangeably herein and are meant to include all crystalline forms and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline Form or amorphous Form is referred to. The compounds of the present disclosure include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. In some embodiments, the crystalline form is a single solid state form, such as polymorph form I.

Definition of the definition

"pharmaceutically acceptable carrier" refers to an ingredient of a pharmaceutical formulation (formulation) that is non-toxic to a subject other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives, such as those known in the art, for example those described in Remington's Pharmaceutical Sciences, 16 th edition, osol, a. Editions (1980).

As used herein, "treatment" or "treatment" is a method for achieving a beneficial or desired result, including and preferably a clinical result. For example, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing symptoms caused by the disease, improving the quality of life of the person suffering from the disease, reducing the dosage of other drugs required to treat the disease, delaying the progression of the disease, and/or extending the survival of the individual.

As used herein, "delay of progression of a disease" means delay, impediment, slowing, delay, stabilization, and/or delay of progression of a disease (such as cancer). Such delays may have different lengths of time depending on the disease history and/or the individual being treated. As will be apparent to those of skill in the art, a sufficient or significant delay may actually encompass prophylaxis, as the individual is not suffering from the disease. For example, advanced cancers (such as the development of metastasis) may be delayed.

As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include results such as elimination or reduction of risk, lessening the severity or delaying the onset of a disease, including biochemical, histological and/or behavioral symptoms of a disease, complications thereof, and intermediate pathological phenotypes exhibited during the development of a disease. For therapeutic use, beneficial or desired results include clinical results, such as reducing one or more symptoms caused by a disease, improving the quality of life of a person suffering from the disease, reducing the dosage of other drugs required to treat the disease, such as enhancing the effect of another drug via targeting, delaying the progression of the disease, and/or extending survival. In the case of cancer or tumor, an effective amount of the drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibit (i.e., slow down and preferably stop to some extent) infiltration of cancer cells into peripheral organs; inhibit (i.e., slow down and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and/or to some extent, alleviate one or more symptoms associated with the disorder. An effective dose may be administered in one or more administrations. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to effect, directly or indirectly, prophylactic or therapeutic treatment. As understood in the clinical setting, an effective dose of a drug, compound, or pharmaceutical composition may be achieved in combination with or without another drug, compound, or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired result is or has been obtained in combination with one or more other agents.

As defined herein, the terms "inhibit", "inhibit" and the like in relation to protein-inhibitor interactions mean negatively affecting (e.g., reducing) the activity or function of a protein relative to the activity or function of the protein in the absence of the inhibitor. Inhibition may refer to a disease or alleviation of 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 deoxycytidine kinase. Thus, inhibiting at least in part includes partially or completely blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing, or down regulating signal transduction or enzyme activity or the amount of protein.

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

The term "modulate" is used in accordance with its ordinary meaning and refers to the effect of altering or changing one or more properties. "modulation" refers to a process that alters or alters one or more properties. For example, modulators of target proteins are altered by increasing or decreasing the nature or function of the target molecule or the amount of the target molecule. Modulators of disease reduce the symptoms, etiology, or characteristics of the disease of interest.

"Selective" or "Selectivity" for a compound, etc., refers to the ability of the compound to distinguish between molecular targets. "specific," "specifically," "specificity," and the like with respect to a compound refer to the ability of the compound to exert a particular effect (such as inhibition) on a particular molecular target with minimal or no effect on other proteins in the cell.

"pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate administration and absorption of an active agent to a subject and that may be included in the compositions of the present invention without significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, naCl, physiological saline solution, ringer's solution of lactic acid, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, saline solutions (such as ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments, and the like. Such formulations (preparations) may be sterilized and, if desired, mixed with adjuvants which do not react deleteriously with the compounds of the invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and/or aromatic substances and the like. Those skilled in the art will recognize that other pharmaceutical excipients may be used in the present invention.

The term "formulation" is intended to include a formulation of an active compound in an encapsulating material as a carrier to provide a capsule, wherein the active ingredient is surrounded by, and thus associated with, the carrier, with or without other carriers. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

As used herein, the term "administration" means oral administration to a subject, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained release device, such as a micro-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

By "co-administration" is meant administration of a compound described herein at the same time, immediately before, or immediately after administration of one or more additional therapies (e.g., anti-cancer agents as described herein). The compounds described herein may be administered alone or may be co-administered to a patient. Co-administration is meant to include administration of the compounds either simultaneously or sequentially, singly or in combination (more than one compound or agent). Thus, the formulation may also be combined with other active substances (e.g., anticancer agents) when desired.

Co-administration includes administration of one active agent (e.g., a complex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g., an anti-cancer agent). Also contemplated herein are embodiments wherein co-administration comprises administration of one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes administration of the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration may be achieved by co-formulation, i.e. the preparation of a single pharmaceutical composition comprising both active agents. In other embodiments, the active agents may be formulated separately. In some embodiments, the active agent and/or the auxiliary agent are linked or conjugated to each other. In some embodiments, the compounds described herein are combined with treatment of cancer, such as chemotherapy or radiation therapy.

In the context of a substance or substance activity or function associated with a disease, the term "associated with" or "associated with … …" means that the disease is caused by (all or part of) the substance or substance activity or function, that symptoms of the disease are caused by (all or part of) the substance or substance activity or function, or that side effects (e.g. toxicity) of the compound are caused by (all or part of) the substance or substance activity or function.

"patient," "subject," "patient in need thereof," and "subject in need thereof" are used interchangeably herein and refer to a living organism having or predisposed to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovine, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. A "cancer patient" is a patient suffering from or susceptible to developing cancer.

The term "individual" as used herein refers to a mammal, including but not limited to bovine, equine, feline, rabbit, canine, rodent, or primate (e.g., human), unless explicitly stated otherwise. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human primate, such as chimpanzees and other apes and monkey species. In some embodiments, the individual is a farm animal, such as a cow, horse, sheep, goat, and pig; pets such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; etc. In some embodiments, the invention finds application in both the human medical and veterinary fields.

"disease" or "condition" refers to the survival or health of a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease as used herein refers to cancer.

"chemotherapeutic agent" or "chemotherapeutic agent" is used in accordance with its ordinary meaning and refers to a chemical composition or compound that has anti-tumor properties or the ability to inhibit the growth or proliferation of cells.

As used herein, a "cancer model organism" is an organism that exhibits in vivo activity indicative of a phenotype or oncogenic factor of cancer. The term cancer is defined above. A variety of organisms can be used as cancer model organisms, and include, for example, cancer cells and mammalian organisms, such as rodents (e.g., mice or rats) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells that exhibit a phenotype or genotype similar to that of in vivo cancer. Cancer cell lines as used herein include cell lines from animals (e.g., mice) and humans.

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

It should be understood that aspects and variations of the present invention described herein include "consisting of" and/or "consisting essentially of" aspects and variations.

Crystalline forms of a compound of formula I

Polymorphs prepared according to the methods of the present invention may be characterized by any method according to the art. For example, polymorphs prepared according to the methods 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).

XRPD: polymorphs according to the present invention may be characterized by XRPD. The relative intensities of XRPD peaks may vary depending on the particle size, sample preparation technique, sample mounting procedure, and the particular instrument used. In addition, instrument variations and other factors may affect the 2-theta value. Thus, the assignment of XRPD peaks may vary, for example by plus or minus about 0.2 degrees.

DSC: polymorphs according to the present invention can also be identified by their characteristic DSC thermograms, such as shown in figures 1, 4, etc. For DSC, it is known that the observed temperature will depend on the rate of temperature change and the sample preparation technique and the particular instrument used. Thus, the values reported herein relating to DSC thermograms may be varied, e.g., plus or minus about 4 ℃.

TGA: the polymorph form of the invention can also produce a thermal behavior that differs from that of an amorphous material or another polymorph form. Thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphic forms from others. In one aspect, polymorphs can be characterized by thermogravimetric analysis.

Polymorphic forms of a compound of formula I may be useful in the manufacture of pharmaceutical formulations and may be obtained by crystallization processes to produce crystalline and semi-crystalline forms or by solidification processes to obtain amorphous forms. In some embodiments, crystallization is performed by: the desired compound (e.g., a compound of formula I) is produced in the reaction mixture and the desired polymorph is isolated from the reaction mixture, or the original compound is dissolved in a solvent, optionally heated, followed by crystallization/solidification of the product by cooling (including active cooling) and/or by addition of an anti-solvent during the time period. In some embodiments, crystallization includes adding a seed form of the desired polymorph. The crystallization or solidification may be followed by drying under controlled conditions until the desired water content is reached in the final polymorph form.

Polymorph form I of a compound of formula I

Figure 1 shows a Differential Scanning Calorimetry (DSC) thermogram of polymorph form I of a compound of formula I.

Figure 2 shows an X-ray powder diffraction (XRPD) pattern of polymorph form I of a compound of formula I.

Figure 3 shows a thermogram of the polymorphic form I of the compound of formula I (TGA).

In one aspect, provided herein is polymorph form I of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine. Some embodiments provide a composition comprising a polymorph form I of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine. In some embodiments, polymorph form I of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine is characterized as having:

(a) X-ray powder diffraction patterns including peaks at 8.2.+ -. 0.2.+ -. 2-theta, 12.7.+ -. 0.2.+ -. 2-theta and 16.4.+ -. 0.2.+ -. 2-theta, as usedIs measured by X-ray powder diffraction;

(b) An X-ray powder diffraction pattern substantially as shown in figure 2;

(c) Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 ℃ to about 160 ℃;

(d) A Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 1;

(e) A thermogram of thermogravimetric analysis (TGA) substantially as shown in figure 3;

or alternatively

(f) A combination thereof.

In some embodiments, polymorph form I is characterized by an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, polymorph form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2- θ, 12.7±0.2° 2- θ, and 16.4±0.2° 2- θ, as usingIs measured by X-ray powder diffraction. In some embodiments, polymorph form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.1° 2- θ, 12.7±0.1° 2- θ, and 16.4±0.1° 2- θ, as using +.>Is measured by X-ray powder diffraction. In some embodiments, polymorph form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 8.2 ° 2-theta, about 12.7 ° 2-theta, and about 16.4 ° 2-theta, as using +.>Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern further comprises a compound selected from 16.9 ± 0.2 ° 2-theta, 17.6 ± 0.2 ° 2-theta, and 22.9 ± 0At least one peak in 2 DEG 2-theta, e.g. usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises 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, e.g., using ± +.>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 16.9 ° 2-theta, about 17.6 ° 2-theta, and about 22.9 ° 2-theta, such as with ∈9-> Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 20.6±0.2° 2- θ, 24.9±0.2° 2- θ, and 19.9±0.2° 2- θ, e.g., usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 20.6±0.1° 2- θ, 24.9±0.1° 2- θ, and 19.9±0.1° 2- θ, e.g., using ± +.>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 20.6 ° 2-theta, about 24.9 ° 2-theta, and about 19.9 ° 2-theta, such as with ∈10 > Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern includes at least one peak selected from the group consisting of 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, as usedIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least two peaks selected from the group consisting of 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, as used> Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least three peaks selected from the group consisting of 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least four peaks selected from the group consisting of 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, as used >Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least five peaks selected from the group consisting of 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least six peaks selected from the group consisting of 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least eight peaks selected from the group consisting of 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, as used >Is measured by X-ray powder diffraction. In some embodiments, X-ray powder diffractionThe graph 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, as usedIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as usedIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes peaks, if used, at about 8.2 ° 2-theta, about 12.7 ° 2-theta, about 16.4 ° 2-theta, about 16.9 ° 2-theta, about 17.6 ° 2-theta, about 22.9 ° 2-theta, about 20.6 ° 2-theta, about 24.9 ° 2-theta, and about 19.9 ° 2-theta>Is measured by X-ray powder diffraction.

In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 1. In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 ℃ to about 160 ℃.

In some embodiments of the present invention, in some embodiments, the polymorph form I is prepared by a process comprising the steps of about 135-160deg.C, 135-158 deg.C, 135-156 deg.C, 135-154 deg.C, 135-152 deg.C, 135-150 deg.C, 135-148 deg.C, 135-146 deg.C, 135-144 deg.C, 135-142 deg.C, 135-140 deg.C, 140-160 deg.C, 140-158 deg.C, 140-156 deg.C, 140-154 deg.C, 140-152 deg.C, and 140-150 ℃, 140-148 ℃, 140-146 ℃, 140-144 ℃, 140-142 ℃, 142-160 ℃, 142-158 ℃, 142-156 ℃, 142-154 ℃, 142-152 ℃, 142-150 ℃, 142-148 ℃, 142-146 ℃, 142-144 ℃, 144-160 ℃, 144-158 ℃, 144-156 ℃, 144-154 ℃, and 144-152 ℃, 144-150 ℃, 144-148 ℃, 144-146 ℃, 146-160 ℃, 146-158 ℃, 146-156 ℃, 146-154 ℃, 146-152 ℃, 146-150 ℃, 146-148 ℃, 148-160 ℃, 148-158 ℃, 148-156 ℃, 148-154 ℃, 148-152 ℃, 148-150 ℃, 150-160 ℃, 150-158 ℃, 150-156 ℃, 150-154 ℃, 150-152 ℃, 152-160 ℃, 152-158 ℃, 152-156 ℃, 154-160 ℃, 154-158 ℃, 156-160 ℃, 156-158 ℃, or 158-160 ℃ by Differential Scanning Calorimetry (DSC) thermograms. In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 135-140 ℃ (e.g., at about 135 ℃, 136 ℃, 137 ℃, 138 ℃, 139 ℃, or 140 ℃). In some embodiments, polymorph form I has a melting point of about 139 ℃. In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 145-150 ℃ (e.g., at about 145 ℃, 146 ℃, 147 ℃, 148 ℃, 149 ℃, or 150 ℃). In some embodiments, polymorph form I has a melting point of about 148 ℃.

In some embodiments, polymorph form I is characterized by a thermogram of thermogravimetric analysis (TGA) substantially as shown in figure 3. In some embodiments, polymorph form I decomposes at a temperature above about 50 ℃, about 100 ℃, about 150 ℃, about 200 ℃, about 250 ℃, about 300 ℃, about 350 ℃, or about 400 ℃. In some embodiments, polymorph form I decomposes at temperatures above about 150 ℃.

In some embodiments, polymorph form I is stable at room temperature. In some examples, polymorph form I can be stored at room temperature for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form I can be stored at room temperature for a period of at least about 1, 2, 3, or 7 days. In some examples, polymorph form I can be stored at room temperature for a period of time exceeding about 7 days. In some examples, polymorph form I can be stored at room temperature 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 examples, polymorph form I can be stored at room temperature for a period of at least 1, 2, 3, or 7 days.

In some embodiments, polymorph form I is stable at temperatures above room temperature and/or at high Relative Humidity (RH). In some examples, polymorph form I can be stored at about 40 ℃ and at about 75% rh for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form I can be stored at about 40 ℃ and at about 75% rh for a period of at least about 1, 2, 3, or 7 days. In some examples, polymorph form I can be stored at about 40 ℃ and at about 75% rh for a period of time exceeding about 7 days. In some examples, polymorph form I can be stored at about 40 ℃ and at about 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 examples, polymorph form I can be stored at about 40 ℃ and at about 75% rh for a period of 1, 2, 3, or 7 days.

In some embodiments, polymorph form I is stable at temperatures above room temperature and/or at high Relative Humidity (RH). In some examples, polymorph form I can be stored at about 60 ℃ for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form I can be stored at about 60 ℃ for a period of at least about 1, 2, 3, or 7 days. In some examples, polymorph form I can be stored at about 60 ℃ for a period of time exceeding about 7 days. In some examples, polymorph form I can be stored at about 60 ℃ 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 examples, polymorph form I can be stored at about 60 ℃ for a period of 1 day, 2 days, 3 days, or 7 days.

Polymorph form II of a compound of formula I

Figure 4 shows a Differential Scanning Calorimetry (DSC) thermogram of polymorph form II of a compound of formula I.

Fig. 5 shows an X-ray powder diffraction (XRPD) pattern of polymorph form II of a compound of formula I.

Figure 6 shows a thermogram of polymorphic form II of the compound of formula I (TGA).

In one aspect, provided herein is polymorph form II of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine. Some embodiments provide a composition comprising polymorph form II of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine. In some embodiments, polymorph form II of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine is characterized as having:

(a) X-ray powder diffraction patterns including peaks at 7.6.+ -. 0.2.+ -. 2-theta, 8.7.+ -. 0.2.+ -. 2-theta and 16.0.+ -. 0.2.+ -. 2-theta, as usedIs measured by X-ray powder diffraction;

(b) An X-ray powder diffraction pattern substantially as shown in figure 5;

(c) Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 ℃ to about 170 ℃;

(d) Further comprising an endothermic Differential Scanning Calorimetry (DSC) thermogram in the range of about 25 ℃ to about 60 ℃;

(e) A Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 4;

(f) A thermogram of thermogravimetric analysis (TGA) substantially as shown in figure 6;

or alternatively

(g) A combination thereof.

In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.2° 2- θ, 8.7±0.2° 2- θ, and 16.0±0.2° 2- θ, as usingIs measured by X-ray powder diffraction. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising peaks at 7.6±0.1° 2- θ, 8.7±0.1° 2- θ, and 16.0±0.1° 2- θ, as using +.>Is measured by X-ray powder diffraction. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising peaks at about 7.6 ° 2-theta, about 8.7 ° 2-theta, and about 16.0 ° 2-theta, as using +. >Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 12.2±0.2° 2- θ, 17.6±0.2° 2- θ, and 19.5±0.2° 2- θ, e.g., usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from the group consisting of 12.2±0.1° 2- θ, 17.6±0.1° 2- θ, and 19.5±0.1° 2- θ, e.g., using ± ± using +.>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises a compound selected from the group consisting ofAt least one peak of about 12.2 deg. 2-theta, about 17.6 deg. 2-theta and about 19.5 deg. 2-theta, such as with +.> Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern further comprises 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, e.g., usingIs measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises 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, as with ± using +. >Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 21.7 ° 2-theta, about 10.8 ° 2-theta, and about 13.4 ° 2-theta, such as with ∈10-> Is measured by X-ray powder diffraction.

In some embodiments, the X-ray powder diffraction pattern 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, as usedIs passed through the X-ray powderMeasured by end diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least two peaks selected from the group consisting of 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used >Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern includes at least six peaks selected from the group consisting of 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, e.g., such thatUse->Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used >Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used>Is measured by X-ray powder diffraction. In some embodiments, the X-ray powder diffraction pattern 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, as used> Is passed through the X-ray powderMeasured by end diffraction. In some embodiments, the X-ray powder diffraction pattern includes peaks, if used, at about 7.6 ° 2-theta, about 8.7 ° 2-theta, about 16.0 ° 2-theta, about 12.2 ° 2-theta, about 17.6 ° 2-theta, about 19.5 ° 2-theta, about 21.7 ° 2-theta, about 10.8 ° 2-theta, and about 13.4 ° 2-theta >Is measured by X-ray powder diffraction.

In some embodiments, polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 4. In some embodiments, polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 ℃ to about 170 ℃.

In some embodiments, polymorph form I is characterized by a differential calorimetric profile comprising a spectrum of heat at about 150-170 ℃, 150-168 ℃, 150-166 ℃, 150-164 ℃, 150-162 ℃, 150-160 ℃, 150-158 ℃, 150-156 ℃, 150-154 ℃, 150-152 ℃, 152-170 ℃, 152-168 ℃, 152-166 ℃, 152-162 ℃, 152-158 ℃, 152-156 ℃, 152-154 ℃, 154-170 ℃, 154-168 ℃, 154-166 ℃, 154-164 ℃, 154-160 ℃, 154-158 ℃, 154-156 ℃, 156-170 ℃, 156-168 ℃, 156-166 ℃, 156-164 ℃, 156-162 ℃, 156-160 ℃, 156-158 ℃, 158-170 ℃, 158-166 ℃, 158-162 ℃, 158-160 ℃, 160-170 ℃, 160-168 ℃, 160-166 ℃, 160-162 ℃, 162-164 ℃, 164-170 ℃, 164-164 ℃, 164-168 ℃, 164-166 ℃, 164-166-170 ℃, or 168-170 ℃, 166-170 ℃, or 168-166-170 ℃, by DSC). In some embodiments, polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm at about 150-155 ℃ (e.g., at about 150 ℃, 151 ℃, 152 ℃, 153 ℃, 154 ℃, or 155 ℃). In some embodiments, polymorph form I has a melting point of about 150-155 ℃.

In some embodiments of the present invention, in some embodiments, the polymorph form II is prepared by the steps of further comprising the steps of preparing the pharmaceutical composition at about 25-60 ℃, 25-58 ℃, 25-56 ℃, 25-54 ℃, 25-52 ℃, 25-50 ℃, 25-48 ℃, 25-46 ℃, 25-44 ℃, 25-42 ℃, 25-40 ℃, 25-38 ℃, 25-36 ℃, 25-34 ℃, 32 ℃, 30-30 ℃, 30-60 ℃, 30-58 ℃, 30-56 ℃, 30-54 ℃, 30-52 ℃, 30-50 ℃, 30-48 ℃, 30-46 ℃, 30-44 ℃, 30-42 ℃, 30-40 ℃, 30-38 ℃, 30-36 ℃, 30-34 ℃, 30-32 ℃, 32-60 ℃, 32-58 ℃, 32-56 ℃, and 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 ℃, and, 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 ℃, 48 ℃, 42-46 ℃, 42-44 ℃, 44-60 ℃, 44-58 ℃, 44-56 ℃, 44-54 ℃, 44-52 ℃, 42-60 ℃, 42-58 ℃, 42-54 ℃, and 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 ℃ or 58-60 ℃.

In some embodiments, polymorph form II is characterized by a thermogram of thermogravimetric analysis (TGA) substantially as shown in figure 6. In some embodiments, polymorph form II decomposes at a temperature above about 50 ℃, about 100 ℃, about 150 ℃, about 200 ℃, about 250 ℃, about 300 ℃, about 350 ℃, or about 400 ℃. In some embodiments, polymorph form II decomposes at temperatures above about 150 ℃.

In some embodiments, polymorph form II is stable below room temperature. In some examples, polymorph form II can be stored at about 2-8 ℃ for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form II can be stored at about 2-8 ℃ for a period of at least about 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 examples, polymorph form II can be stored at about 2-8 ℃ for a period of time exceeding about 36 months. In some of the examples of the present invention, the polymorph form II can be stored at about 2-8deg.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, 1-15 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, 6-33 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, 15-36 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, 24-30 months, 27-33 months, 27-36 months, 30-33 months, 30-36 months or 33 periods of time. In some examples, polymorph form II can be stored at about 2-8 ℃ 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.

In some embodiments, polymorph form II is stable at room temperature and relative humidity. In some examples, polymorph form II can be stored at about 25 ℃ and at about 60% rh for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form II can be stored at about 25 ℃ and at about 60% for a period of at least about 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some examples, polymorph form II can be stored at about 25 ℃ and at about 60% rh for a period of time exceeding about 6 months. In some examples, polymorph form II can be stored at about 25℃ and at about 60% 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, 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, 5 months, or 5-6 months. In some examples, polymorph form II can be stored at about 25 ℃ and at about 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.

In some embodiments, polymorph form II is stable at temperatures above room temperature and/or at high Relative Humidity (RH). In some examples, polymorph form II can be stored at about 40 ℃ and at about 75% rh for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form II can be stored at about 40 ℃ and at about 75% rh for a period of at least about 1, 2, 3, or 7 days. In some examples, polymorph form II can be stored at about 40 ℃ and at about 75% rh for a period of time exceeding about 7 days. In some examples, polymorph form II can be stored at about 40 ℃ and at about 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 examples, polymorph form II can be stored at about 40 ℃ and at about 75% rh for a period of 1, 2, 3, or 7 days.

In some embodiments, polymorph form II is stable at temperatures above room temperature and/or at high Relative Humidity (RH). In some examples, polymorph form II can be stored at about 60 ℃ for extended periods of time without significant chemical degradation or change in crystalline form. In some examples, polymorph form II can be stored at about 60 ℃ for a period of at least about 1, 2, 3, or 7 days. In some examples, polymorph form II can be stored at about 60 ℃ for a period of time exceeding about 7 days. In some examples, polymorph form II can be stored at 60 ℃ 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 examples, polymorph form II can be stored at about 60 ℃ for a period of 1 day, 2 days, 3 days, or 7 days.

Process for preparing compounds of formula I and polymorphs thereof

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" are available from standard commercial sources, including Acros Organics (Geel, belgium), aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), apin Chemicals ltd (miltonian park, UK Pharm, inc. (lebfuville, il), avocado Research (lank county, UK), BDH inc (toronto, canada), bionet (UK Kang Woer), chemspardevice inc (west pennsylvania), combi-blocks (san diego, CA), crescent Chemical co (haupauge, NY), e molecular Chemicals (san diego, CA), fisher Scientific co (pisburg, pa), fischer Chemicals (leicesburgh, UK), frontier Scientific (royal ), ICN Biomedicals, inc. (Costa Mesa, CA), key Organics (UK Kang Woer), lancaster Synthesis (new hampshire, wendemam), matrix Scientific (columbia, south carolina), maybridge Chemical co.ltd. (UK Kang Woer), parish Chemical co (oslemm, utah), pfaltz & Bauer, inc. (Waterbury, CN), polyorganix (houston, texas), pierce Chemical co (rocfoord, il), riedel de Haen AG (hanowe, ryan Scientific, inc.) (south carolina, manadent), spectrum Chemicals (california, ndia), ndia, TCI America (oregano, russian), etc.), trans World Chemicals, inc. (rocyverer, maryland) and WuXi (Shanghai, china).

Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing a reference to articles describing the preparation include, for example, "Synthetic Organic Chemistry", john Wiley & Sons, inc; S.R. Sandler et al, "Organic Functional Group Preparations," 2 nd edition, academic Press, N.Y., 1983; h.o.house, "Modern Synthetic Reactions", 2 nd edition, W.A.Benjamin, inc.Menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2 nd edition, john Wiley & Sons, new York, 1992; march, "Advanced Organic Chemistry: reactions, mechanisms and Structure", 4 th edition, wiley-Interscience, new York, 1992. Additional suitable references and papers that detail the synthesis of reactants useful in preparing the compounds described herein or that provide a reference to articles describing the preparation include, for example, fuhrhop, j. And Penzlin g. "Organic Synthesis: peptides, methods, starting Materials", second revised and expanded edition (1994) John Wiley & Sons ISBN:3-527-29074-5; hoffman, R.V. "Organic Chemistry, an Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2 nd edition (1999) Wiley-VCH, ISBN:0-471-19031-4; march, J. "Advanced Organic Chemistry: reactions, mechanisms, and Structure" 4 th edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; otera, J. (edit) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:3-527-29871-1; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN:0-471-93022-9; solomons, T.W.G. "Organic Chemistry" 7 th edition (2000) John Wiley & Sons, ISBN:0-471-19095-0; stowell, J.C. "Intermediate Organic Chemistry" 2 nd 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, volume 8; "Organic Reactions" (1942-2000) John Wiley & Sons, volume 55; and "Chemistry of Functional Groups" John Wiley & Sons, volume 73.

Specific and similar reactants are also identified by an index of known chemicals made by the chemical abstracts service of the american chemical society, which is available in most public and university libraries, and by an online database (american chemical society, washington, d.c.). Chemicals known in the catalog but not commercially available are prepared by custom chemical synthesis companies, many of which provide custom synthesis services (e.g., those listed above). References for the preparation and selection of pharmaceutically acceptable salts of pyrazole compounds described herein are p.h.stahl & c.g.weruth "Handbook of Pharmaceutical Salts", verlag Helvetica Chimica Acta, zurich,2002.

Isomers of

Furthermore, in some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers, and their corresponding mixtures. In some cases, the compounds exist in tautomeric forms. The compounds described herein include all possible tautomers in the formulae described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimeric forms as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers thereof by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer as well as the resolving agent is then recovered by any practical means that does not result in racemization.

Labeled compounds

In some embodiments, the compounds described herein are present in their isotopically-labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, compounds disclosed herein include isotopically-labeled compounds, which are identical to those described herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Incorporated into the compounds of the inventionExamples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, such as ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ^l5 N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds described herein, as well as pharmaceutically acceptable salts, solvates, hydrates or derivatives thereof, that contain the above-described isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example, into which a radioisotope such as ³ H and ¹⁴ the compound of C can be used for medicine and/or substrate tissue distribution determination. Tritiated (i.e ³ H) And carbon 14 (i.e ¹⁴ C) Isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, the use of heavy isotopes such as deuterium (i.e ² H) Substitution results in certain therapeutic advantages due to higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically-labeled compound, pharmaceutically-acceptable salts, solvates, hydrates, or derivatives thereof, are prepared by any suitable method.

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

Pharmaceutically acceptable salts

In some embodiments, the compounds described herein are present in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein have an acidic group or a basic group and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

Solvates of the formula

In some embodiments, the compounds described herein exist in the form of solvates. The present invention provides methods of treating diseases by administering such solvates. The invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the course of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous solvent/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran or MeOH. Furthermore, the compounds provided herein exist in unsolvated forms as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

In one aspect, provided herein are methods of preparing one or more polymorphs of a compound of formula I:

the compounds of formula I may be prepared as previously described in US 9,598,404, US 9,981,961, US 9,688,673, WO 2016/130581, US 10,570,124 and WO 2016/130562. In some embodiments, the compounds of formula I are prepared according to the examples herein.

The polymorphs provided herein are not limited by the starting materials used to produce the compounds of formula I.

In one aspect, provided herein is a process for preparing polymorphs of a compound of formula I or a pharmaceutically acceptable salt and/or solvate thereof by: the desired polymorph is isolated as a first solid form after synthesis of the compound of formula I, or alternatively as a transition from a previous solid form of the compound of formula I. The transition from one form to another is within the scope of the present disclosure, as they may be alternative manufacturing methods for obtaining the form required for the production of a pharmaceutical formulation.

Polymorphs of a compound of formula I may be selected from the group consisting of polymorph form I, polymorph form II, and mixtures thereof, according to the methods provided herein.

Isolation and purification of the chemical entities and intermediates described herein may be performed by any suitable isolation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, or thick layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be made with reference to the following examples. However, other equivalent separation or isolation procedures may be used. The compound of formula I may be isolated prior to crystallization at about 50% chemical purity, 55% chemical purity, 60% chemical purity, 65% chemical purity, 70% chemical purity, 75% chemical purity, 80% chemical purity, 90% chemical purity, 91% chemical purity, 92% chemical purity, 93% chemical purity, 94% chemical purity, 95% chemical purity, 96% chemical purity, 97% chemical purity, 98% chemical purity, 99% chemical purity, about 98% chemical purity, or about 100% chemical purity.

In some embodiments, the crystalline forms disclosed herein are obtained by crystallizing 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% of a compound of formula I. In some embodiments, the crystalline form is obtained by crystallizing a compound of formula I having 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 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%.

Preparation of polymorph form I

In one embodiment, the desired polymorph is polymorph form I of the maleate salt of the compound of formula I, and the isolating step comprises recrystallizing the crude reaction product from a single solvent system. In some embodiments, the desired polymorph is polymorph form I of the maleate salt of the compound of formula I, and the isolating step comprises recrystallizing the crude product from a binary, ternary or higher solvent system (collectively referred to as a multiple solvent system). In some embodiments, the desired polymorph is polymorph form I of the maleate salt of the compound of formula I, and the isolating step comprises crystallization from a single solvent or a multi-solvent system, wherein crystallization comprises dissolving the compound of formula I and maleic acid in the single solvent or multi-solvent system at a temperature above ambient temperature. In some examples, the dissolution of the compound of formula I and maleic acid in a single or multiple solvent system is performed at about 40-90 ℃, 45-90 ℃, 50-90 ℃, 55-90 ℃, 60-90 ℃, 65-90 ℃, 70-90 ℃, 75-90 ℃, 40-85 ℃, 45-85 ℃, 50-85 ℃, 55-85 ℃, 60-85 ℃, 65-85 ℃, 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 ℃, 50-70 ℃, 55-70 ℃, 60-70 ℃, 65-65 ℃, 45-65 ℃, 50-65 ℃, 55-65 ℃, 60 ℃, 40-60 ℃, 50-60 ℃, 55-60 ℃, 40-55 ℃, 45-55 ℃, 50-50 ℃, or 45-50 ℃. In some examples, the recrystallization solvent comprises ethanol/ethyl acetate, and the dissolution of the compound of formula I and maleic acid in the solvent is performed at a temperature of about 60 ℃. Any suitable amount of solvent may be used to dissolve the compound of formula I and the maleic acid. In some embodiments, the amount of solvent (e.g., 1:1 ethanol/ethyl acetate) used to dissolve the compound of formula I and the maleic acid is about 1-10mL/g of the compound of formula I. For example, in some embodiments, the amount of solvent used to dissolve the compound of formula I is 7.3mL/g of the compound of formula I. In some examples, the recrystallization solvent comprises ethanol/ethyl acetate, the dissolution of the compound of formula I and maleic acid in the solvent system is performed at a temperature of about 60 ℃, and the amount of solvent used for the dissolution is about 7.3mL/g of the compound of formula I.

In some embodiments, crystallization further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of, for example, about 0-40 ℃, 0-30 ℃, 0-20 ℃, 0-10 ℃, 10-40 ℃, 10-30 ℃, 10-20 ℃, 20-40 ℃, 20-30 ℃, 20-10 ℃, or 30 ℃ -40 ℃. In some embodiments, crystallizing further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of about 25 ℃. In some embodiments, the solution containing the dissolved maleate salt of the compound of formula I is further maintained at the lower temperature for a period of time such as 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.

In some embodiments, crystallization further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of, for example, about 0-40 ℃, 0-30 ℃, 0-20 ℃, 0-10 ℃, 10-40 ℃, 10-30 ℃, 10-20 ℃, 20-40 ℃, 20-30 ℃, 20-10 ℃, or 30 ℃ -40 ℃. In some embodiments, crystallizing further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of about 0 ℃. In some embodiments, the solution containing the dissolved maleate salt of the compound of formula I is further maintained at the lower temperature for a period of time such as 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.

In some embodiments, crystallizing further comprises filtering a solution containing crystals of the obtained maleate salt of the compound of formula I. In some embodiments, crystallizing optionally includes washing the obtained crystals one or more times with a solvent, such as by recrystallising the solvent. In some embodiments, crystallizing optionally includes drying the obtained crystals, e.g., drying the obtained crystals under vacuum at a temperature of about 55 ℃.

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

Preparation of polymorph form II

In one embodiment, the desired polymorph is polymorph form II of the maleate salt of the compound of formula I, and the isolating step comprises recrystallizing the crude reaction product from a single solvent system. In some embodiments, the desired polymorph is polymorph form II of the maleate salt of the compound of formula I, and the isolating step comprises recrystallizing the crude product from a binary, ternary or higher solvent system (collectively referred to as a multiple solvent system). In some embodiments, the desired polymorph is polymorph form II of the maleate salt of the compound of formula I, and the isolating step comprises crystallizing from a single solvent or a multi-solvent system, wherein crystallizing comprises dissolving the maleate salt of the compound of formula I in the single solvent or multi-solvent system at a temperature above ambient temperature. In some examples, the dissolution of the maleate salt of the compound of formula I in a single or multiple solvent system is performed at about 40-90 ℃, 45-90 ℃, 50-90 ℃, 55-90 ℃, 60-90 ℃, 65-90 ℃, 70-90 ℃, 75-90 ℃, 40-85 ℃, 45-85 ℃, 50-85 ℃, 55-85 ℃, 60-85 ℃, 65-85 ℃, 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 ℃, 50-70 ℃, 55-70 ℃, 60-70 ℃, 65-65 ℃, 45-65 ℃, 50-65 ℃, 55-65 ℃, 60 ℃, 40-60 ℃, 50-60 ℃, 55-60 ℃, 40-55 ℃, 45-55 ℃, 50-50 ℃, or 45-50 ℃. In some examples, the recrystallization solvent comprises 1:1 DCM/methanol, and the dissolution of the maleate salt of the compound of formula I in the solvent is performed at a temperature of about 45 ℃. Any suitable amount of solvent may be used to dissolve the maleate salt of the compound of formula I. In some embodiments, the amount of solvent (e.g., 1:1 DCM/methanol) used to dissolve the maleate salt of the compound is about 1-20mL/g of the maleate salt of the compound of formula I. For example, in some embodiments, the amount of solvent used to dissolve the maleate salt of the compound of formula I is 7.4mL/g of the maleate salt of the compound of formula I. In some examples, the recrystallization solvent comprises 1:1 DCM/methanol, the dissolution of the maleate salt of the compound of formula I in the solvent system is performed at a temperature of about 45 ℃, and the amount of solvent used for dissolution is about 7.4mL/g of maleate salt of the compound of formula I.

In some embodiments, crystallization further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of, for example, about 0-40 ℃, 0-30 ℃, 0-20 ℃, 0-10 ℃, 10-40 ℃, 10-30 ℃, 10-20 ℃, 20-40 ℃, 20-30 ℃, 20-10 ℃, or 30 ℃ -40 ℃. In some embodiments, crystallizing further comprises actively cooling the heated solution containing the dissolved maleate salt of the compound of formula I to a temperature of about 5 ℃. In some embodiments, the solution containing the dissolved maleate salt of the compound of formula I is further maintained at the lower temperature for a period of time such as 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.

In some embodiments, crystallizing further comprises filtering a solution containing crystals of the obtained maleate salt of the compound of formula I. In some embodiments, crystallizing optionally includes washing the obtained crystals one or more times with a solvent, such as by recrystallising the solvent. In some embodiments, crystallizing optionally includes drying the obtained crystals, e.g., drying the obtained crystals under vacuum at a temperature of about 70 ℃.

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

In some embodiments, polymorph form II is dried. In some embodiments, polymorph form II is unsolvated. In some embodiments, polymorph form II is non-hydrated. In some embodiments, polymorph form II is anhydrous. In some embodiments, polymorph form II is solvated. In some embodiments, polymorph form II is hydrated.

Pharmaceutical composition

The present disclosure provides compositions, including pharmaceutical compositions, comprising one or more crystalline forms of the present invention.

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

In some embodiments, one or more polymorphs of a compound of formula I are formulated as a pharmaceutical composition. In particular embodiments, pharmaceutical compositions are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds/polymorphs into preparations which can be used pharmaceutically. Suitable formulations depend on the route of administration selected. Any pharmaceutically acceptable technique, carrier and excipient may be suitably used to formulate the pharmaceutical compositions described herein: remington, the Science and Practice of Pharmacy, 19 th edition (Easton, pa.: mack Publishing Company, 1995); hoover, john e, remington's Pharmaceutical Sciences, mack Publishing co., oiston, pennsylvania, 1975; liberman, h.a. and Lachman, l. Editions, pharmaceutical Dosage Forms, marcel Decker, new york city, new york, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7 th edition (Lippincott Williams & Wilkins 1999).

Provided herein are 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, wherein the one or more polymorphs are admixed with other active ingredients, such as in combination therapy. All combinations of the active agents set forth in the following combination therapy section and throughout this disclosure are encompassed herein. In particular embodiments, the pharmaceutical compositions comprise one or more polymorphs of a compound of formula I.

A pharmaceutical composition as used herein refers to a mixture of one or more polymorphs of a compound of formula I with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners and/or excipients. In certain embodiments, the pharmaceutical compositions facilitate administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or methods of use provided herein, a therapeutically effective amount of one or more polymorphs of a compound of formula I is administered to a mammal having a disease or condition to be treated in the form of a pharmaceutical composition. In a specific embodiment, 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 of the subject, and other factors. One or more polymorphs of a compound of formula I described herein are used alone or in combination with one or more therapeutic agents as components of a mixture.

In one embodiment, one or more polymorphs of a compound of formula I are formulated in aqueous solution. In particular embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as a hank's solution, ringer's solution, or physiological saline buffer. In other embodiments, one or more polymorphs of a compound of formula I are formulated for transmucosal administration. In particular embodiments, the transmucosal formulation contains penetrants appropriate to the barrier to be permeated. In other embodiments in which one or more polymorphs described herein are formulated for other parenteral injection, suitable formulations include aqueous solutions or non-aqueous solutions. In particular embodiments, such solutions include physiologically compatible buffers and/or excipients.

In another embodiment, the polymorphs described herein are formulated for oral administration. Polymorphs of a compound of formula I are formulated by combining the polymorphs with, for example, a pharmaceutically acceptable carrier or excipient. In some embodiments, polymorphs described herein are formulated into oral dosage forms including, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

In certain embodiments, a pharmaceutical formulation for oral use is obtained by mixing one or more solid excipients with one or more polymorphs described herein, optionally grinding the resulting mixture, and processing the particulate mixture after adding suitable adjuvants (if desired) to obtain a tablet or dragee core. Suitable excipients are in particular fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In particular embodiments, a disintegrant is optionally added. By way of example only, disintegrants include crosslinked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coatings. In particular embodiments, the concentrated sugar solution is used to coat a dosage form. The sugar solution optionally contains additional components such as, by way of example only, gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and/or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and/or pigments are optionally used to characterize different combinations of active compound doses.

In certain embodiments, a therapeutically effective amount of at least one of the polymorphs described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit (push-fit) capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerin or sorbitol. In particular embodiments, push-fit capsules contain the active ingredient mixed with one or more fillers. By way of example only, fillers include lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, the soft capsules comprise one or more active compounds dissolved or suspended in a suitable liquid. By way of example only, suitable liquids include one or more fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers are optionally added.

In other embodiments, a therapeutically effective amount of at least one of the polymorphs described herein is formulated for buccal or sublingual administration. By way of example only, formulations suitable for buccal or sublingual administration include tablets, troches or gels. In other embodiments, polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In particular embodiments, the formulation for injection is presented in unit dosage form (e.g., in ampules) or in multi-dose containers. Optionally, a preservative is added to the injection formulation. In other embodiments, pharmaceutical compositions of polymorphs of a compound of formula I are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily vehicles (vehicle) or aqueous vehicles. The parenteral injection formulation optionally comprises formulation aids (formulatory agent), such as suspending, stabilizing and/or dispersing agents. In particular embodiments, pharmaceutical formulations for parenteral administration comprise aqueous solutions of the active polymorphs in water-soluble form. In additional embodiments, suspensions of the active polymorphs are prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, the aqueous injection suspension comprises a substance that increases the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension comprises a suitable stabilizer or agent that increases the solubility of the polymorph to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for formulation with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use.

In other embodiments, one or more polymorphs of a compound of formula I are administered topically. One or more polymorphs described herein are formulated into various topically administrable compositions such as solutions, suspensions, lotions, gels, pastes, sticks, balms (balms), creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

In other embodiments, one or more polymorphs of a compound of formula I are formulated for transdermal administration. In particular embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches, and may be lipophilic emulsions or buffered aqueous solutions dissolved and/or dispersed in a polymer or adhesive. In some embodiments, such patches are configured for continuous delivery, pulsed delivery, or on-demand delivery of a pharmaceutical agent. In additional embodiments, transdermal delivery of one or more polymorphs of a compound of formula I is accomplished by iontophoretic patch or the like. In certain embodiments, the transdermal patch provides for controlled delivery of one or more polymorphs of the compound of formula I. In particular embodiments, the rate of absorption is slowed by the use of a rate controlling membrane or by entrapment of the compound in a polymer matrix or gel. In an alternative embodiment, an absorption enhancer is used to increase absorption. The absorption enhancer or carrier includes an absorbable pharmaceutically acceptable solvent that aids in passing through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound (optionally together with a carrier), a rate controlling barrier that delivers the compound to the skin of the host, optionally at a controlled and predetermined rate, for an extended period of time, and means for securing the device to the skin.

In other embodiments, one or more polymorphs of a compound of formula I are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, sprays (mists) or powders. Pharmaceutical compositions of polymorphs of a compound of formula I are conveniently delivered from a pressurized package or nebulizer in the form of aerosol spray presentation using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In particular embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve to deliver a metered amount. In certain embodiments, by way of example only, gelatin capsules and cartridges for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

In other embodiments, one or more polymorphs of a compound of formula I are formulated as rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the suppository form of the composition, a low melting wax, such as but not limited to a mixture of fatty acid glycerides, is first melted, optionally in combination with cocoa butter.

In certain embodiments, the pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Suitable formulations depend on the route of administration selected. Any pharmaceutically acceptable technique, carrier and excipient are optionally suitable for use. Pharmaceutical compositions comprising one or more polymorphs of a compound of formula I are prepared in conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.

A pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent or excipient and, as active ingredient, at least one polymorph of a compound of formula I described herein. The active ingredient is in the form of a free acid or free base, or a pharmaceutically acceptable salt. All tautomers of the compounds described herein are included within the scope of the compounds described herein. Furthermore, the compounds described herein encompass unsolvated forms and solvated forms that contain pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical composition optionally comprises other medical or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters (solution promoter), salts for regulating osmotic pressure, buffers and/or other therapeutically valuable substances.

A process for preparing a composition comprising one or more polymorphs of a compound of formula I described herein comprises formulating the polymorphs with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid agent. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions having a compound dissolved therein, emulsions comprising a compound, or solutions comprising liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like.

In some embodiments, the pharmaceutical composition comprising at least one polymorph of a compound of formula I illustratively takes the form of a liquid, wherein the agent is present in the solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the agent is present in the solution and a second portion of the agent is present in the particulate form, in the suspension, in the liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

In certain embodiments, useful aqueous suspensions comprise one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise mucoadhesive polymers selected from, for example, carboxymethyl cellulose, carbomers (acrylic acid polymers), poly (methyl methacrylate), polyacrylamides, polycarbophil, acrylic acid/butyl acrylate copolymers, sodium alginate, and dextran.

Useful pharmaceutical compositions also optionally include a solubilizing agent to aid in the solubility of the polymorphs of the compound of formula I. The term "solubilizing agent" generally includes agents that result in the formation of a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, may be used as solubilizing agents, such as glycols, polyglycols, such as polyethylene glycol 400 and glycol ethers, which may be ophthalmically acceptable.

In addition, useful pharmaceutical compositions optionally comprise one or more pH adjusting agents 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 tris (hydroxymethyl) aminomethane; 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 acceptable ranges.

In addition, useful compositions optionally also include one or more salts in an amount necessary to bring the osmolality of the composition to an acceptable range. Such salts include salts with sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulphite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing materials such as phenylmercuric borate (merfen) and thimerosal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

Other useful compositions 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; and polyoxyethylene alkyl ethers and alkylphenyl ethers, such as octylphenol polyether 10, octylphenol polyether 40.

Other useful compositions include one or more antioxidants to enhance chemical stability when desired. By way of example only, suitable antioxidants include ascorbic acid and sodium metabisulfite.

In certain embodiments, the aqueous suspension composition is packaged in a single dose non-reclosable container. Alternatively, multiple doses of a reclosable container are used, in which case preservatives are typically included in the composition.

In alternative embodiments, other delivery systems for hydrophobic drug compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers that can be used herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, polymorphs described herein are delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials are useful herein. In some embodiments, the sustained release capsule releases the polymorph over a period of several weeks to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization are employed.

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

Therapeutic method

Disclosed herein are methods of inhibiting deoxycytidine kinase (dCK) activity comprising contacting a compound or polymorph detailed herein with deoxycytidine kinase in vitro (e.g., in an enzymatic or cell-based assay context) or in vivo (e.g., in an animal model or in an individual subject in need of treatment). The compounds and polymorphs provided herein bind to and inhibit the activity of deoxycytidine kinase polypeptides. Thus, in another aspect, methods are provided for inhibiting dCK activity and treating diseases and conditions in which dCK activity is implicated.

In some embodiments, a method for treating cancer in an individual is provided, the method comprising administering to the individual an effective amount of a compound detailed herein, or a pharmaceutically acceptable salt or polymorph thereof.

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

The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organ and is generally characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally classified clinically based on the following: (1) Duration and character of the disease—acute or chronic; (2) types of cells involved: myeloid (myelogenous), lymphoid (lymphogenic) or monocytic; and (3) an increase or no increase in the number of abnormal cells in the blood: leukemia or non-leukemia (sub-leukemia). Murine leukemia models are widely regarded as predictive of anti-leukemia activity in vivo. It is believed that compounds that test positive in the P388 cell assay will generally exhibit a certain level of anti-leukemia activity, regardless of the type of leukemia being treated. Accordingly, the present invention includes a method of treating leukemia, it comprises the treatment of acute myeloid leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemia, basal cell leukemia, blast leukemia, bovine leukemia, chronic myelogenous leukemia, skin leukemia, embryonal leukemia, eosinophilic leukemia, gros ' leukemia, hairy's leukemia, hematopoietic leukemia (hemoblastic leukemia), embryogenic leukemia (hemocytoblastic leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia lymphoblastic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryoblastic leukemia, micro-myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelomonocytic leukemia, internal gurley leukemia (Naegeli leukemia), plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, li delta cell leukemia (Rieder cell leukemia), schilin leukemia (schiling's leukemia), stem cell leukemia, sub Bai Xiexing (subukemic) leukemia, and undifferentiated cell leukemia.

The term "sarcoma" generally refers to a tumor that consists of a substance like embryonic connective tissue, and generally consists of closely packed cells embedded in a fibrillar or homogenous substance. Sarcomas which can be treated with a combination of an anti-neoplastic thiol-binding mitochondrial oxidant and an anti-cancer agent include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, ebolonine's sarcoma (Abemethyl's sarcoma), liposarcoma, acinar soft tissue sarcoma, ameloblastic sarcoma, vitoides sarcoma, chloroma sarcoma, choriocarcinoma, embryogenic sarcoma, wei Erm S ' tumor sarcoma (Wilms ' tumouroas), endometrial sarcoma, stromal sarcoma, ewing's sarcoma (Ewing's sarcoma), fascia sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytosarcoma, hodgkin's sarcoma, idiopathic multiple pigmentation hemangiosarcoma, B cell immunoblastic sarcoma, lymphoma, T cell immunoblastic sarcoma, zhan Senshi sarcoma (Jensen's sarcoma), kaposi's sarcoma, proc sarcoma (Kupffer cell sarcoma), vascular sarcoma, leukemia sarcoma, infrared sarcoma, osteosarcoma, omental sarcoma, and capillary sarcoma (telangiectaltic sarcoma, capillary sarcoma).

The term "melanoma" is used to mean a tumor produced by the melanocyte system of the skin and other organs. Melanoma that can be treated with a combination of an anti-neoplastic thiol in combination with a mitochondrial oxidant and an anti-cancer agent include, for example, acro-freckle-like melanoma, non-melanoma, benign adolescent melanoma, claudeman' S melanoma, S91 melanoma, harding-Passey melanoma (Harding-Passey melanoma), juvenile melanoma, malignant nevus melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial diffuse melanoma.

The term "cancer" refers to a malignant neoplasm consisting of epithelial cells that tend to infiltrate surrounding tissue and cause metastasis. Exemplary cancers that can be treated with the combination of an anti-tumor thiol-binding mitochondrial oxidant and an anti-cancer agent include, for example, acinar, adenocystic, adeno, adrenocortical, alveolar, basal cell carcinoma (basal cell carcinoma), basal cell carcinoma (carcinoma basocellulare), basal cell-like, basal squamous cell carcinoma, adenoid cystic, alveolar, basal cell carcinoma bronchioloalveolar carcinoma, bronchiogenic carcinoma, brain (cerebriform carcinoma), small bile duct carcinoma, choriocarcinoma, colloid-like carcinoma, acne carcinoma, uterine body carcinoma, sieve-like carcinoma, armor-like carcinoma, skin carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma (carpinoma durum), embryonal carcinoma, brain-like carcinoma, epidermoid carcinoma adenoid epithelial cancer (carcinoma epitheliale adenoides), exogenic cancer, ulcerative cancer, fibrocarcinoma, gel-like cancer (gelatinifoni carcinoma), gelatinous cancer, giant cell cancer (giant cell carcinoma), giant cell cancer (carcinoma gigantocellulare), adenoid cancer, granulosa cell cancer, hair matrix cancer (hair-matrix cancer), blood sample cancer, hepatocellular cancer, xu Telai-cell cancer (Hurthle cell carcinoma), transparent cancer, adrenal-like cancer, infant embryogenic cancer, carcinoma in situ, intraepidermal cancer, intraepithelial cancer, krompche cancer, kulchitzky-cell cancer, large cell cancer, bean-like cancer (lenticular carcinoma), bean-like cancer (carcinoma lenticulare), lipoma cancer, lymphatic epithelial cancer, medullary cancer (carcinoma medullare), medullary cancer (medullary carcinoma), melanin cancer, soft cancer (carpinoma molle), mucous cancer (mucinous carcinoma), mucous membrane cancer, mucous (carcinoma muciparum), mucous cell, epidermoid, mucous (carcinoma mucosum), mucous (mucocarpioma), myxomatoid (carcinoma myxomatodes), nasopharyngeal, oat, osseous, bone, papillary, periportal, precancerous, acanthocellular, medullary (pultaceous carcinoma), renal cell, stock cell (reserve cell carcinoma), sarcoidosis, schneider (schneiderian carcinoma), hard (scirrhous carcinoma), scrotal, seal ring, simple, small cell, potato, globular, spindle, spongiform, squamous cell, chordal (string-binding), vasodilatory (carcinoma telangiectaticum), vasodilatory (carcinoma telangiectodes), transitional cell, nodular skin (carcinoma tuberosum), nodular skin (tuberous carcinoma), warty (verrucous carcinoma), and villous.

In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is Acute Lymphoblastic Leukemia (ALL). In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is characterized by a high level of replicative stress as 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 a head or neck cancer.

In some embodiments of this section, there is provided a method for treating an immune disorder in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound detailed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the immune disorder 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.

In another aspect, provided herein is a method of treating Acute Disseminated Encephalomyelitis (ADEM) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

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, administration of the compound of formula I is performed twelve hours apart.

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

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

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

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

In some embodiments, the compounds of formula I are formulated for oral administration. In some embodiments, the compounds of formula I are formulated as tablets, pills, capsules, powders, liquids, suspensions, solutions, suppositories, or aerosols. 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 compounds of formula I are formulated as liquid agents. In some embodiments, the compounds of formula I are formulated as suspensions. In some embodiments, the compounds of formula I are formulated as suppositories. In some embodiments, the compound of formula I is formulated as an aerosol.

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

In some embodiments, administration of a compound of formula I results in a decrease in the level of interferon gamma (ifnγ) in the subject.

In another aspect, provided herein is a method of treating an autoimmune disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is administered once daily.

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).

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

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

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

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

In some embodiments, the compounds of formula I are formulated for oral administration. In some embodiments, the compounds of formula I are formulated as tablets, pills, capsules, powders, liquids, suspensions, solutions, suppositories, or aerosols. 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 compounds of formula I are formulated as liquid agents. In some embodiments, the compounds of formula I are formulated as suspensions. In some embodiments, the compounds of formula I are formulated as suppositories. In some embodiments, the compound of formula I is formulated as an aerosol.

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

In some embodiments, administration of a compound of formula I results in a decrease in the level of interferon gamma (ifnγ) in the subject.

Combination therapy

In some embodiments, a method for treating cancer in an individual is provided, the method comprising administering to the individual an effective amount of a compound or polymorph detailed herein or a pharmaceutically acceptable salt thereof, and thymidine. In some embodiments, the compound or polymorph is co-administered with thymidine. In some embodiments, the compound or polymorph is administered before, during, or after administration of thymidine. Examples of cancers 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 independent of the tissue of origin, characterized by genomic instability and/or activation of DNA damage response. Inhibition of dCK by a compound or polymorph detailed herein or a pharmaceutically acceptable salt thereof cooperates with thymidine to induce cell cycle arrest in tumors.

In some embodiments, the compounds and polymorphs described herein are used in combination with each other, with other active agents known to be useful in treating diseases (e.g., anticancer agents), or with auxiliary agents that may be ineffective when used alone but may contribute to the efficacy of the active agents. In some embodiments, the compounds and polymorphs described herein are co-administered with each other or with other active agents known to be useful in treating disease.

"anticancer agent" is used in accordance with its simple and ordinary meaning and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-tumor properties or the ability to inhibit the growth or proliferation of cells. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the united states for the treatment of cancer.

Examples of anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK 2) inhibitors (e.g., XL518, CI-1040, PD035901, semetinib)/AZD 6244, GSK 1120212/tramatinib (trametinib), GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, dichloromethyl diethylamine, uracil mustard, thiotepa, nitrosoureas, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil), ethyleneimine and methyl (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin), triazenes (amikacin), antimetabolites (e.g., 5-azathioprine, leucovorin, capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, fluorouridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, penstatin), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., vinblastine, irinotecan, topotecan, amsacrine, etoposide (VP 16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin (doxorubicin), doxorubicin (adriamycin), daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone Pramipexole, etc.), platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin), anthracenedione (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD 032501, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or other drugs 294002, k inhibitors, mTOR inhibitors, antibodies (e.g., rituximab), gossypol, antisense oligonucleotides (genasene), polyphenols E, chlorofusin, all-trans-deoxynixin, atrobatin, il-associated with 2, granisethionin, 17, pervogliptin-17, b-5, pervogliptin-17, b-70, b-5, g., pervogliptin, b-17; 5-ethynyl uracil; abiraterone; aclacinomycin; acyl fulvene (acylfulvene); adenosine cyclopentanol; aldolizhen; an aclidinium interleukin; ALL-TK antagonists; altretamine (altretamine); amoustine; 2, 4-dichlorophenoxyacetic acid (amidox); amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide (anagaride); anastrozole; andrographolide (andrographolide); an angiogenesis inhibitor; antagonist D; antagonist G; an Leili g (antarelix); anti-dorsal morphogenic protein-1 (anti-dorsalizingmorphogenetic protein-1); antiandrogens, prostate cancer; antiestrogens; anti-neoplastic ketones (antineoplaston); an antisense oligonucleotide; glycine afidomycin (aphidicolin glycinate); apoptosis gene modulators; apoptosis modulators; depurination nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; aust Sha Naning (asulocin); altamitazone (atamestane); amustine (attimus) tine); an avistatin 1 (axistatin 1); an aviostatin 2 (axistatin 2); an avistatin 3 (axistatin 3); azasetron (azasetron); azatolsine (azatoxin); diazotyrosine; baccatin III derivative (baccatinIII derivatives); ban Lannuo (balanol); bat (bat); BCR/ABL antagonists; benzochlorins (benzochlorins); benzoyl staurosporine (benzoyl staurosporine); beta lactam derivatives; beta-alixin (beta-aliethine); beta bleomycin B (betaclamycin B); betulinic acid; bFGF inhibitors; bicalutamide (bicalutamide); bisantrene (bisantrene); bis-aziridinyl spermine (bisaziridinyl spermine); binnafide (bisnafide); bistratene a, bizelesin, brix (breglate); bromopirimine (bripirtine); butatitane (budotitane); sulfoximine; calcipotriol; calcineurin C (calphostin C); camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-aminotriazole (carboxamide-amino-triazole); carboxamide triazoles; calst M3; CARN 700; cartilage derivative inhibitors; new catazelesin (carzelesin); casein kinase Inhibitors (ICOS); castanospermine (castanospermine); cecropin B (cecropin B); cetrorelix (cetrorelix); chlorins; chloroquinoxaline sulfonamide; cilazaprost (cicaprost); cis-porphyrin; cladribine (cladribine); clomiphene analogs; clotrimazole; clindamycin A (collismycin A); clindamycin B (collismycin B); combretastatin A4 (combretastatin A4); combretastatin analogues; kang Najing Ni (conagenin); kana Bei Xiting 816 (crambescidin 816); kriratol (crisnatol); candidiasis cyclic peptide 8; a candidiasis cyclic peptide a derivative; karabinin a (curacin a); cyclopentaanthraquinone; cycloplanum (cycloplatam); sirtuin (cypemycin); cytarabine sodium phosphate (cytarabine sodium phosphate); a cytolytic factor; hexane estrol phosphate (cytostatin); dacliximab; decitabine; dehydromembranous ecteinascidin B; delorelin (deslorelin); dexamethasone; right ifosfamide (dexifosfamide); right-hand razoxane (dexrazoxane); right verapamil (dexverapamil); deaquinone (diaziquone); ecteinascidin B; didox (didox); diethyl norspermine (diethyl norspermine); dihydro-5-azacells Glycoside (dihydro-5-azacytidine); 9-dioxamycin (9-dioxamycin); diphenyl spiromustine; behenyl alcohol (docosanol); dolasetron; deoxyfluorouridine; droloxifene; dronabinol; sesquialter mycin SA (duocannycin SA); ebselen; icotemustine; edefloxin; ibrutinab; efluoornithine (eflornithine); elemene; bupirimate; epirubicin; eplerite (epristeride); estramustine and analogues thereof; an estrogen agonist; estrogen antagonists; itraconazole; etoposide phosphate; exemestane; fadrozole; fazab; vitamin a amide (vitamin a amide); febuxostat; finasteride; fraapidol (flavopiridol); fusiformestine (flezelastine); fusterone (flusterone); fludarabine; fludaunomycin hydrochloride (fluorodaunorunicin hydrochloride); fofenamic (forfenimex); formestane (formestane); fosetrexine (fostricin); fotemustine (fotemustine); gadolinium-de-porphyrin (gadolinium texaphyrin); gallium nitrate; galocitabine (Galocitabine); ganirelix (ganirelix); a gelatinase inhibitor; gemcitabine; glutathione inhibitors; pran Su M (hepsulfam); heregulin; hexamethylenediacetamide; hypericin; ibandronic acid; idarubicin; idoxifene (idoxifene); iblock Meng Tong (idramantone); tamofosin (ilmofosine); ilomastat (ilomastat); imidazolacridone (imidazoacridones); imiquimod (imiquimod); an immunostimulatory peptide; insulin-like growth factor-1 receptor inhibitors; an interferon agonist; interferons; an interleukin; iodobenzyl guanidine; iododoxorubicin; sweet potato picrol, 4-; i Luo Pula (iroplac); eosgladine (irsogladine); isoguanazole (isobenzazole); different high halichondrin B (isohomohalicondrin B); itasetron; jespplakolide (jasplakinelide); kahalal F (kahalalide F); lamellarin-N (triacetate); lanreotide (lanreotide); leinamycin; leigstim (lenograstim); lentinan sulfate (lentinan sulfate); ritostatin (leptin); letrozole; leukemia inhibitory factor; leukocyte interferon-alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liazole (liarozole); linear polyamine analogs; lipophilic II A glycopeptide; lipophilic platinum compounds; risoxode Lin Xianan (lisroclinamide 7); lobaplatin; earthworm phospholipid (lombricine); lometrexol (lometrexol); lonidamine (lonidamine); losoxantrone (losoxantrone); loxoribine (loxoribine); lurtoltecan (lurtotecan); lutetium de porphyrin (lutetium texaphyrin); lithotheophylline (lysofyline); cleaving the peptide; maytansine (maytansine); mannitol A (mannostatin A); marimastat; maxolol; ma Sifei (maspin); matrix dissolution factor inhibitors; matrix metalloproteinase inhibitors; minoxidil (menogaril); mebarone (merberone); meterelin (metaorelin); methioninase; metoclopramide; MIF inhibitors; mifepristone (mifepriston); miltefosine (miltefosine); midirstim (mirimostim); mismatched double stranded RNA; mitoguazone (mitoguazone); dibromodulcitol; mitomycin analogs; mitonafide (mitonafide); mitoxin fibroblast growth factor-saponin; mitoxantrone (mitoxantrone); mo Faluo (mofarotene); moraxetin (molgramostim); monoclonal antibodies, human chorionic gonadotrophin; monophosphoryl lipid a + myobacterium cell wall sk; mo Pai dar alcohol; a multi-drug resistance gene inhibitor; therapy based on multiple tumor suppressor 1; an anticancer agent of mustard; mecaperol B (mycaperoxide B); mycobacterial cell wall extracts; mesoralen ((myriaporone); N-acetyldinaline); N-substituted benzamide); nafarelin (nafarelin); nagracetin (nagrestip); naltrexone + pentazocine); naproxen (naprovin); nafarelin (napterpin); nattostein (narrograstim); nedaplatin); nemorubicin (nemorubicin); neridrosicin), neridronic acid, neutral endopeptidase (nilutamide); nisamycin (nisamycin); nitric oxide regulator; nitric oxide antioxidant (nifauryl), O6-benzyl guanine; octreotide (octreotide), octone (okenevin); oligonuleotide; onapristone (onapristone); ondansetron (ondansetron); ondansetron (ondanstein); ondansetron (Nedaplatin), and (Neoprene (Neopraplatin); neutramine platinum (Neutramine), oral-platinum (Neutramine), and (Neutramine) oral-acetyl-ne (Neutramine) oxan); pamidronate; panaxatriol; panomifene (panomifene); parabactin (Parabactin); pazelliptine (pazelliptine); pegasporarase (pegasporagase); pidesine (peldesine); sodium pentosan polysulfate; penstatin (penstatin); penconazole (pentazole); perfluorobromoalkane (perfluron); pesphosphamide; perillyl alcohol; benzodiazepines (phenazinomycin); phenylacetate (phenylacetate); a phosphatase inhibitor; sarbanil (picibanil); pilocarpine hydrochloride (pilocarpine hydrochloride); pirarubicin (pirarubicin); pirimicin (piritexim); placetin A; placetin B; a plasminogen activator inhibitor; a platinum complex; a platinum compound; platinum-triamine complexes; sodium bofem; bleomycin; prednisone; propyl bisacridone; prostaglandin J2; a proteasome inhibitor; protein a-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors; microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; a violet pigment; pyrazoloacridine; a pyridyloxylated hemoglobin polyoxyethylene ether conjugate; raf antagonists; raltitrexed (raltitrexed); ramosetron (ramosetron); ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated retiring; rhenium Re 186 hydroxyethylphosphonate; rhizobian (rhizoxin); a ribozyme; RII retinoic acid amide; rosiglitazone; roxitoxine; romide tides; luo Kuimei g; rubiginone B1; ruboxyl; sha Fenge (safingol); saintopin; sarCNU; sarcophyll a; a sauce pavilion; sdi 1 mimetic; semustine; aging derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a signal transduction modulator; a single chain antigen binding protein; dorzolopyran (sizofuran); sobuczoxan (Sobuczoxan); sodium boron calix (sodium borocaptate); sodium phenylacetate; sol verol; growth hormone binding protein; sonermin (sonerm); phosphonic acid (sparfossic acid); spiramycin D (spicamycin D); spiromustine; spleen pentapeptide (splenentin); cavernosum 1; squalamine; stem cell inhibitors; stem cell division inhibitors; stipiamide; matrix lysin inhibitors; sulfofine; superactive vasoactive intestinal peptide antagonists; suradista; suramin; swainsonine; synthesizing glycosaminoglycan; tamoxifen A light source; tamoxifen methyl iodide (tamoxifen methiodide); bezoar temustine (tauroustin); tazarotene (tazarote); tekeglalan sodium (tecogalan sodium); tegafur (tegafur); a telmurapyrylium; telomerase inhibitors; temopofen; temozolomide; teniposide; tetrachlorodecaoxide (tetrachlorethaoxide); tetrazomine; thialipstatin (thialiplastine); thiocoraline (thiocoraline); thrombopoietin (thrombopoetin); thrombopoietin mimetics; thymalfasin (thymalfasin); an agonist of the thymic hormone receptor; thymic treonam (thymofrinan); thyroid stimulating hormone; ethyltin protorhodopsin (tin ethyl etiopurpurin); tirapazamine (tirapazamine); titanocene dichloride (titanocene bichloride); topfacitin; toremifene (toremifene); totipotent stem cell factor; a translation inhibitor; tretinoin; triacetyl uridine; triciribine (triciribine); trimetric sand (trimetrexa); triptorelin (triporelin); tropisetron (tropisetron); tolorosea (urosporide); tyrosine kinase inhibitors; tyrosine phosphorylation inhibitors (tyrphostin); UBC inhibitors; ubenimex (ubenimex); urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreote (vapreote); variolin B; vector system, erythrocyte gene therapy; velaresol (Velaresol); veramine (veramine); verdins; verteporfin (verteporfin); vinorelbine; vinxaltine; vitaxin; vorozole (vorozole); zanoterone (zanoteron); paniplatin (zeniplatin); benzylidene vitamin C (zilasorb); a net span Ding Benma polymer (net span (stinalamer)); doxorubicin; d, actinomycin; bleomycin; vinblastine; cisplatin; acitretin (acivin); aclacinomycin; acodazole hydrochloride (acodazole hydrochloride); alcronine (acronine); aldolizhen; an aclidinium interleukin; altretamine; an Bomei element; amolatanoquinone acetate (ametantrone acetate); amitraz is a compound of amitraz; amsacrine; anastrozole; an aflatoxin; asparaginase; qu Linjun element (asperlin); azacitidine; azatepa (azetepa); azotomycin; bat (bat); benzodepa (benzodepa); bicalutamide (bicalutamide); hydrochloride acid ratio group (bisantrene hydrochloride); dimethyl Bis-naphthalene sulfonate (bisnafide dimesylate); bizelesin; bleomycin sulfate; sodium buchnique (breuinar sodium); bromopirimine (bripirtine); busulfan; actinomycin c; carbosterone (calibretone); carpacemine (caracemide); card Bei Tim (carbetimer); carboplatin; carmustine; cartubicin hydrochloride (carubicin hydrochloride); the card is folded for new use; sidefagol (ceffingol); chlorambucil; cyclic mycin (cirolemycin); cladribine; criranaftoside mesylate (crisnatol mesylate); cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; right omaplatin (dexomaptin); deazaguanning; dezaguanosine mesylate (dezaguanine mesylate); deaquinone (diaziquone); doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; drotaandrosterone propionate (dromostanolone propionate); daptomycin; edatraxate (edatrexate); efluoroornithine hydrochloride (eflornithine hydrochloride); elsamitrucin (elsamitrucin); enluo platinum; enpromate (enpromate); epiridine; epirubicin hydrochloride; erbzol; eosubicin hydrochloride (esorubicin hydrochloride); estramustine (estramustine); estramustine sodium phosphate; itraconazole; etoposide; etoposide phosphate; etoprine (etoprine); a hydrochloric acid process Qu; fazarabine (fazarabine); vitamin c acid amide (fenretinide); fluorouridine; fludarabine phosphate; fluorouracil; flucitabine; a fosquidone (fosquidone); fusi Qu Xingna (fostriecin sodium); gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; emofosine (iimofosine); interferon I1 (including recombinant interleukin II or rlL.sub.2), interferon alpha-2 a; interferon alpha-2 b; interferon alpha-n 1; interferon alpha-n 3; interferon beta-1 a; interferon gamma-1 b; platinum isopropoxide; irinotecan hydrochloride; lanreotide acetate (lanreotide acetate); letrozole; leuprorelin acetate; liazole hydrochloride; lomet Qu Suona (lometrexol sodium); lomustine; losoxanone hydrochloride (losoxantrone hydrochloride); masoprocol (masoprocol); maytansine (maytansine); dichloromethyl diethylamine hydrochloride; megestrol acetate (megestrol acetate); melengestrol acetate (melengestrol acetate) The method comprises the steps of carrying out a first treatment on the surface of the Melphalan; minoxidil (menogaril); mercaptopurine; methotrexate; methotrexate sodium; chlorphenidine (metaprine); meturedepa (Meturedepa); rice Ding Duan (mitingomide); mitocarpacin (mitocarpin); mitomycin; mitogillin (mitogillin); mi Tuoma Star (mitomalcin); mitomycin; mitosper (mitosper); mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; noralamycin (nogalamycin); oxaliplatin (ormaplatin); oxybis Shu Lun (oxasuran); pegasporarase (pegasporagase); a pelimycin; nemustine (pentamustine); pelomycin sulfate (peplomycin sulfate); perindophoramide (perfosfamide); pipobromine; piposulfan (piposulfan); p Luo Antong (piroxantrone hydrochloride) hydrochloride; plicamycin; pralometane (plostane); porphin sodium (porfimer sodium); pofemycin (porfironmycin); prednisomustine (prednimustine); methylbenzyl hydrazine hydrochloride; puromycin (puromycin); puromycin hydrochloride; pyrazofurin (pyrazofurin); liboprine (riboprine); roglymide (rogletimide); sha Fenge; sha Fenge with hydrochloric acid; semustine; xin Quqin (simtrazene); sodium phosphoacetoacetate (sparfosate sodium); sparsomycin (sparsomycin); spiral germanium hydrochloride (spirogermanium hydrochloride); spiromustine (spiromustine); spiroplatinum; streptozotocin (streptozotocin); streptozotocin; sulfochlorphenylurea (sulofenur); talarmycin (tamicomycin); tekeglalan sodium (tecogalan sodium); tegafur; tilonthraquinone hydrochloride (teloxantrone hydrochloride); temopofen; teniposide; ti Luo Xilong (teroxirone); testosterone (testolactone); thioazane; thioguanine; thiotepa; thiazole furin (tiazofurin); tirapazamine (tirapazamine); toremifene citrate; tritolone acetate (trestolone acetate); tricitabine phosphate; trimetha sand; glucuronic acid trimetrase; triptorelin; tobrazizole hydrochloride (tubulozole hydrochloride); uracil mustard (uracilmustard); uredepa (uredepa); vaptan; verteporfin (verteporfin); vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinegar picoline sulfate; vinpocine glycinate sulfate; vincristine sulfate; vinorelbine tartrate; sulfuric acid heterolength Spring alkali (vinrosidine sulfate); vinblastidine sulfate (vinzolidine sulfate); fucloxazole; platinum; clean stastatin (zinostatin); zorubicin hydrochloride (zorubicin hydrochloride), agents that block G2-M phase cells and/or modulate microtubule formation or stability (e.g., paclitaxel. TM (taxol. TM) (i.e., paclitaxel), taxotere. TM (taxotere. TM), compounds comprising a taxane skeleton, ertalozole (i.e., R-55104), dolastatin 10 (Dolastatin 10) (i.e., DLS-10 and NSC-376128), mi Fu brin isethionate (Mivobulin isethionate) (i.e., as CI-980), vincristine, NSC-639829, discodermolide (Discodermolide) (i.e., as NVP-XX-a-296), ABT-751 (Abbott, i.e., E-7010), altorhyrtins (e.g., altohydtin a and altohydtin C), spongoxins (e.g., spongosine 1, spongosine 2, spongosine 3, spongosine 4, spongosine 5, spongosine 6, spongosine 7, spongosine 8, and spongosine 9), cimadodine hydrochloride (Cemadotin hydrochloride) (i.e., LU-103793 and NSC-D-669356), epothilones (e.g., epothilone a, epothilone B, epothilone C (i.e., deoxyepothilone a or diepoa), epothilone D (i.e., KOS-862, diepob, and deoxyepothilone B), epothilone E, epothilone F, epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-amino epothilone B (i.e., BMS-310705), 21-hydroxy epothilone D (i.e., deoxyepothilone F and dEpoF), 26-fluoro epothilone, auristatin (Auristatin), PE (i.e., NSC-654663), shu Bili-t (soblid) (i.e., TZT-1027), LS-4559-P (Pharmacia, i.e., LS-4577), LS-4578 (Pharmacia, i.e., LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, namely WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, namely ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), nostoc 52 (Cryptophyllin 52) (namely LY-355703), AC-7739 (Ajinomoto, namely AVE-8063A and CS-39. HCl), AC-7700 (Ajinomoto, namely AVE-8062, AVE-8062-39-L-Ser. HCl and R-7700) PR-258062A), vitilevuamide, tubulysin A, canadensol, procyanidin (Centaureidin) (i.e., NSC-106969), T-138067 (Tularik (i.e., T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute, i.e., DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), methyl 3, 5-diiodo-4- (4-methoxyphenoxy) benzoate (Oncocidin A1) (i.e., BTO-956 and DIME), DDE-313 (Parker Hughes Institute), fijianilide B, leiomycin (Laulimide), SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, namely spike-P), 3-IAABU (Cytoskeleton/mt. Sinai School of Medicine, namely MF-569), narcotine (Narcosine) (also known as NSC-5366), 2- (1- (4-chlorobenzyl) -1H-indol-3-yl) -2-oxo-N- (pyridin-4-yl) acetamide (Nascapine), D-24851 (Asta medical), a-105972 (Abbott), hamitelin (Hemiasterlin), 3-BAABU (Cytoskeleton/mt. Sinai School of Medicine, namely MF-191), TMPN (Arizona State University), dicyclopentadiene vanadium acetylacetonate (Vanadocene acetylacetonate), T-138026 (Tularik), monsatrol, lnanocine (i.e.NSC-698666), 3-IAABE (Cytoskeleton/Mt.Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, namely T-900607), RPR-115781 (Aventis), soft coral alcohols (such as desmethyl soft coral alcohol (desmethyl soft coral alcohol), desmethyl soft coral alcohol (desethyl soft coral alcohol), iso-soft coral alcohol A, and Z-soft coral alcohol), caribaeoside (Caribaeosin), halichondrin B (Halichondrin B), D-64131 (Asta medical), D-68144 (Asta medical), chlorocyclic peptide A (Diazonamide A), A-293620 (Abbott), NPI-2350 (Nereus), tuber lactone A (Taccalonolide A), TUB-245 (Aventis), A-259754 (Abbott), dioztatin, (-) -phenyl-Western medicine ((-) -Phenylahistin) (i.e.g. NSCL-96F 037), D-68838 (Asta), D-68836 (Asta), myomatriprotein 62, D-7444 (Asta medical), chlorocyclic peptide A (Diazonamide A) (A-293620 (Abbott), NPI-2350 (Nereal), tuber lactone A (Taccalonolide A), TUB-245 (Aventis), A-259754 (Abbot), dioztatin, (-) -phenyl-Western medicine (-) -Phenylalastin) (i.e., BPR-OY-007 (National Health Research Institutes) and SSR-250411 (Sanofi)), steroids (e.g., dexamethasone), finasteride (finasteride), aromatase inhibitors, gonadotrophin releasing hormone agonists (GnRH) such as goserelin (goserelin) or leuprolide, adrenal steroids (e.g., prednisone), progestins (e.g., hydroxygestrel caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoromethylol testosterone), antiandrogens (e.g., flutamide)), immunostimulants (e.g., bacillus Calmette-gumerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD 20, anti-HER 2, anti-CD 52, anti-HLA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD 33 monoclonal antibody-spinosyn conjugates, anti-CD 22 monoclonal antibody-pseudomonas exotoxin, etc.), radioimmunotherapy (e.g., with ¹¹¹ In、 ⁹⁰ Y, or ¹³¹ I conjugated anti-CD 20 monoclonal antibodies, etc.), triptolide (tripeptide), homoharringtonine, actinomycin D, doxorubicin, epirubicin, topotecan, itraconazole (itraconazole), vindesine, cerivastatin (cerivastatin), vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine (clofazimine), 5-hydroxytryptamine (5-nonyloxypyrimide), vitamin Mo Feini (vemurafenib), dabrafenib (dabrafenib), erlotinib (erlotinib), gefitinib), EGFR inhibitors, epidermal Growth Factor Receptor (EGFR) -targeted therapies or treatments (e.g., gefitinib (Iressa) ^TM ) Erlotinib (Tarceva) ^TM ) Cetuximab (Erbitux) ^TM ) Lapattinib (Tykerb) ^TM ) Panitumumab (Vectibix) ^TM ) Vandetanib (vanretanib) (Caprelsa) ^TM ) Afratinib (afatinib)/BIBW 2992, CI-1033/cancritinib (canertinib), lenatinib (necatinib)/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib (dacomitinib)/PF 299804, OSI-420/norerlotinib (desmethyl erlotinib), AZD8931, AEE788, pelitinib (pelitinib)/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035,BMS-599626), sorafenib (sorafenib), imatinib, sunitinib, dasatinib (dasatinib), and the like.

When a polymorph of a compound of formula I is administered to a human subject, the daily dose will typically be determined by the prescribing physician, wherein the dose typically varies according to the age, weight and response of the individual subject and the severity of the subject's symptoms.

In one exemplary application, a suitable amount of at least one polymorph of a compound of formula I is administered to a mammal receiving treatment for cancer (e.g., breast cancer). Administration typically occurs in an amount of about 0.01mg/kg body weight to about 100mg/kg body weight per day (administered in single or divided doses), such as at least about 0.1mg/kg body weight per day. Specific therapeutic doses may include, for example, from about 0.01mg to about 1000mg of a polymorph of a compound of formula I, such as including, for example, from about 1mg to about 1000mg. The amount of at least one polymorph of a compound of formula I in a unit dose formulation can vary or be adjusted from about 0.1mg to 1000mg, such as from about 1mg to 300mg, for example 10mg to 200mg, depending on the particular application. The amount to be administered will depend on the particular IC of at least one polymorph of the compound of formula I used ₅₀ The values and judgment of the attending clinician will vary taking into account factors such as health, weight and age. In combination applications where at least one polymorph of a compound of formula I described herein is not the sole active ingredient, smaller amounts of at least one polymorph of a compound of formula I may be administered and still have a therapeutic or prophylactic effect.

In some embodiments, the pharmaceutical formulation is in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the polymorphs of the compound of formula I, e.g., effective amounts to achieve the desired purpose.

The actual dosage employed may vary depending on the needs of the subject and the severity of the condition being treated. It is within the ability of those skilled in the art to determine an appropriate dosage for a particular situation. Typically, the treatment is started with a smaller dose than the optimal dose for at least one polymorph of the compound of formula I. Thereafter, the dosage is increased by a small amount until the optimal effect is reached in this case. For convenience, the total daily dose may be divided into portions and administered during the course of the day, if desired.

The amount and frequency of administration of at least one polymorph of a compound of formula I and, if applicable, other chemotherapeutic agents and/or radiation therapy will be adjusted according to the discretion of the attending clinician (physician) taking into account such factors as the age, condition and size of the subject and the severity of the disease being treated.

The chemotherapeutic agent and/or radiation therapy may 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 the chemotherapeutic agent and/or radiation therapy may vary depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on the disease. Furthermore, the treatment regimen (e.g., dose and number of administrations) may vary, based on the knowledge of the experienced clinician, depending on the observed effect of the administered therapeutic agent (i.e., anti-tumor agent or radiation) on the subject and on the observed response of the disease to the administered therapeutic agent.

Furthermore, typically, at least one polymorph of a compound of formula I need not be administered in the same pharmaceutical composition as the chemotherapeutic agent, and may be administered by different routes due to different physical and chemical properties. For example, polymorphs/compositions may be administered orally to produce and maintain good blood levels thereof, while chemotherapeutic agents may be administered intravenously. Determining the mode of administration and suitability of administration in the same pharmaceutical composition is well within the knowledge of an experienced clinician, where possible. The initial administration may be performed according to established protocols known in the art, and then, based on the observed effect, the dosage, mode of administration, and number of administrations may be modified by an experienced clinician.

The particular choice of polymorph (and, where appropriate, chemotherapeutic agent and/or radiation) will depend on the diagnosis of the attending physician and his judgment of the subject's condition and appropriate treatment regimen.

One or more polymorphs (and where appropriate, chemotherapeutic agents and/or radiation) of a compound of formula I may be administered concurrently (e.g., simultaneously, substantially simultaneously or in the same treatment regimen) or sequentially, depending on the nature of the proliferative disease, the condition of the subject, and the actual choice of chemotherapeutic agent and/or radiation to be administered in combination with (i.e., in a single treatment regimen) one or more polymorphs/compositions.

In combination applications and uses, the one or more polymorphs/compositions and the chemotherapeutic agent and/or radiation need not be administered simultaneously or substantially simultaneously, and the initial order of administration of the one or more polymorphs/compositions and the chemotherapeutic agent and/or radiation may not be important. Thus, at least one polymorph of a compound of formula I can be administered first, followed by administration of a chemotherapeutic agent and/or radiation; alternatively, the chemotherapeutic agent and/or radiation may be administered first, followed by administration of at least one polymorph of the compound of formula I. This alternating administration may be repeated during a single treatment regimen. After assessing the disease being treated and the pathology of the subject, the determination of the order of administration and the number of repeated administrations of each therapeutic agent during the treatment regimen is well within the knowledge of the skilled physician. For example, the chemotherapeutic agent and/or radiation may be administered first, then the treatment may be continued by administering at least one polymorph of the compound of formula I, if determined to be beneficial, then the chemotherapeutic agent and/or radiation, etc., until the treatment regimen is completed.

Thus, as the treatment proceeds, the practitioner can modify each administration regimen of the polymorph/composition of the compound of formula I for treatment according to the needs of the individual subject, empirically and knowledgeably.

The attending clinician will consider the overall health of the subject, as well as more definite signs, such as alleviation of disease-related symptoms, inhibition of tumor growth, actual reduction of tumor, or inhibition of metastasis, in judging whether the treatment is effective at the administered dose. The size of the tumor can be measured by standard methods (such as radiological studies, e.g., CAT or MRI scans), and continuous measurements can be used to determine whether the growth of the tumor is retarded or even reversed. Alleviation of disease-related symptoms such as pain and improvement of overall condition may also be used to help judge the effectiveness of the treatment.

Route of administration

Suitable routes of administration include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, transmucosal administration, transdermal administration, vaginal administration, otic administration, nasal administration, and topical administration. Further, by way of example only, parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, as well as intrathecal injection, direct intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

In certain embodiments, the polymorph of the compound of formula I is administered in a local rather than systemic manner, e.g., via direct injection of the polymorph into an organ, typically in the form of a depot formulation (depot preparation) or a sustained release formulation. In particular embodiments, the depot formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, e.g., in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In other embodiments, polymorphs of the compound of formula I are provided in the form of quick release formulations, in the form of extended release formulations, or in the form of intermediate release formulations. In other embodiments, polymorphs of a compound of formula I are administered topically.

Kit and article of manufacture

Kits and articles of manufacture are also provided for use in the therapeutic applications described herein. In some embodiments, such kits comprise a carrier, package, or container that is partitioned to hold one or more containers, such as vials, tubes, and the like, each container comprising one of the separate elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container is made of various materials such as glass or plastic.

Articles provided herein include packaging materials. Packaging materials for packaging pharmaceutical products include those found in, for example, U.S. patent nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packages, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, the container includes one or more polymorphs described herein, optionally in a composition or in combination with another agent disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprise a compound with an identifying description or label or instructions associated with its use in the methods described herein.

For example, kits typically include one or more additional containers, each container having one or more of the various materials (such as reagents, optionally in concentrated form, and/or devices) desired from a commercial and user perspective for use of the compounds described herein. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; a carrier, package, container, vial, and/or tube label listing the contents and/or instructions for use, and a package insert with instructions for use. A set of specifications will also typically be included. The label is optionally on or associated with the container. For example, when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, the label is on the container, and when the label is present in a receptacle or carrier that also houses the container, for example as a package insert, the label is associated with the container. In addition, the label is used to indicate that the contents are to be used for a particular therapeutic application. Further, the label indicates instructions for use of the contents, for example in the methods described herein. In certain embodiments, the pharmaceutical compositions are present in a package or dispenser device comprising one or more unit dosage forms containing the compounds provided herein. The package comprises, for example, a metal or plastic foil, such as a blister package. Alternatively, the package or dispenser device is accompanied by instructions for administration. Alternatively, the package or dispenser is accompanied by a notification associated with the container in a format prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals, which notification reflects approval by the agency of the pharmaceutical form for human or veterinary administration. For example, such notification is a label approved by the U.S. food and drug administration for prescription drugs or an approved product insert. In some embodiments, compositions containing polymorphs of a compound of formula I formulated in a compatible pharmaceutical carrier are prepared, placed in a suitable container, and labeled for use in treating a specified condition.

Examples

Example 1: preparation of 2- (1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethylthio) pyrimidine-4, 6-diamine (6)

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 100deg.C in a solvent mixture of DMF (40 mL) and acetone (25 mL) for 8 hours. After cooling to room temperature (rt), the reaction mixture was diluted with aq.HCl (0.1M, 150 mL) and taken up with CH ₂ Cl ₂ (3X 15 mL) extraction. The combined organic layers were removed under reduced pressure and CH was used ₂ Cl ₂ MeOH (40:1) as eluent on silica gel purification of the crude residue. The desired product 1 was obtained as a yellow oil in 85% yield. For C ₁₄ H ₁₈ N ₂ O ₃ HRMS was calculated as 263.1390 and found to be 263.1386.

Step 2: synthesis of 4-methoxy-3- (2-morpholinoethoxy) thiobenzamide (2).

Compound 1 (2.46 g,9.4 mmol) was dissolved inTo pyridine (5 mL,61.8 mmol) was added Et ₃ N (1.44 mL,10.3 mmol) followed by aq. ammonium sulfide (20%, 12mL,35.2 mmol). The reaction mixture was stirred and heated to 60 ℃ overnight. After cooling to room temperature, the solvent was removed under reduced pressure and combined with EtOAc (50 mL) and saturated aq.nh ₄ Cl (200 mL) was mixed. The mixture was extracted with EtOAc (2X 20 mL). The combined organic solvents were removed under reduced pressure and the residue was dried to give the desired product 2 as a yellow solid in 79% yield. For C ₁₄ H ₂₀ N ₂ O ₃ HRMS calculated for S was 297.1267 and found to be 297.1266.

Step 3: synthesis of 1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethan-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 ℃ for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was taken up with CH ₂ Cl ₂ (20 mL) and water (100 mL). The mixture was treated with CH ₂ Cl ₂ (2X 10 mL) and the combined organic solvents were removed under reduced pressure. Without further purification, product 3 was obtained as a brown solid in 76% yield. For C ₁₉ H ₂₄ N ₂ O ₄ HRMS calculated for S was 377.1530 and found to be 377.1526.

Step 4: synthesis of 1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethan-1-ol (4).

3 (1.35 g,3.6 mmol) in CH ₂ Cl ₂ The solution in (40 mL) was cooled to-78deg.C and DIBAL-H (in CH) was slowly added ₂ Cl ₂ 1M,14.3mL,14.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30min. The solution was cooled to 0 ℃ and saturated aq. potassium sodium tartrate (10 mL) was added and the mixture was stirred for 1 hour. By CH ₂ Cl ₂ (3X 10 mL) and the combined organic solvents were removed under reduced pressure. Use in CH ₂ Cl ₂ The crude residue was purified on silica gel with 5-10% meoh. Obtained in 40% yieldPure product 4 was obtained as a yellow oil. For C ₁₉ H ₂₆ N ₂ O ₄ HRMS calculated for S was 379.1686 and found to be 379.1684.

Step 5: synthesis of 1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl 2, 2-trifluoroacetate (5).

Compound 4 (47 mg,0.12 mmol) in CH ₂ Cl ₂ The solution in (5 mL) was cooled to 0deg.C and trifluoroacetic anhydride (70 μL,0.5 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0 ℃ and ice-cold water (20 mL) was added. By CH ₂ Cl ₂ The mixture was extracted (2×5 mL) and the combined organic layers were removed under reduced pressure to give the desired compound 5 in quantitative yield.

Step 6: synthesis of 2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-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) was added potassium carbonate (87 mg,0.63 mmol) followed by 5 (75 mg,0.16 mmol). The solution was stirred and heated to 80 ℃ overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and with CH ₂ Cl ₂ (3X 5 mL) extraction. The organic layers were combined and the solvent was removed under reduced pressure. Use in CH ₂ Cl ₂ The crude residue was purified on silica gel with 5-10% meoh to give the desired final compound 6 in 25% yield. For C ₂₃ H ₃₀ N ₆ O ₃ S ₂ HRMS was calculated as 503.1894 and found to be 503.1876.

Example 2: preparation of (R) -2- ((1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl) thio) pyrimidine-4, 6-diamine (a compound of formula I)

Step 1: synthesis of (S) -1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethanol (7).

To a stirred solution of (R) - (+) -2-methyl-CBS-oxazaborolidine in THF (1.0M solution in toluene) at-78 ℃ was added borane-tetrahydrofuran complex (1.0M solution in THF) followed by a solution of 3 in THF. After the addition of the 3 solution was completed with a syringe pump for 6 hours, the reaction mixture was stirred at-78 ℃ for an additional 20min. Adding H ₂ O and MeOH, and the mixture was allowed to warm to room temperature. After concentration to remove residual solvent, the resulting residue was washed with brine and extracted with ethyl acetate. The organic layer was washed three times with water, over anhydrous Na ₂ SO ₄ Dried and concentrated in vacuo, and the crude residue was purified by flash column chromatography on silica gel to give alcohol 7 as a white solid. For C ₁₉ H ₂₆ N ₂ O ₄ HRMS calculated for S was 379.1686 and found to be 379.1684.

Step 2: synthesis of (S) -1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethyl 2, 2-trifluoroacetate (8).

Will be at CH ₂ Cl ₂ A solution of Compound 7 (47 mg,0.12 mmol) in (5 mL) was cooled to 0deg.C, and trifluoroacetic anhydride (70 μL,0.5 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0 ℃ and ice-cold water (20 mL) was added. By CH ₂ Cl ₂ The mixture was extracted (2×5 mL) and the combined organic layers were removed under reduced pressure to give the desired compound 8 in quantitative yield.

Step 3: synthesis of (R) -2- (1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-4-yl) ethylthio) pyrimidine-4, 6-diamine (9R) and (S) -2- (1- (2- (4-methoxy-3- (2-morpholinoethoxy) phenyl) -5-methylthiazol-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) was added potassium carbonate (87 mg,0.63 mmol) followed by 8 (75 mg,0.16 mmol). The solution was stirred and heated to 80 ℃ overnight. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and with CH ₂ Cl ₂ (3X 5 mL) extraction. The organic layers were combined and the solvent was removed under reduced pressure. Use in CH ₂ Cl ₂ The crude residue was purified on silica gel with 5-10% meoh to give enantiomer pairs 9R and 9S as white solids. The enantiomer was recrystallized from MeOH/acetone solvent system to give 9R in 93% ee. For C ₂₃ H ₃₀ N ₆ O ₃ S ₂ HRMS was calculated as 503.1894 and found to be 503.1876.

Example 3: preparation of polymorph form I of Compound of formula I

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

Example 4: preparation of polymorph form II of a Compound of formula I

Polymorph form I (323.15 g) of a compound of formula I was dissolved in 1:1 DCM/methanol (2.4L) at 45℃with stirring. The reaction mixture was cooled to 5 ℃ over the course of 1 hour and stirred at 5 ℃ for 16 hours. The reaction mixture was diluted with methyl tert-butyl ether (2.4L) over 2 hours, stirred at 5℃for 2 hours, and filtered. The filter cake was washed with methyl tert-butyl ether (700 mL) and dried at 70 ℃ for 47 hours to give polymorph form I (295.41 g,98.4% purity) of the compound of formula I.

Example 5: x-ray powder diffraction (XRPD)

X-ray powder diffraction (XRPD) patterns were obtained on a Rigaku Miniflex. The CuK source (= 1.54056 angstroms) operating at a minimum of 40kV and 15mA scans each sample between 3 degrees and 45 degrees 2-theta. The step size was 0.02 degrees 2- θ and the scan speed was 2.5 degrees per minute.

XRPD patterns obtained for polymorph form I of the compound of formula I are summarized in table 1 and fig. 2.

Table 1.

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XRPD patterns obtained for polymorph form II of the compound of formula I are summarized in table 2 and fig. 5.

Table 2.

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Example 6: thermogravimetric analysis (TGA)

Thermogravimetric analysis was performed on a TA Instruments Q5000 thermogravimetric analyzer. The sample was heated in an aluminum pan from ambient temperature to 250 ℃ at 15 ℃/min with a nitrogen purge of 60mL/min. The TGA thermogram obtained for polymorph form I of the compound of formula I is summarized in figure 3. The TGA thermogram obtained for polymorph form II of the compound of formula I is summarized in figure 6.

Example 7: differential Scanning Calorimetry (DSC)

Differential scanning calorimetry analysis was performed on a TA Instruments Discovery thermogravimetric analyzer. The samples were heated from ambient temperature to 250 ℃ in a sealed aluminum pan at 10 ℃/min. The DSC thermograms obtained for polymorph form I of the compound of formula I are summarized in figure 1. The DSC thermograms obtained for polymorph form II of the compound of formula I are summarized in figure 4.

Example 8: high Performance Liquid Chromatography (HPLC)

High Performance Liquid Chromatography (HPLC) was performed using the following instruments and/or conditions.

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Example 9: stability test of polymorph form II

The results of polymorph form II in the accelerated stability test are shown in table 3.

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 experimental groups and allowed to acclimate for one week before starting the study. On day 0 and day 7, animals were dosed with an emulsion of MOG35-55 and Complete Freund's Adjuvant (CFA) (200. Mu.L/mouse). MOG35-55 (300. Mu.g/mouse) was purchased as a powder and reconstituted with NaCl (0.9%) at an initial concentration of 3 mg/mL. After reconstitution, the MOG35-55 solution was mixed with an equal volume of CFA prepared by reconstitution of Mycobacterium tuberculosis (Mycobacterium Tuberculosis) H37Ra in incomplete Freund's adjuvant at an initial concentration of 5mg/mL to obtain a final concentration of 2.5 mg/mL. Injections were performed under gas (isoflurane) anesthesia in the two lower quadrants of the back (100 μl per side) on day 0 and in the two upper quadrants of the back (100 μl per side) on day 7. Pertussis toxin (PTx, 500 ng/mouse) prepared in phosphate buffered saline (PBS, 100 μl/mouse) was administered to animals by intraperitoneal injection on day 0 (immediately after MOG injection) and on day 2.

The treatment was administered according to the administration regimen shown in table 4.

Preventive treatment was performed twice daily (BID) from day 1 for groups 1, 2 and 4, and therapeutic treatment was performed from day 8 for group 3. All experimental groups were n=12. The administration interval was 12 hours and the administration volume was 5mL/kg.

Since weight loss is known to be an important indicator of EAE corresponding to the onset of initial symptoms, animals were weighed daily from day of immunization (day 0) until the end of the experiment. The changes in body weight observed for the different experimental groups over the course of the experiment are summarized in fig. 7, expressed as mean ± SEM. As expected, significant weight loss was observed in a time-dependent manner in vehicle-treated animals (p<0.001). At the first time MOG administration _35-55 Immediately thereafter, significant weight loss was observed, after which the 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 these two interdependent variables (time x treatment effect) revealed a significant overall effect (p=0.002), indicating that body weight increased in a similar manner over time in all experimental groups.

Next, in order to evaluate the overall effect of pharmacological treatment, an analysis of the area under the curve (AUC) was performed. The area under the curve values of the percentage change in body weight from baseline for the different experimental groups are summarized in fig. 8, expressed as mean ± SEM. AUC analysis confirmed weight loss data and showed no significant differences between the group treated with compound 1 and the vehicle-treated group. Prophylactic treatment with compound 1 showed a small trend of decrease in AUC values, indicating greater weight loss in this group compared to vehicle. However, it fails to reach the significance threshold (p=0.72).

From day 0 until the end of the experiment, animals were scored daily for clinical signs of EAE to include paresis and paralysis affecting the tail and limbs. The following scales were used:

(0) No abnormality, normal animal movement and behavior;

(1) Weak tails, which hang flaccidly when the mouse is held to the base of the tail;

(2) Hind limb partial paralysis, spastic paralysis or paralysis affects one hind limb;

(3) Complete hind limb paralysis, spastic paralysis or paralysis affects both hind limbs;

(4) Paralysis of the forelimbs and hind limbs, spastic paralysis or paralysis affects one or both forelimbs;

(5) Foment is carried out.

The variation in EAE scores observed for the different experimental groups over the course of the experiment is summarized in fig. 9, expressed as mean ± SEM. Analysis of the clinical EAE profile showed that the first clinical symptoms occurred on day 7 post immunization in almost all experimental groups. On day 8, treatment of group 3 with compound 1 was started, and the group was administered with vehicle until that day. The vehicle treated group showed an increasing disease profile over time (p < 0.0001). For the group prophylactically treated with compound 1, a similar course of disease was observed. In contrast, as a positive control, both compound 1 administration and prophylactic dexamethasone administration after the treatment method significantly improved the disease profile (p < 0.0001).

Next, in order to evaluate the overall effect of pharmacological treatment, an analysis of AUC was performed. Area under the curve values of EAE clinical scores for the different experimental groups are summarized in fig. 10, expressed as mean ± SEM. AUC analysis confirmed the observed change in disease profile over time. Therapeutic treatment with compound 1 reduced the calculated AUC, indicating improvement in symptoms. However, although showing a clear trend, a significant threshold is not reached. A trend of decreasing AUC values was also observed in the compound 1 prophylaxis group. Treatment with dexamethasone significantly reduced the profile, thus reducing the calculated AUC indicative of improvement of symptoms (vehicle versus dexamethasone: p < 0.0001).

The overall effect of treatment was analyzed by calculating the average cumulative score obtained for each animal in each experimental group, which added the disease scores from the day of first symptom appearance until day 25, and dividing this value by the number of days the animals showed clinical scores. The cumulative disease scores of the different experimental groups are summarized in fig. 11, expressed as mean ± Standard Error of Mean (SEM). The Kruskal-Wallis test (Kruskal-Wallis statistic: 24.74) reveals an overall significant effect of the treatment, but the Dunn multiple comparison test only determines significant differences (p <0.0001 versus vehicle) in the dexamethasone treated group.

An additional parameter considered for EAE analysis is to draw and analyze "extension data". While the graph shown in fig. 9 includes disease scores for animals that terminate prior to the scheduled end until the day they each terminate (e.g., if animals terminate on day 20, the subsequent time points in the graph will contain fewer animals), the graph shown in fig. 12 shows the disease profile developed by all animals, showing disease scores up to day 25 (e.g., animals that terminate earlier keep their scores on the termination day until day 25). This is a common method of representing EAE disease profiles that can be used to assess population effects.

In a similar situation to that described above for fig. 9, the vehicle treated group showed an increasing disease profile over time (p < 0.0001). For the group prophylactically treated with compound 1, a similar course of disease was observed. In contrast, as a positive control, both compound 1 administration and prophylactic dexamethasone administration following the treatment method significantly improved the disease profile (p < 0.0001).

Next, in order to evaluate the overall effect of drug treatment, AUC analysis was performed on the extended disease score. The area under the curve values of the extended disease scores for the different experimental groups are summarized in fig. 13, expressed as mean ± SEM. AUC analysis confirmed the observed change in disease profile over time. Therapeutic treatment with compound 1 reduced the calculated AUC, indicating improvement in symptoms. However, although showing a clear trend, a significant threshold is not reached. Treatment with dexamethasone significantly reduced the profile, thus reducing the calculated AUC indicative of improvement of symptoms (vehicle versus dexamethasone: p < 0.0001).

Analysis of the incidence in vehicle-treated groups and in groups treated therapeutically and prophylactically with compound 1 was considered as a percentage of asymptomatic animals at any of the analyzed time points, revealing that at any of the analyzed time points, a higher percentage of animals in the group treated with compound 1 showed no disease symptoms than the corresponding vehicle-treated group (fig. 14, upper panel). Furthermore, while the therapeutic treated group never reached 100% incidence (19-92% on day 19), the vehicle treated group reached 100% incidence on day 13. Animals treated therapeutically with compound 1 showed not only significant relief reflected by improvement of symptoms after day 20 (fig. 9 and 12), but-27% of animals showed no symptoms at all, indicating complete relief after day 20 in these animals (fig. 14, upper panel). For the group prophylactically treated with compound 1, no percentage difference was observed for asymptomatic animals (fig. 14, lower panel), even though animals remaining in the group did show improvement in symptoms compared to vehicle treated animals (fig. 9 and 12).

At termination, spleens were removed and weighed. The spleen weights observed for the different experimental groups are summarized in fig. 15 and expressed as mean ± SEM. No difference was observed between spleen sizes recorded for vehicle treated groups and both groups treated with compound 1. Animals treated with dexamethasone showed significantly lower spleen weights than vehicle treated groups.

Analysis of plasma cytokine levels using Luminex showed lower levels of all cytokines measured (IFN- γ, IL-6, IL-10, IL-17a and TNF- α), with most samples reporting values near or below the lower limit of functional quantification (LLOQ) for each cytokine assay (fig. 16-20).

The IFN- γ levels observed for the different experimental groups are summarized in FIG. 16 and expressed as mean+ -SEM. Overall, despite the trend of decreasing from vehicle to dexamethasone, no statistically significant change was observed for IFN- γ (p=0.096), thus reflecting in vivo clinical scoring data. A decrease in IFN- γ was observed for both prophylactic and therapeutic compound 1 treatment, with therapeutic treatment almost matching the dexamethasone group.

The levels of interleukin 6 (IL-6), expressed as mean ± SEM, observed for the different experimental groups are summarized in fig. 17. IL-6 was present at low or below the detection limit in plasma from all samples, and no significant differences were observed between the groups.

The levels of interleukin 10 (IL-10), expressed as mean ± SEM, observed for the different experimental groups are summarized in fig. 18. No significant changes were observed for IL-10.

The levels of interleukin 17a (IL-17 a) observed for the different experimental groups are summarized in fig. 19, expressed as mean ± SEM. IL-17a showed a similar trend to IFN-gamma, with a decrease in the dexamethasone group and a slight decrease in both treatment groups. However, in general, none of these changes achieved significance.

Levels of tumor necrosis factor alpha (TNF-alpha), expressed as mean ± SEM, observed for the different experimental groups are summarized in fig. 20. Prophylactic compound 1 and dexamethasone induced a very slight decrease in TNF- α. However, none of these changes were statistically significant.

In this study, the use of MOG _35-55 7 days after the immunization-induced disease, all animals developed signs of EAE. Compound 1 efficacy was tested in the model by using a prophylactic method (group 2, treatment started on day 1) and a therapeutic method (group 3, treatment started on day 8). Prophylactic treatment with compound 1 did not prevent or improve clinical EAE distribution when the effect was analyzed over time, or when the overall effect was studied using AUC analysis. In contrast, therapeutic administration of compound 1 improved the disease profile statistically significantly at the earlier time points (days 13 and 14) and at the later stages (days 22-25), which is often associated with a more neurodegenerative mechanism. Compound 1 treatment compared to vehicle AUC Therapeutic treatment also showed a trend towards reduced AUC values. As expected, treatment with the positive control dexamethasone reduced EAE scores (days 8-25) as well as clinical profiles statistically significantly compared to vehicle, as assessed by AUC. Based on the validation data of this model and several independent studies showing the efficacy of dexamethasone treatment in EAE, the corticosteroid was used as a positive control. Notably, animals treated with compound 1 in a therapeutic manner showed significant relief of symptoms, and-27% of the animals had a relief of symptoms to zero. Although plasma cytokine levels did not show any significant differences between vehicle and treatment groups, there was a general trend in the treatment groups for the decrease in levels of certain cytokines such as IFN- γ, IL-17a and TNF- α.

Example 11: efficacy of various doses of compound 1 in mice models of Myelin Oligodendrocyte Glycoprotein (MOG) -induced Experimental Autoimmune Encephalomyelitis (EAE)

60 female C57BL/6 mice were housed for a 1 week adaptation period. After random grouping, 53 mice were enrolled in the study, with body weights between 18.3-22.3g at study day 1 reduction, with an average body weight of 19.7g per group.

To induce MOG-EAE, MOG was administered in Phosphate Buffered Saline (PBS) and Complete Freund's Adjuvant (CFA) _35-55 A peptide. MOG in PBS was homogenized via 7mL tube pre-filled with 2.8mm ceramic beads in Omni BeadRuptor Elite ₃₅ The 55 peptide was emulsified in a 1:1 (v: v) mixture with CFA. Briefly, MOG was performed in cold PBS _35-55 The peptide reached 1mg/mL and 1.75mL was aliquoted into each homogenization tube. An equal volume (1.75 mL) of CFA was then added to ice, with a total volume of 3.5mL. Two rounds of homogenization were performed using a speed of 3.5 m/s; 3 cycles of 45 seconds with 30 seconds of dwell at 4 ℃, followed by a third cycle with 2 cycles of 45 seconds and 30 seconds of dwell at 4 ℃. Between each round, the samples were placed on ice for 15 minutes. The tube was centrifuged at 300g for 1 min at 4 ℃. Mice were anesthetized under isoflurane anesthesia. Then 100. Mu.L (50. Mu.g MOG) _35-55 ) Subcutaneous injection into the side of each leg (total two shotsPenetrate and sum 100. Mu.g MOG _35-55 ). On study day 0 and day 2 pertussis toxin was formulated in PBS at a concentration of 2 ng/. Mu.L, and 100. Mu.L (200 ng) pertussis toxin was injected into each animal by intraperitoneal injection.

The treatment was administered according to the administration regimen shown in table 5.

BID was treated starting on day 1 for groups 2, 3 and 4 and once daily (QD) for group 5 starting on day 1. All experimental groups were n=12. The administration interval was 12 hours and the administration volume was 5mL/kg.

All animals were weight-measured daily except for study day 5, 6, 8, 9, 11 and 27, at which time body weight was not falsely recorded in the control group (initial mice). The changes in body weight observed for the different experimental groups over the course of the experiment are summarized in fig. 21, expressed as mean ± SD. The percentage of body weight change from baseline observed for the different experimental groups over the course of the experiment is summarized in fig. 22, expressed as mean ± SD. Group 5 (compound 1, 100mg/kg, once daily) showed significantly less weight loss near the end of the study on days 19-20 of the study, then starting on study day 22 until the end of the study on day 28, as compared to group 2 (vehicle). On study days 2 and 3 (p < 0.05), 17 (p < 0.01), 18 (p < 0.001) and 19-28 (p < 0.0001), group 2 had significantly lower body weight when compared to group 1 (initial animals).

All animals were monitored for physical status scores on study day 0, day 7, day 10 and every other day thereafter. Physical status scoring was performed according to the scale shown in fig. 23. The average physical condition scores observed for the different experimental groups over the course of the experiment are summarized in fig. 24, expressed as mean ± SD. Group 5 showed statistically significant improvement over animals from group 2 on days 22 (p < 0.01), 24 (p < 0.0001), 26 and 28 (p < 0.001). Group 4 showed statistically significant effects compared to group 2 on study days 24 and 26 (p < 0.05) and day 28 (p < 0.01). Group 3 showed a statistically significant decrease in physical status score (< p < 0.01) only on study day 28. Group 2 had significantly lower physical status scores than group 1 on day 22 (p < 0.001) and 24-28 days (p < 0.0001).

Disease severity was scored for all groups on day 0, day 7, and every 2 days from day 10. The following scales were used:

(0) Normal;

(1) Tail loss;

(2) Tail loss, and hindlimb weakness;

(3) The two limbs/single limb are seriously weak and paralyzed;

(4) 2 or more limb paralysis;

(5) Death.

The average disease scores observed for the different experimental groups over the course of the experiment are summarized in fig. 25, expressed as mean ± SD. The average disease score for each group was calculated by averaging the individual disease scores in each group. Disease severity increased in all groups starting from day 14-18. Disease severity was statistically significantly reduced in group 5 receiving 100mg/kg of compound 1 compared to vehicle group from study day 18 to day 28.

Disease incidence was calculated as a percentage of the total number of animals per group starting on day 0 and ending on day 28 of the study. The percentage of disease-free mice observed for the different experimental groups during the course of the experiment is summarized in fig. 26. Group 5 showed lower incidence and later onset of disease. The log rank (Mantel-Cox) test comparing vehicle BID, compound 1 75mg/kg BID, compound 1 25mg/kg BID, and compound 1 100mg/kg QD gave p-values of 0.039, with average onset times of 18 days, 19 days, 18 days, and 20 days, respectively.

Spleen weights were determined for all mice and all groups during necropsy on study day 28. The spleen weights observed for the different experimental groups are summarized in fig. 27 and expressed as mean ± SEM. Group 5 showed significantly higher spleen weights than group 2.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims are intended to define the scope of the invention and their methods and structures and their equivalents are therefore covered thereby.

Claims (121)

1. A composition comprising a crystalline form of a compound of formula I:

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

3. The composition of claim 2, wherein the polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 135 ℃ to about 160 ℃.

4. A composition according to claim 2 or 3, wherein the polymorph form I has a melting point of about 139 ℃.

5. A composition according to claim 2 or 3, wherein the polymorph form I has a melting point of about 148 ℃.

6. The composition of any one of claims 2 to 5, wherein the polymorph form I is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 1.

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

8. The composition of any one of claims 2 to 7, wherein the polymorph form I is characterized by an X-ray powder diffraction pattern comprising peaks at 8.2±0.2° 2- θ, 12.7±0.2° 2- θ, and 16.4±0.2° 2- θ, as usingIs measured by X-ray powder diffraction.

9. The composition of claim 8, wherein the X-ray powder diffraction pattern further comprises at least one peak selected from 16.9 ± 0.2 ° 2-theta, 17.6 ± 0.2 ° 2-theta, and 22.9 ± 0.2 ° 2-theta, as usedIs measured by X-ray powder diffraction.

10. The composition of claim 8 or 9, wherein the X-ray powder diffraction pattern further comprises 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, as usedIs measured by X-ray powder diffraction.

11. The composition of any one of claims 8 to 10, wherein the X-ray powder diffraction pattern comprises a compound selected from 8.2±0.2° 2- θ, 12.7±0.2° 2- θ, 16.4±0.2° 2- θAt least five peaks among 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, as usedIs measured by X-ray powder diffraction.

12. The composition of any one of claims 8 to 11, wherein the X-ray powder diffraction pattern comprises 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, as usedIs measured by X-ray powder diffraction.

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

14. The composition of any one of claims 2 to 13, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of about 1% to about 5% over a temperature range of about 25 ℃ to about 125 ℃.

15. The composition of any one of claims 2 to 14, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of less than about 4% over a temperature range of about 25 ℃ to about 125 ℃.

16. The composition of any one of claims 2 to 15, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of less than about 2% over a temperature range of about 25 ℃ to about 125 ℃.

17. The composition of any one of claims 2 to 14, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of about 4% over a temperature range of about 25 ℃ to about 125 ℃.

18. The composition of any one of claims 2 to 17, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of about 5% to about 15% over a temperature range of about 125 ℃ to about 200 ℃.

19. The composition of any one of claims 2 to 18, wherein the polymorph form I is characterized by a thermogram comprising a mass loss of about 10.3% over a temperature range of about 125 ℃ to about 200 ℃.

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

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

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

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

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

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

26. The composition of claim 25, wherein the polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram comprising an endotherm in the range of about 150 ℃ to about 170 ℃.

27. The composition of claim 25 or 26, wherein the Differential Scanning Calorimetry (DSC) thermogram further comprises an endotherm in the range of about 25 ℃ to about 60 ℃.

28. The composition of any one of claims 25 to 27, wherein the polymorph form II has a melting point in the range of about 150 ℃ to about 155 ℃.

29. The composition of any one of claims 25 to 28, wherein the polymorph form II is characterized by a Differential Scanning Calorimetry (DSC) thermogram substantially as shown in figure 4.

30. The composition of any one of claims 25-29, wherein the polymorph form II comprises small needle-like particles.

31. The composition of claim 30, wherein the needle has a size in the range of about 1 μιη to about 50 μιη.

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

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

34. The composition of claim 33, wherein the X-ray powder diffraction pattern further comprises 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, as usedIs measured by X-ray powder diffraction.

35. The composition of claim 33 or 34, wherein the X-ray powder diffraction pattern further comprises 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, as usedIs measured by X-ray powder diffraction.

36. The composition of any one of claims 33 to 35, wherein the X-ray powder diffraction pattern comprises 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, as usedIs measured by X-ray powder diffraction.

37. The composition of any one of claims 33 to 36, wherein the X-ray powder diffraction pattern comprises 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 Peaks at 4.+ -. 0.2 DEG 2- θ, e.g. usingIs measured by X-ray powder diffraction.

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

39. The composition of any one of claims 25-38, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 1% to about 5% over a temperature range of about 25 ℃ to about 80 ℃.

40. The composition of any one of claims 25-39, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 2.0% to about 2.5% over a temperature range of about 25 ℃ to about 80 ℃.

41. The composition of any one of claims 25 to 40, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 1.8% over a temperature range of about 25 ℃ to about 80 ℃.

42. The composition of any one of claims 25-39, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 2.9% over a temperature range of about 25 ℃ to about 70 ℃.

43. The composition of any one of claims 25 to 42, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 0% to about 1% over a temperature range of about 70 ℃ to about 130 ℃.

44. The composition of any one of claims 25 to 43, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 0.5% over a temperature range of about 70 ℃ to about 130 ℃.

45. The composition of any one of claims 25 to 44, wherein the polymorph form II is characterized by a thermogram comprising a mass loss of about 0.5% over a temperature range of about 80 ℃ to about 130 ℃.

46. The composition of any one of claims 25-45, wherein the polymorph form II comprises less than 5% water.

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

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

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

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

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

52. The composition of any one of claims 1 to 51, wherein the composition comprises less than about 2% by weight of impurities.

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

54. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 52 or the pharmaceutical composition of claim 53.

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

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

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

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

59. A process for preparing a first crystalline form of the maleate salt of a compound of formula I:

wherein the method comprises:

(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;

(iv) The solution was filtered and the resulting solid was dried at a fourth temperature.

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

61. The method of claim 59 or 60, wherein the first crystalline form is polymorph form I.

62. The process of 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 ℃.

63. The process of any one of claims 59 to 62, wherein the second solvent is EtOAc and the second temperature is about 20 ℃ to about 25 ℃.

64. The method of any one of claims 59-63, wherein the third temperature is about-5 ℃ to about 5 ℃.

65. The method of any one of claims 59 to 64, wherein the fourth temperature is about 50 ℃ to about 55 ℃.

66. A process for preparing a second crystalline form of the maleate salt of the compound of formula I:

wherein the process comprises drying the first crystalline form of the maleate salt of the compound of formula I at a temperature of about 70 ℃.

67. The method of claim 66, wherein the second crystalline form is polymorph form II.

68. The method of claim 66 or 67, wherein said first crystalline form is polymorph form I.

69. A process for preparing a second crystalline form of a maleate salt of a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein the method comprises slurrying the first crystalline form of the maleate salt of the compound of formula I or the mixture of crystalline forms of the maleate salt of the compound of formula I in water.

70. The method of claim 69, wherein the second crystalline form is polymorph form II.

71. The method of claim 69 or 70, wherein the first crystalline form is polymorph form I.

72. A method of treating Acute Disseminated Encephalomyelitis (ADEM) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

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

74. The method of claim 72, wherein the compound of formula I is administered twice daily.

75. The method of claim 74, wherein the administration of the compound of formula I is performed twelve hours apart.

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

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

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

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

80. The method of claim 77, wherein said unit dosage form comprises about 100mg/kg of said compound of formula I.

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

82. The method of claim 77, wherein said unit dosage form comprises about 320mg/kg of said compound of formula I.

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

84. The method of claim 83, wherein the total amount of the compound of formula I administered daily is about 50mg/kg.

85. The method of claim 83, wherein the total amount of the compound of formula I administered daily is about 100mg/kg.

86. The method of claim 83, wherein the total amount of the compound of formula I administered daily is about 150mg/kg.

87. The method of claim 83, wherein the total amount of the compound of formula I administered daily is about 320mg/kg.

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

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

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

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

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

93. The method of claim 92, wherein the solution comprises about 5mg/mL of the compound of formula I.

94. The method of claim 92, wherein the solution comprises about 15mg/mL of the compound of formula I.

95. The method of claim 92, wherein the solution comprises about 20mg/mL of the compound of formula I.

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

97. A method of treating an autoimmune disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount 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 of claim 97, wherein the disease or disorder is multiple sclerosis.

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

100. The method of claim 97, wherein the disease or disorder is Acute Disseminated Encephalomyelitis (ADEM).

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

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

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

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

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

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

107. The method of claim 102, wherein the unit dosage form comprises about 320mg/kg of the compound of formula I.

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

109. The method of claim 108, wherein the total amount of the compound of formula I administered daily is about 50mg/kg.

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

111. The method of claim 108, wherein the total amount of the compound of formula I administered daily is about 150mg/kg.

112. The method of claim 108, wherein the total amount of the compound of formula I administered daily is about 320mg/kg.

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

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

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

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

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

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

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

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

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