Polymorphic compounds and their uses

Abstract

To provide polymorphic compounds and uses thereof.SOLUTION: The present invention relates to compounds and methods useful for selectively modulating mTORC1 activity. The present invention relates to compounds and methods useful for activating mTORC1. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using the compositions in the treatment of various disorders. The present invention provides a method of eliciting a positive behavioral response in a subject, comprising the step of administering to the subject a provided compound or pharmaceutically acceptable composition thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds and methods useful for modulating mTORC1 activity. The present invention relates to compounds and methods useful for selectively modulating mTORC1 activity. The present invention relates to compounds and methods useful for activating mTORC1. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods for using said compositions in the treatment of various disorders. [Background technology]

[0002] Background of the Invention The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that senses a variety of environmental cues, including growth factors, cellular stress, and nutrient and energy levels. When activated, mTORC1 phosphorylates substrates that activate anabolic processes such as mRNA translation and lipid synthesis, and restricts catabolic processes such as autophagy. Dysregulation of mTORC1 occurs in a wide range of diseases, including diabetes, epilepsy, neurodegeneration, immune responses, suppression of skeletal muscle growth, and cancer (Howell et al., (2013) Biochemical Society Transactions, Vol. 41, pp. 906-912; Kim et al., (2013) Molecules and Cells, Vol. 35, pp. 463-473; Laplante and Sabatini, (2012) Cell, Vol. 149, pp. 274-293). There is an urgent and critical medical need for more effective treatment of diseases, disorders, or conditions associated with mTORC1. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Howell et al., (2013) Biochemical Society Transactions, Vol. 41, pp. 906-912. [Non-Patent Document 2] Kim et al., (2013) Molecules and Cells, Vol. 35, pp. 463-473. [Non-Patent Document 3] Laplante and Sabatini, (2012) Cell, Vol. 149, pp. 274-293. [Overview of the Initiative] [Means for solving the problem]

[0004] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, have now been found to be effective as mTORC1 modulators. Such compounds have the following chemical structure, represented as compound A: [ka] It is represented by [this].

[0005] The compounds of the present invention and their pharmaceutically acceptable compositions are useful for treating a variety of diseases, disorders, or conditions, including those described herein. These compounds and their pharmaceutically acceptable compositions are useful for treating a variety of diseases, disorders, or conditions related to mTORC1. Such diseases, disorders, or conditions include diabetes, epilepsy, neurodegeneration, immune responses, inhibition of skeletal muscle growth, and cell proliferation disorders (e.g., cancer), including those described herein. [Brief explanation of the drawing]

[0006] [Figure 1] Figure 1 shows the XRPD pattern of compound A in form A.

[0007] [Figure 2] Figure 2 shows the TGA trace of compound A in form A.

[0008] [Figure 3] Figure 3 shows the DSC trace of compound A in form A.

[0009] [Figure 4] Figure 4 is a diagram of the XRPD pattern of Form B of Compound A.

[0010] [Figure 5] Figure 5 is a diagram of the TGA trace of Form B of Compound A.

[0011] [Figure 6] Figure 6 is a diagram of the DSC trace of Form B of Compound A.

[0012] [Figure 7] Figure 7 is a diagram of the XRPD pattern of Form C of Compound A.

[0013] [Figure 8] Figure 8 is a diagram of the TGA trace of Form C of Compound A.

[0014] [Figure 9] Figure 9 is a diagram of the DSC trace of Form C of Compound A.

[0015] [Figure 10] Figure 10 is a diagram of the unit cell of Form A of Compound 1.

[0016] [Figure 11] Figure 11 is a diagram of the modeled XRPD pattern of Form A of Compound 1. [Modes for Carrying Out the Invention]

[0017] General Description of Certain Specific Embodiments of the Present Invention U.S. Patent Application No. 10,100,066 ("Patent No. 066"), filed on 21 October 2016 as U.S. Patent Application No. 15 / 331,362 and published as U.S. Patent Publication No. 2017 / 0114080 ("Patent No. 080"), each of which is incorporated herein by reference in its entirety, describes a particular mTORC1 modulo compound. Such a compound is Compound A: [ka] Includes.

[0018] Compound A, ((S)-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid), is represented as Compound I-90 in Patent No. 066, and the synthesis of Compound A is described in detail in Example 90 of Patent No. 066.

[0019] It is desirable to provide a solid form of compound A (for example, as its free base or hydrate) that offers improved water solubility, stability, and ease of formulation. Therefore, the present invention provides compound A in both free base and hydrate forms. Free base form of compound A

[0020] Compound A is intended to exist in various physical forms. For example, compound A can exist in solution, suspension, or solid form. In certain embodiments, compound A is in solid form. When compound A is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0021] In some embodiments, the present invention provides a form of compound A that is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the compound is free of significant amounts of foreign substances. Such foreign substances may include different forms of compound A, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound A. In certain embodiments, the form of compound A is present in at least about 95% by weight. In yet another embodiment of the present invention, the form of compound A is present in at least about 99% by weight.

[0022] According to one embodiment, the form of compound A is present in amounts of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, and 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, the form of compound A contains total organic impurities of about 3.0 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram, and in a particular embodiment, it contains total organic impurities of about 1.5 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram. In other embodiments, the form of compound A contains any single impurity of about 1.0 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram, and any single impurity of about 0.6 area percent HPLC or less, and in a particular embodiment, any single impurity of about 0.5 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram.

[0023] The illustrated structures of compound A are also intended to include all tautomers of compound A. Furthermore, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding those where carbon is replaced by carbon-rich carbon, fall within the scope of the present invention.

[0024] Compound A has been found to exist in various solid forms. Exemplary such forms include polymorphisms, such as those described herein.

[0025] As used herein, the term "polymorph" refers to a different crystalline structure in which a compound, or a salt or solvate thereof, may crystallize.

[0026] In certain embodiments, compound A is a crystalline solid. In other embodiments, compound A is a crystalline solid substantially free of amorphous compound A. As used herein, the term "substantially free of amorphous compound A" means that the compound does not contain a significant amount of amorphous compound A. In certain embodiments, crystalline compound A is present in an amount of at least about 95% by weight. In yet another embodiment of the present invention, crystalline compound A is present in an amount of at least about 99% by weight.

[0027] It has been found that compound A can exist in at least three distinct polymorphs. In certain embodiments, the present invention provides a polymorph of compound A referred to herein as form A. In certain embodiments, the present invention provides a polymorph of compound A referred to herein as form B. In certain embodiments, the present invention provides a polymorph of compound A referred to herein as form C.

[0028] In some embodiments, compound A is amorphous. In some embodiments, compound A is amorphous and substantially does not contain crystalline compound A. Form A of compound A

[0029] In some embodiments, form A of compound A has at least one, two, three, four, or five spectral peaks selected from the peaks listed in Table 1 below. [Table 1-1] [Table 1-2]

[0030] In some embodiments, form A of compound A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ. In some embodiments, form A of compound A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ. In some embodiments, form A of compound A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ. As used herein, the term “approximately” means that when used in reference to the degree value of 2θ, 2θ is within ±0.2 degrees of the stated value.

[0031] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD shown in Figure 1.

[0032] The method for preparing form A of compound A is described below. Form B of compound A

[0033] In some embodiments, form B of compound A has at least one, two, three, four, or five spectral peaks selected from the peaks listed in Table 2 below. [Table 2-1] [Table 2-2]

[0034] In some embodiments, form B of compound A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 5.0, approximately 15.2, and approximately 17.5 degrees 2θ. In some embodiments, form B of compound A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 5.0, approximately 15.2, and approximately 17.5 degrees 2θ. In some embodiments, form B of compound A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at approximately 5.0, approximately 15.2, and approximately 17.5 degrees 2θ.

[0035] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD shown in Figure 4.

[0036] A method for preparing form B of compound A is described below. Form C of compound A

[0037] In some embodiments, form C of compound A has at least one, two, three, four, or five spectral peaks selected from the peaks listed in Table 3 below. [Table 3-1] [Table 3-2]

[0038] In some embodiments, form C of compound A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ. In some embodiments, form C of compound A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ. In some embodiments, form C of compound A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ.

[0039] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD shown in Figure 7.

[0040] A method for preparing form C of compound A is described below.

[0041] In some embodiments, the present invention relates to compound A: [ka] The present invention provides compound A, wherein the compound is crystalline.

[0042] In some embodiments, the present invention provides compound A, wherein the compound substantially does not contain amorphous compound A.

[0043] In some embodiments, the present invention provides compound A, wherein the compound is substantially free of impurities.

[0044] In some embodiments, the present invention provides compound A, wherein in its XRPD, it has one or more peaks selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ. In some such embodiments, the present invention provides compound 1, wherein in its XRPD, it has at least two peaks selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ. In some such embodiments, the present invention provides compound A, which is compound A in form A.

[0045] In some embodiments, the present invention provides compound A having an XRPD substantially similar to that shown in Figure 1.

[0046] In some embodiments, the present invention provides compound A having one or more peaks in its XRPD selected from peaks at about 5.0, about 15.2, and about 17.5 degrees 2θ. In some such embodiments, the present invention provides compound A having at least two peaks in its XRPD selected from peaks at about 5.0, about 15.2, and about 17.5 degrees 2θ. In some such embodiments, the present invention provides compound A, which is compound A in form B.

[0047] In some embodiments, the present invention provides compound A having an XRPD substantially similar to that shown in Figure 4.

[0048] In some embodiments, the present invention provides compound A having one or more peaks in its XRPD selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ. In some such embodiments, the present invention provides compound A having at least two peaks in its XRPD selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ. In some such embodiments, the present invention provides compound A which is form C.

[0049] In some embodiments, the present invention provides compound A having an XRPD substantially similar to that shown in Figure 7.

[0050] In some embodiments, the present invention provides a composition comprising compound A and a pharmaceutically acceptable carrier or excipient.

[0051] In some embodiments, the present invention provides: a compound selected from: form A of compound A; form B of compound A; and form C of compound A.

[0052] In some embodiments, the present invention provides a method for modulating mTORC1 activity in a patient, comprising the step of administering compound A or a composition thereof to the patient. In some embodiments, the present invention provides a method for selectively modulating mTORC1 activity in a patient, comprising the step of administering compound A or a composition thereof to the patient. In some embodiments, the present invention provides a method for activating mTORC1 in a patient, comprising the step of administering compound A or a composition thereof to the patient.

[0053] In some embodiments, the present invention provides a method for treating a disease, disorder, or condition selected from treatment-resistant depression, lysosomal storage disorder, JNCL, cystinosis, Fabry disease, MLIV, intellectual disability, or autism, comprising the step of administering compound A or a composition thereof to a patient.

[0054] In some embodiments, the present invention provides a method for preparing a solid form of compound A, comprising one or more steps consisting of solvent removal and solvent addition. In some embodiments, the solvent added is the same as the solvent removed. In some embodiments, the solvent added is different from the solvent removed. Means for solvent removal are known in synthetic and chemical arts and include, but are not limited to, any of the techniques described herein and in the examples.

[0055] In some embodiments, a method for preparing the solid form of compound A includes one or more steps, comprising heating or cooling the preparation.

[0056] In some embodiments, a method for preparing the solid form of compound A includes one or more steps, which consist of stirring or agitating the preparation.

[0057] In some embodiments, a method for preparing the solid form of compound A includes the step of adding a suitable acid to a solution or slurry of compound A.

[0058] In some embodiments, the method for preparing the solid form of compound A includes a heating step.

[0059] In one particular embodiment, the solid form of compound A precipitates from the mixture. In another embodiment, the solid form of compound A crystallizes from the mixture. In yet another embodiment, the solid form of compound A crystallizes from the solution after a seed crystal is added to the solution (i.e., a crystal of compound A is added to the solution).

[0060] The solid form of compound A can be precipitated from the reaction mixture, or produced by removing some or all of the solvent by methods such as solvent evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an antisolvent such as heptane, by cooling, or by various combinations of these methods.

[0061] As generally described above, the solid form of compound A is isolated as needed. Those skilled in the art will understand that the solid form of compound A can be isolated by any suitable physical means known to them. In certain embodiments, the precipitated solid form of compound A is separated from the supernatant by filtration. In other embodiments, the precipitated solid form of compound A is separated from the supernatant by decantation of the supernatant.

[0062] In a particular embodiment, the solid form of compound A is separated from the supernatant by filtration.

[0063] In one particular embodiment, the isolated solid form of compound A is dried in air. In other embodiments, the isolated solid form of compound A is dried under reduced pressure and, if necessary, at a high temperature.

[0064] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0065] In certain embodiments, preferred solvents are methanol, ethanol, isopropanol, or acetone, which are either anhydrous or combined with water or heptane. In some embodiments, preferred solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, a preferred solvent is ethanol. In some embodiments, a preferred solvent is anhydrous ethanol. In some embodiments, a preferred solvent is MTBE.

[0066] In some embodiments, a preferred solvent is ethyl acetate. In some embodiments, a preferred solvent is a mixture of methanol and methylene chloride. In some embodiments, a preferred solvent is a mixture of acetonitrile and water. In certain embodiments, a preferred solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, a preferred solvent is diethyl ether. In certain embodiments, a preferred solvent is water. In certain embodiments, a preferred solvent is methyl ethyl ketone. In certain embodiments, a preferred solvent is toluene. Hydrate form of compound A

[0067] In some embodiments, water and compound A bond ionically or hydrogenally to form compound 1, described below. Compound 1 is intended to exist in various physical forms. For example, compound 1 may exist in solution, suspension, or solid form. In certain embodiments, compound 1 is in solid form. When compound 1 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of compound 1 are described in more detail below. Compound 1 (hydrate of compound A)

[0068] According to one embodiment, the present invention relates to a hydrate of compound A, represented by compound 1: [ka] (wherein 0<x≦about 1) is provided.

[0069] It will be understood by those skilled in the art that water and Compound A form Compound 1 through ionic bonding or hydrogen bonding. It is contemplated that Compound 1 can exist in various physical forms. For example, Compound 1 can exist in a solution, a suspension, or a solid form. In certain embodiments, Compound 1 is in a solid form. When Compound 1 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in further detail below.

[0070] In some embodiments, the present invention provides Compound 1 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign substances. Such foreign substances may include excess 1,2-ethanedisulfonic acid, excess Compound A, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, Compound 1 is present in an amount of at least about 95% by weight. In still other embodiments of the present invention, Compound 1 is present in an amount of at least about 99% by weight.

[0071] According to one embodiment, compound 1 is present in amounts of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, and 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, compound 1 contains total organic impurities of about 3.0 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram, and in a particular embodiment, it contains total organic impurities of about 1.5 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram. In yet another embodiment, compound 1 contains any single impurity of about 1.0 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram, any single impurity of about 0.6 area percent HPLC or less, and in a particular embodiment, any single impurity of about 0.5 area percent HPLC or less relative to the total area of ​​the HPLC chromatogram.

[0072] The illustrated structure of compound 1 is also intended to include all tautomers of compound 1. Furthermore, the illustrated structures herein are intended to include compounds that differ only in the presence of one or more isotope-rich atoms, for example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding those where carbon is replaced by carbon-rich carbon, fall within the scope of the present invention.

[0073] Compound 1 has been found to exist in a variety of solid forms. Exemplary such forms include polymorphisms such as those described herein. In some embodiments, compound A and water are in a ratio of about 1:1. In some embodiments, water and compound A are in a ratio of about 1:2. In some embodiments, water and compound A are in a ratio of about 3:4. In some embodiments, water and compound A are in a ratio of about 1:4. In some embodiments, water and compound A are in a ratio of about 2:3. In some embodiments, water and compound A are in a ratio of about 1:3. In some embodiments, x is about 1 / 4 of compound 1. In some embodiments, x is about 1 / 2 of compound 1. In some embodiments, x is about 3 / 4 of compound 1. In some embodiments, x is about 2 / 3 of compound 1. In some embodiments, x is about 1 / 3 of compound 1. In some embodiments, x is about 1 / 1 of compound 1.

[0074] In certain embodiments, compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound does not contain a significant amount of amorphous compound 1. In certain embodiments, crystalline compound 1 is present in an amount of at least about 95% by weight. In yet another embodiment of the present invention, crystalline compound 1 is present in an amount of at least about 99% by weight.

[0075] It has been found that compound 1 can exist in at least one distinguishable polymorph. In some embodiments, the present invention provides a polymorph of compound 1 referred to herein as form A. In certain embodiments, form A of compound 1 comprises water and compound A in a ratio of about 3:4. In certain embodiments, x is about 3 / 4 of form A of compound 1.

[0076] In some embodiments, compound 1 is amorphous. In some embodiments, compound 1 is amorphous and substantially does not contain crystalline compound 1. Form A of Compound 1

[0077] In some embodiments, Form A of Compound 1 has at least 1, 2, 3, 4 or 5 spectral peaks selected from the peaks listed in Table 4 below.

Table 4-1

Table 4-2

[0078] In some embodiments, Form A of Compound 1 is characterized by having one or more peaks selected from the peaks at about 17.1, about 17.3 and about 18.3 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 1 is characterized by having two or more peaks selected from the peaks at about 17.1, about 17.3 and about 18.3 degrees 2θ in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 1 is characterized by having all three peaks selected from the peaks at about 17.1, about 17.3 and about 18.3 degrees 2θ in its X-ray powder diffraction pattern.

[0079] In certain specific embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD presented in Figure 11. In certain specific embodiments, Form A of Compound 1 comprises water and Compound A in a ratio of about 3:4. In certain specific embodiments, x is about 3 / 4 with respect to Form A of Compound 1.

[0080] Methods for preparing Form A of Compound 1 are described below.

[0081] In some embodiments, the present invention provides Compound 1:

Chemical Formula

[0082] In some embodiments, the present invention provides compound 1, which is crystalline.

[0083] In some embodiments, the present invention provides compound 1, which is a crystalline solid substantially free of amorphous compound 1.

[0084] In some embodiments, the present invention provides a compound 1 which is substantially free of impurities.

[0085] In some embodiments, the present invention provides compound 1 having one or more peaks in its XRPD selected from peaks at approximately 17.1, approximately 17.3, and approximately 18.3 degrees 2θ. In some such embodiments, the present invention provides compound 1 having at least two peaks in its XRPD selected from peaks at approximately 17.1, approximately 17.3, and approximately 18.3 degrees 2θ. In some such embodiments, the present invention provides compound 1, which is compound 1 in form A.

[0086] In some embodiments, the present invention provides compound 1 having an XRPD substantially similar to that shown in Figure 11.

[0087] In some embodiments, the present invention provides a composition comprising compound 1 and a pharmaceutically acceptable carrier or excipient.

[0088] In some embodiments, the present invention provides compounds selected from form A of compound 1.

[0089] In some embodiments, the present invention provides a method for modulating mTORC1 activity in a patient, comprising the step of administering compound 1 or a composition thereof to the patient. In some embodiments, the present invention provides a method for selectively modulating mTORC1 activity in a patient, comprising the step of administering compound 1 or a composition thereof to the patient. In some embodiments, the present invention provides a method for activating mTORC1 in a patient, comprising the step of administering compound 1 or a composition thereof to the patient.

[0090] In some embodiments, the present invention provides a method for treating a disease, disorder, or condition selected from treatment-resistant depression, lysosomal storage disorder, JNCL, cystinosis, Fabry disease, MLIV, intellectual disability, or autism, comprising the step of administering compound 1 or a composition thereof to a patient.

[0091] In some embodiments, the present invention provides a method for preparing a solid form of compound 1, comprising one or more steps consisting of solvent removal and solvent addition. In some embodiments, the solvent added is the same as the solvent removed. In some embodiments, the solvent added is different from the solvent removed. Means for solvent removal are known in synthetic and chemical arts and include, but are not limited to, any of the techniques described herein and in the examples.

[0092] In some embodiments, a method for preparing the solid form of compound 1 includes one or more steps, comprising heating or cooling the preparation.

[0093] In some embodiments, a method for preparing the solid form of compound 1 includes one or more steps, comprising stirring or agitating the preparation.

[0094] In some embodiments, a method for preparing the solid form of compound 1 includes the step of adding a suitable acid to a solution or slurry of compound 1.

[0095] In some embodiments, the method for preparing the solid form of compound 1 includes a heating step.

[0096] In one particular embodiment, the solid form of compound 1 precipitates from the mixture. In another embodiment, the solid form of compound 1 crystallizes from the mixture. In yet another embodiment, the solid form of compound 1 crystallizes from the solution after a seed crystal is added to the solution (i.e., a crystal of compound 1 is added to the solution).

[0097] The solid form of compound 1 can be precipitated from the reaction mixture, or produced by removing some or all of the solvent by methods such as solvent evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an antisolvent such as heptane, by cooling, or by various combinations of these methods.

[0098] As generally described above, the solid form of compound 1 is isolated as needed. It will be understood that the solid form of compound 1 can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid form of compound 1 is separated from the supernatant by filtration. In other embodiments, the precipitated solid form of compound 1 is separated from the supernatant by decantation of the supernatant.

[0099] In a particular embodiment, the solid form of compound 1 is separated from the supernatant by filtration.

[0100] In one particular embodiment, the isolated solid form of compound 1 is dried in air. In other embodiments, the isolated solid form of compound 1 is dried under reduced pressure and, if necessary, at a high temperature.

[0101] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0102] In certain embodiments, preferred solvents are methanol, ethanol, isopropanol, or acetone, which are either anhydrous or combined with water or heptane. In some embodiments, preferred solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, a preferred solvent is ethanol. In some embodiments, a preferred solvent is anhydrous ethanol. In some embodiments, a preferred solvent is MTBE.

[0103] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, a suitable solvent is a mixture of acetonitrile and water. In certain embodiments, a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, a suitable solvent is diethyl ether. In certain embodiments, a suitable solvent is water. In certain embodiments, a suitable solvent is methyl ethyl ketone. In certain embodiments, a suitable solvent is toluene. Pharmaceutically acceptable compositions

[0104] According to another embodiment, the present invention provides compositions comprising the compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is effective in modulating mTORC1 activity to a measurable degree in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is effective in measurably activating mTORC1 in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0105] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0106] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound formulated together with it. pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0107] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally, or via implantable reservoir. The term "parenterally," as used herein, includes injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, synovial, intrasternal, intrastellar, intrahepatic, intrafocal, and intracranial regions. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The injectable sterile forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated in accordance with techniques known in the art using suitable dispersants or wetting and suspending agents. The injectable sterile preparations may also be injectable sterile solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterilization non-volatile oils can be conveniently used as solvents or suspension media.

[0108] For this purpose, any non-irritating, non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and in particular, naturally pharmaceutically acceptable oils such as olive oil or castor oil, in their polyoxyethylated versions, are also useful. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants such as carboxymethylcellulose, or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tween, Span, and other emulsifiers, or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms may also be used for formulation.

[0109] The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets intended for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. With regard to oral administration in capsule form, useful diluents include lactose and dried corn starch. Where aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Certain sweeteners, flavorings, or colorings may also be added, if desired.

[0110] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus dissolves in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0111] The pharmaceutically acceptable compositions of the present invention may also be administered topically, in particular, when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Suitable topical formulations for each of these areas or organs are readily prepared.

[0112] Local administration to the lower intestinal tract can be done with rectal suppositories (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0113] With regard to topical administration, the pharmaceutically acceptable compositions provided may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0114] With regard to ophthalmic use, the pharmaceutically acceptable composition provided may be formulated as a micronizing suspension in pH-adjusted isotonic sterile saline, or as a solution in pH-adjusted isotonic sterile saline, preferably with or without a preservative such as benzylalkonium chloride. Alternatively, with regard to ophthalmic use, the pharmaceutically acceptable composition may be formulated in an ointment such as petrolatum.

[0115] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulations and may be prepared as solutions in saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers that enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0116] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0117] The amount of the compound of the present invention, which may be combined with a carrier material to produce a single-dose composition, varies depending on the host being treated and the specific form of administration. Preferably, the compositions provided should be formulated so that a dose in which the inhibitor is between 0.01 and 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0118] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, elimination rate, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition. Use of compounds and pharmaceutically acceptable compositions

[0119] The compounds and compositions described herein are generally useful for modulating mTORC1 activity. In some embodiments, the provided compounds or compositions are mTORC1 activators.

[0120] As used herein, the terms “treatment,” “to treat,” and “to treat” mean, as described herein, reversal, alleviation, delay, or inhibition of the progression of a disease or disorder, or one or more of its symptoms. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of symptom history and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay their recurrence.

[0121] As used herein, the terms “mTORC1-mediated” disorder, disease and / or condition mean any disease or other adverse condition in which mTORC1 is known to play a role. Accordingly, another embodiment of the present invention relates to treating or mitigating the severity of one or more diseases in which mTORC1 is known to play a role.

[0122] In some embodiments, methods for activating mTORC are used to treat or prevent depression (see Ignacio et al., (2015) Br J Clin Pharmacol. November 27). Accordingly, in some embodiments, the present invention provides a method for treating or preventing depression in a patient who requires treatment or prevention of depression, the method comprising the step of administering to the patient a compound provided or a pharmaceutically acceptable composition thereof. In some embodiments, the depression is treatment-resistant depression ("TRD"). In some embodiments, treatment-resistant depression is a first-line treatment. It is resistant to treatment. In some embodiments, treatment-resistant depression is resistant to second-line treatment.

[0123] In some embodiments, the present invention provides a method for treating depression in a patient requiring treatment for depression, wherein the patient experiences a 50% reduction in depression scale scores. In some embodiments, the patient experiences a 50% reduction in depression scale scores within six weeks of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, the patient experiences a 50% reduction in depression scale scores within four weeks of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, the patient experiences a 50% reduction in depression scale scores within two weeks of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, the patient experiences a 50% reduction in depression scale scores within two weeks of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, the patient experiences a 50% reduction in depression scale scores within one week of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, the patient experiences a 50% reduction in depression scale scores within seven days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 6 days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 5 days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 4 days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 3 days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 2 days of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 1 day of administration of the compound or a pharmaceutically acceptable composition. In some embodiments, patients experience a 50% reduction in their depression scale score within 24 hours of administration of the compound or a pharmaceutically acceptable composition.In some embodiments, depression scale scores are selected from the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAMD-6), the List of Self-Rating Scales for Depressive Symptoms (IDS-SR), and the Clinical Global Impression Severity Scale (CGI-S).

[0124] In some embodiments, the present invention provides a method for treating depression in a patient requiring treatment of depression, comprising the step of orally administering a compound or a pharmaceutically acceptable composition thereof to the patient, wherein the patient experiences a reduction in depression scale scores equivalent to that of ketamine administered by intraperitoneal injection. In some embodiments, the reduction in depression scale scores results from a single oral dose. In some embodiments, the reduction in depression scale scores results from multiple oral doses.

[0125] In some embodiments, a method of activating mTORC1 is used to induce rapid onset of antidepressant activity. Accordingly, in some embodiments, the present invention provides a method for inducing rapid onset of antidepressant activity in a patient suffering from a TRD who requires the induction of rapid onset of antidepressant activity, the method comprising the step of administering to the patient the compound or a pharmaceutically acceptable composition thereof. In some embodiments, rapid onset of antidepressant activity occurs within two weeks of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within one week of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within seven days of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within six days of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within five days of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within four days of administration of the compound or composition. In some embodiments, rapid onset of antidepressant activity occurs within three days of administration of the compound or composition. In some embodiments, the onset of rapid antidepressant activity occurs within two days of administration of the compound or composition. In some embodiments, the onset of rapid antidepressant activity occurs within one day of administration of the compound or composition. In some embodiments, the onset of rapid antidepressant activity occurs within 24 hours of administration of the compound or composition.

[0126] In some embodiments, the present invention provides a method for inducing long-acting sustained-release antidepressant activity in a patient suffering from depression who requires the induction of such activity, the method comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided. In some embodiments, the patient requiring the induction suffers from TRD. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 24 hours after a single dose of the compound or a pharmaceutically acceptable composition thereof provided. In some embodiments, the long-acting sustained-release antidepressant activity lasts for longer than 1 day. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 2 days. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 3 days. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 4 days. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 5 days. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 6 days. In some embodiments, the long-acting sustained-release antidepressant activity lasts for at least 7 days.

[0127] In some embodiments, the present invention provides a method for inducing antidepressant activity that exhibits both rapid onset and long-lasting effects.

[0128] In some embodiments, the present invention provides a method for inducing a positive behavioral response in a subject, comprising the step of administering to the subject a compound or a pharmaceutically acceptable composition thereof provided for. In some embodiments, the positive behavioral response correlates with an improvement in mood. In some embodiments, the positive behavioral response correlates with a reduction in anxiety. In some embodiments, the positive behavioral response corresponds to an improvement in mood. In some embodiments, the positive behavioral response correlates with an improvement in the ability to cope with stress.

[0129] In some embodiments, the present invention provides a method for inducing the onset of a rapid positive behavioral response in a subject, comprising the step of administering to the subject a compound or a pharmaceutically acceptable composition thereof provided for. In some embodiments, the positive behavioral response occurs within 24 hours of administration. In some embodiments, the positive behavioral response occurs within 1 day of administration. In some embodiments, the positive behavioral response occurs within 2 days of administration. In some embodiments, the positive behavioral response occurs within 3 days of administration. In some embodiments, the positive behavioral response occurs within 4 days of administration. In some embodiments, the positive behavioral response occurs within 5 days of administration. In some embodiments, the positive behavioral response occurs within 6 days of administration. In some embodiments, the positive behavioral response occurs within 7 days of administration. In some embodiments, the positive behavioral response occurs within 1 week of administration.

[0130] In some embodiments, the present invention provides a method for inducing a long-acting, sustained positive behavioral response in a subject, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided for. In some embodiments, the long-acting, sustained positive behavioral response lasts longer than one day. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least two days. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least three days. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least four days. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least five days. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least six days. In some embodiments, the long-acting, sustained positive behavioral response lasts for at least seven days.

[0131] In some embodiments, the present invention provides a method for inducing a positive behavioral response that exhibits both rapid onset and long-lasting effects.

[0132] In some embodiments, the present invention provides a method for improving and / or reversing behavioral and synaptic deficits caused by chronic and unpredictable stress (CUS) in a patient who requires improvement and / or reversal of such deficits, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. In some embodiments, the method improves and / or reverses behavioral deficits caused by CUS. In some embodiments, the method improves and / or reverses synaptic deficits caused by CUS. In some embodiments, the synaptic deficit caused by CUS is a decrease in postsynaptic protein expression. In some embodiments, the decrease in postsynaptic protein expression is a decrease in GLUR1 or PSD95 expression.

[0133] In some embodiments, methods for activating mTORC1 are used to treat or prevent forms of autism (Novarino et al., (2012) Science, October 19, vol. 338:61 (See Issue 05, pp. 394-397). Accordingly, in some embodiments, the present invention provides a method for treating or preventing a form of autism in a subject who requires treatment or prevention of a form of autism, the method comprising the step of administering to the subject a compound or a pharmaceutically acceptable composition thereof. In some embodiments, autism is a genetic form of autism.

[0134] In some embodiments, the present invention provides a method for treating a genetic form of autism in a patient requiring treatment of the genetic form of autism, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. SHANK3 haploinsufficiency is responsible for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (Bidinostietal. (2016) Science Reports 351, 1199-1203). Downregulation of mTORC1 in SHANK3 is due to enhanced phosphorylation and activation of B56b, a serine / threonine protein phosphatase 2A (PP2A) regulatory subunit, by its kinase, Cdc2-like kinase 2 (Bidinostietal. (2016) Science Reports 351, 1199-1203). SHANK3 mutant mice exhibit autistic traits (Yang et al. (2012) The Journal of Neuroscience 32, 6525-6541). Patients with autistic traits and motor delay have harmful homozygous mutations in the SLC7A5 gene. Solute carrier transporter 7a5 (SLC7A5), a large native amino acid transporter localized to the blood-brain barrier (BBB), plays an essential role in maintaining normal levels of BCAAs in the brain. Intracerebroventricular administration of leucine improves abnormal behavior in adult mutant mice (Tarlungeanuetal. (2016) Cell 167, 1481-1494).

[0135] In some embodiments, the present invention provides a method for treating a lysosomal storage disorder ("LSD") in a patient requiring treatment of the LSD, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. LSDs are a group of hereditary metabolic disorders resulting from deficiencies in lysosomal function. Lysosomal storage disorders are caused by lysosomal dysfunction, typically resulting from a deficiency in one enzyme necessary for the metabolism of lipids, glycoproteins (sugar-containing proteins), or so-called mucopolysaccharides. In some embodiments, the present invention provides a method for treating a lipid storage disorder in a patient requiring treatment of the LSD, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. In some embodiments, the lipid storage disorder is selected from sphingolipidosis (e.g., gangliosidosis, Gaucher disease, Niemann-Pick disease, or metachromatic leukodystrophy). In some embodiments, the present invention provides a method for treating gangliosidosis (e.g., Tay-Sachs disease or leukodystrophy). In some embodiments, the present invention provides a method for treating mucopolysaccharidosis in a patient requiring treatment of the mucopolysaccharidosis, comprising the step of administering to the patient a compound provided or a pharmaceutically acceptable composition thereof. In some embodiments, the mucopolysaccharidosis is Hunter syndrome or Hurler's disease.

[0136] In some embodiments, the present invention provides a method for treating JNCL (Batten disease) in a patient requiring treatment of JNCL, comprising the step of administering to the patient a compound provided or a pharmaceutically acceptable composition thereof. JNCL is caused by deletions of exons 7 and 8 of the CLN3 gene, resulting in a non-functional protein. Battenin, the full-length protein encoded by CLN3, is a transmembrane protein that localizes to late endosomes and lysosomes, and has been shown to help regulate pH, amino acid balance, and vesicular transport (Pearce et al. (1999) Nature Genetics 22, 1; Fossale et al. (2004) BMC Neuroscience 10, 5). In in vitro and in vivo models of JNCL, mTOR activation requires intracellular nutrients delivered by autophagy, which is reduced by the lack of functional battenin (Caoetal. (2006) Journal of Biological Chemistry 281, 29).

[0137] In some embodiments, the present invention provides a method for treating cystinosis in a patient requiring treatment for cystinosis, comprising the step of administering to the patient a compound provided or a pharmaceutically acceptable composition thereof. Cystinosis is an autosomal recessive genetic disorder affecting individuals with two mutated alleles in the CSTN gene, where cystinosine, the lysosomal cystine transporter, is defective in the efflux of cystine from lysosomes, leading to the formation of cystine crystals in renal epithelial tubules and loss of renal function. Studies have shown defects or reductions in mTORC1 signaling in CSTN-deficient cells and misplaced mTORs (Ivanova et al. (2016) J Inherit Metab Dis.39(3), 457-64; Andrzejewska et al. (2016) JAm Soc Nephrol. 27(6)). 1678-1688e). These deficiencies cannot be rescued by cysteamine (Ivanova et al. (2016) J Inherit MetabDis. 39(3), 457-64; Andrzejewska et al. (2016) JAm Soc Nephrol. 27(6), 1678-1688e). Cystinosine has also been found to bind to v-ATPase, Rag, and regulatory factors, which are components of the mTORC1 pathway (Andrzejewska et al. (2016) J Am Soc Nephrol. 27(6), 1678-1688e). CTNS-deficient cells are, This results in an increase in the number of autophagosomes and a decrease in chaperone-mediated autophagy (Napolitano et al. (2015) EMBO Mol Med.7(2), 158-74).

[0138] In some embodiments, the present invention provides a method for treating Fabry disease in a patient requiring treatment for Fabry disease, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. In Fabry disease, alpha-galactosidase deficiency leads to the accumulation of globotriaosylceramide lipids in lysosomes. In a cell model of Fabry disease in which alpha-galactosidase is knocked down by shRNA, decreased mTOR activity and increased autophagy have been observed in vitro and in vivo (Liebau et al. (2013)). PLoS 8, e63506). Hyperactive autophagy is also linked to alpha-galactosidase. It is observed in the brains of mice that have been conditioned (Nelsonet al. (2014) Acta Neuropathologica Communications2, 20).

[0139] In some embodiments, the present invention provides a method for treating mucolipidosis type IV (MLIV) in a patient requiring treatment for the condition, comprising the step of administering to the patient a compound provided or a pharmaceutically acceptable composition thereof. In MLIV, mutations in the TRPML1 lysosomal Ca(2+) channel cause impaired lysosomal membrane trafficking. MLIV knockout in Drosophila results in upregulation of autophagy and decreased mTOR activity, both of which can be reversed by genetically activating mTORC1 or by feeding the animals a high-protein diet (Wonget al. (2012) Curr Biol. 22(17), 1616-1621). Increased autophagy is also a factor in MLIV patients. It is also observed in fibroblasts (Vergarajauregui et al. (2008) Human Molecular Genetics 17,2723-2737).

[0140] In some embodiments, the present invention provides a method for treating intellectual disability in a patient requiring treatment of intellectual disability, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof provided to the patient. In Homo sapiens, cereblon mutations are linked to a mild form of autosomal recessive non-syndromic intellectual disability. In cereblon knockout mouse models of intellectual disability, loss of cereblon in the cerebellum activates AMPK, inhibits mTOR, and reduces protein translation (Leeet al. (2014) J Biol Chem. 289, 23343-52; Xu et al. (2013) JBiol Chem. 288, 29573-85).

[0141] In some embodiments, the present invention provides a method for increasing neuronal protein expression in a subject, comprising the step of administering to the subject a compound provided or a pharmaceutically acceptable composition thereof. In some embodiments, the increase in neuronal protein expression occurs in postsynaptic neurons. In some embodiments, the increase in neuronal protein expression includes an increase in the expression of brain-derived neurotrophic factor (BDNF). In some embodiments, the increase in neuronal protein expression includes an increase in the expression of glutamate receptor 1 (GluR1). In some embodiments, the increase in neuronal protein expression includes an increase in the expression of synapsin. In some embodiments, the increase in neuronal protein expression includes an increase in the expression of PSD95.

[0142] In some embodiments, the present invention provides a method for increasing synapse formation in a subject, comprising the step of administering to the subject a compound or a pharmaceutically acceptable composition thereof provided for. In some embodiments, the increase in synapse formation includes synaptic reorganization. In some embodiments, the increase in synapse formation includes induction of dendritic spines. In some embodiments, induction of dendritic spines causes an increase in the density of dendritic spines. In some embodiments, the dendritic spines are thin spines. In some embodiments, the dendritic spines are mushroom-shaped spines.

[0143] In some embodiments, the present invention provides a method for enhancing synoptic function in a subject, comprising the step of administering to the subject a compound provided or a pharmaceutically acceptable composition thereof. In some embodiments, the enhancement of synoptic function in the subject includes an increase in excitatory postsynaptic current (EPSC).

[0144] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, enterally, parenterally, intravesically, vaginally, intraperitoneally, topically (such as in powder, ointment, or drop), or orally, as oral or nasal spray formulations, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention To obtain the desired therapeutic effect, it can be administered orally or parenterally once or more times a day, at a dose level of approximately 0.01 mg / kg to approximately 50 mg / kg per day of the subject's body weight, and preferably approximately 1 mg / kg to approximately 25 mg / kg.

[0145] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. The formulation contains an active compound. In addition to the active compound, the liquid formulation may contain, for example, inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, as well as mixtures thereof. In addition to the inert diluent, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0146] Injectable preparations, such as injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting and suspending agents. Injectable sterile preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (United States Pharmacopeia), and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils are conveniently used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0147] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0148] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This can be done by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. The absorption rate of the compound may then depend on the dissolution rate, and consequently, on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms can be achieved by dissolving or suspending them in an oily vehicle. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations are also prepared by capturing the compound in liposomes or microemulsions that are compatible with body tissues.

[0149] The compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0150] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is accompanied by at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate), and / or a) filler or bulking agent (such as starch, lactose, sucrose, glucose, mannitol, and silicic acid), b) binder (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), c) humectant (such as glycerol), and d) disintegrant (agar, calcium carbonate, potato). It is mixed with (e) ostem or tapioca starch, alginic acid, certain silicates and sodium carbonate, etc., (f) dissolution retarders (such as paraffin), (g) absorption enhancers (such as quaternary ammonium compounds), (g) wetting agents (e.g., cetyl alcohol and glycerol monostearate), (h) absorbents (such as kaolin and bentonite clay), and (i) lubricants (talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, these dosage forms may also contain buffering agents.

[0151] Similar types of solid compositions may also be used as fillers in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical field. They may optionally contain opacifiers and may be compositions that release only or preferentially the active ingredient(s) to a portion of the gastrointestinal tract in an optionally delayed manner. Examples of embedding compositions that can be used include polymer substances and waxes. Similar types of solid compositions may also be used in soft and rigid gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. It may also be used as a filler inside.

[0152] The active compound can also be in a microencapsulated form with one or more excipients, as described above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical compounding. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain further substances other than inert diluents, such as tablet lubricants and other tablet adjuvants, such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. They may optionally contain opacifiers and may be compositions that release the active ingredient(s) to a portion of the gastrointestinal tract, either alone or preferentially, in a delayed manner, optionally. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0153] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active components are mixed with a pharmaceutically acceptable carrier under sterile conditions, and any necessary preservatives or buffers may be required. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. Furthermore, the present invention intends for the use of transdermal patches, which have the additional advantage of achieving controlled delivery of the compounds to the body. Such dosage forms can be prepared by dissolving or aliquoting the compounds in a suitable medium. Absorption enhancers can also be used to improve the inflow of the compounds through the skin. This rate can be controlled either by providing a rate control membrane or by dispersing the compounds in a polymer matrix or gel.

[0154] According to one embodiment, the present invention relates to a method for modulating or selectively modulating mTORC1 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0155] The term “biological sample” as used herein includes, but is not limited to, cell cultures or their extracts; biopsy material obtained from mammals or their extracts; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or their extracts.

[0156] Another embodiment of the present invention relates to a method for activating mTORC1 in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing the compound.

[0157] In another embodiment, the present invention provides a method for treating mTORC1-mediated disorders in a patient requiring treatment of such disorders, comprising the step of administering to the patient a compound or a pharmaceutically acceptable composition thereof according to the present invention. Such disorders are described in detail herein. Combination with other therapeutic agents

[0158] Depending on the specific condition or disease being treated, additional therapeutic agents typically administered to treat such condition may also be present in the composition of the present invention. As used herein, additional therapeutic agents typically administered to treat a specific disease or condition are known as “suitable for the disease or condition being treated.”

[0159] In some embodiments, the compounds provided are administered in combination with antidepressants. Antidepressants are well known to those skilled in the art and include selective serotonin reuptake inhibitors ("SSRIs," e.g., sertraline, escitalopram, citalopram, fluvoxamine, fluoxetine, paroxetine) and antidepressants (e.g., bupropion, venlafaxine, mirtazapine, duloxetine, amitriptyline, imipramine, celeziline, nortriptyline, trazodone, desvenlafaxine, and aripiprazole).

[0160] In some embodiments, the compounds provided are administered in combination with additional therapeutic agents or methods useful for treating one or more LSDs. In some embodiments, the compounds provided are administered in combination with enzyme substitution therapy, chemical chaperone therapy, bone marrow transplantation, substrate reduction therapy, α-L-idulonidase, recombinant human N-acetylgalactosamine-4-sulfatase (arylsulfatase B), glycosphingolipid synthesis inhibitors, N-butyldeoxynojirimycin (miglustat), hydrophobic iminosaccharides, or α-galactosidase A inhibitors (e.g., 1-deoxy-galactonojirimycin).

[0161] These additional agents may be administered individually from a composition containing the compound of the present invention as part of a multi-dose regimen. Alternatively, they may be part of a single-dose formulation mixed with the compound of the present invention in a single composition. When administered as part of a multi-dose regimen, the two activators may be administered simultaneously, sequentially, or typically within a 5-hour interval between each other.

[0162] As used herein, the terms “combination,” “combined,” and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention may be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising the compounds of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0163] The amounts of both the compound of the present invention and additional therapeutic agents (in such compositions containing the additional therapeutic agents) for producing a single-dose formulation in combination with a carrier material will vary depending on the host being treated and the specific form of administration. Preferably, the compositions of the present invention should be formulated so that the compound of the present invention can be administered in doses between 0.01 and 100 mg / kg body weight / day.

[0164] In such compositions containing additional therapeutic agents, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions is less than the amount required for monotherapy using only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered in doses between 0.01 and 1,000 μg / kg body weight / day.

[0165] The amount of additional therapeutic agent present in the composition of the present invention is less than or equal to the amount typically administered in a composition containing the therapeutic agent as an activator alone. Preferably, the amount of additional therapeutic agent in the disclosed composition is in the range of about 50% to 100% of the amount typically present in a composition containing the agent as a therapeutic activator alone.

[0166] The compounds of the present invention or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of coagulation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention.

[0167] All features of each aspect of the present invention are applied to all other aspects with modifications where appropriate.

[0168] The following examples are provided to allow for a more complete understanding of the invention described herein. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way. [Examples]

[0169] Example As illustrated in the following examples, in some exemplary embodiments, the compounds are prepared according to the following general procedure. While the general method illustrates the synthesis of a compound of the present invention, it is recognized that the following general method and other methods known to those skilled in the art can be applied to all compounds described herein, as well as to their respective subclasses and species. General Procedure

[0170] X-ray powder diffraction (XRPD) analysis was performed in transmission mode using the standard Aptuit method with a Panalytical X'Pert Pro or Empyrean instrument equipped with an X'Celerator detector. Data were evaluated using HighScore Plus software. The instrument parameters used are listed in Table 5 below. [Table 5]

[0171] XRPD analysis results under controlled environmental conditions were collected in reflection mode using a Panalytical Empyrean instrument equipped with an Anton-Paar CHC+ chamber featuring a Pixel3D detector. The data were evaluated using HighScore Plus software. The instrument parameters used are listed in Table 6 below. [Table 6]

[0172] Thermogravimetric analysis (TGA) was performed using a TA Q5000IR instrument. The method parameters are listed in Table 7 below. [Table 7]

[0173] Differential scanning calorimetry (DSC) analysis was performed using a TA Q2000 MDSC instrument. The method parameters are listed in Table 8 below. [Table 8]

[0174] Chiral HPLC analysis was performed using the parameters listed in Table 9 below. [Table 9]

[0175] Gravimetric vapor deposition (GVS) analysis was performed using an IGASorp instrument by Hiden Analytical. The method parameters are listed in Table 10 below. [Table 10]

[0176] Compound A can be prepared in accordance with the method described in U.S. Patent No. 10,100,066, which is incorporated herein by reference in its entirety. (Example 1) Preparation of free base form A of compound A [ka] Form A of compound A

[0177] Form A of compound A was prepared as described below. Form A of compound A - Preparation method 1

[0178] The slurry was prepared by weighing approximately 65 mg of compound A, suspending it in 0.8 mL of acetone, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form A of compound A - Preparation method 2

[0179] The slurry was prepared by weighing approximately 55 mg of compound A, suspending compound A in 1.0 mL of acetonitrile, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form A of compound A - Preparation method 3

[0180] The slurry was prepared by weighing approximately 60 mg of compound A, suspending compound A in 0.8 mL of 1-butanol, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form A of compound A - Preparation method 4

[0181] The slurry was prepared by weighing approximately 60 mg of compound A, suspending it in 0.5 mL of 2-butanone (MEK), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form A of compound A - Preparation method 5

[0182] The slurry was prepared by weighing approximately 55 mg of compound A, suspending it in 0.7 mL of ethyl acetate, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form A of compound A - Preparation method 6

[0183] The slurry was prepared by weighing approximately 55 mg of compound A, suspending compound A in 0.9 mL of isopropanol, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours.

[0184] Table 1 above is reproduced below, and the X-ray diffraction peaks observed for form A of compound A are explained. [Table 1-3] [Table 1-4]

[0185] Figure 1 illustrates the XRPD pattern of compound A in form A.

[0186] Figure 2 shows the DSC trace of compound A in form A.

[0187] Figure 3 illustrates a TGA tray of compound A in form A. (Example 2) Preparation of free base form B of compound A [ka] Form B of compound A

[0188] Form B of compound A was prepared as described below. Form B of compound A - Preparation method 1

[0189] Approximately 4 g of compound A was suspended in 5 volumes (20 mL; total volume 24 mL, 167 mg / mL) of IPA / water 70:30 in a 50 mL EasyMax reactor equipped with an FBRM Lasentec® probe, and the progress of crystallization was monitored. This contents were heated to the maximum temperature (79°C) permissible by the system. Stirring with a propeller blade was applied. The compound tended to dissolve slowly. Since dissolution was not achieved, 1 volume of the solvent mixture was added. A clear solution was observed with some heavy plate-like particles and deposits in the upper space of the reactor. A further 0.5 volume of the solvent mixture was added. The particles disappeared, but some crust remained (total volume 30 mL). (133 mg / mL). This contents were cooled to 76°C at 0.5 K / min. After a few minutes, a freshly prepared suspension in IPA / water 70 / 30 (0.2 mL), immediately dissolved seed crystal (30 mg, calculated as 1% w / w based on the predicted production rate), was added. This contents were cooled to 72°C at 0.5 K / min. After a few minutes, dried seed crystal (30 mg, calculated as 1% w / w based on the predicted production rate) was added again. The contents were held at this temperature for 4 hours to confirm seed crystal persistence, and then cooled to 20°C at 0.2 K / min. The material was cooled. It initially crystallized and appeared to dissolve completely within an hour, then autocrystallized at 50°C during gradient cooling. At 20°C, a large amount of deposit was observed along the upper wall of the solvent and at the bottom of the reactor. Using a spatula, the crust was pressed into the slurry, and after some time, the slurry became homogenized. A sample was taken for XRPD analysis, and morphology B was obtained.

[0190] Due to the large volume involved, this experiment was continued in a 100 mL reactor. The reactor was rapidly heated to 80°C. Approximately 1 mL of solvent was needed to compensate for evaporation. The solution appeared clear, but the crust rings remained. The contents were cooled to 74°C at 0.5 K / min. After a few minutes, a dry seed crystal (A / 2919 / 27 / 3~30 mg, calculated based on the predicted production rate as 1% w / w) was added. The seed crystal did not dissolve within 1 hour. IPA (13 volume, 52 mL) was added at a rate of 0.3 mL / min (3 hours). During this time, the contents were maintained at 74°C. The addition of IPA caused a large amount of precipitation, resulting in the formation of a jelly-like slurry that could not be stirred with an impeller. The contents were cooled to 20°C at 0.2 K / min. A static solid mass was found the following day, and stirring was limited to the center of the impeller. The slurry was made homogenized by moving the solid mass using a spatula. This solid was isolated by filtration on a filter syringe (PTFE frit, 20 μm porosity). During this operation, it was necessary to recycle a portion of the mother liquor to completely recover the material from the reactor. After dewatering before washing, a sample was taken for XRPD analysis, yielding morphology B plus some extra reflectors. Next, washing solution (IPA / water 90 / 10, 10 mL, approximately 1 cake volume) was applied, and this solid was dried under vacuum for 1 hour. After washing, a sample was taken for XRPD analysis, yielding morphology B. This solid was dried in a vacuum oven at 40°C for 20 hours. Form B of compound A - Preparation method 2

[0191] Approximately 4 g of compound A was suspended in 5 volumes (20 mL; total volume 24 mL, 167 mg / mL) of IPA / water 70:30 in a 50 mL EasyMax reactor equipped with an FBRM Lasentec® probe, and the progress of crystallization was monitored. Stirring with a propeller blade was applied at 500 rpm. The contents were heated to the maximum temperature allowed by the system (81 °C, speed 3 K / min), but complete dissolution was not achieved (Lasentec: 1800 counts), and therefore, 1 volume of the solvent mixture was added. Crust formation was observed on the reactor wall surface above the solvent level. The temperature was reduced to 78 °C and maintained below the boiling point of the solvent mixture, and an additional 0.5 volume of solvent was added. The suspended particles disappeared, but some crust remained (total volume 30 mL, 133 mg / mL). The contents were cooled to 75 °C at a rate of 0.5 K / min. A few minutes later, a dry seed crystal (A / 2919 / 27 / 3, 30 mg, calculated based on the predicted production rate as 1% w / w) was added. The Lasentec count number surged to 33,000 and then began to decline rapidly. The temperature was reduced to 73°C (rate 0.5 K / min) to prevent complete dissolution (as observed in the previous experiment A / 2919 / 40), and a sample was taken to confirm the crystal morphology: A / 2919 / 42 / 1 (wet) showed the presence of morphology 2 in the mixture, with reflections not attributed by XRD analysis. The reactor was held at 73°C for 4 hours and then cooled to 20°C at 0.2 K / min. While maintaining this reactor at 73°C, gradient cooling was initiated after a continued slow decline in the Lasentec count number. This may be due to crust formation. At 20°C, the contents appeared with large deposits along the reactor wall above the solvent level. The crust was pressed into the slurry using a spatula. A sample was taken for XRPD analysis, and morphology B was obtained.

[0192] To further clarify what happened after the addition of the seed crystal, the substance was redissolved at 79°C (3 K / min). Several crusts were present on the reactor wall. The temperature was reduced to 70°C at a rate of 0.2 K / min. The solution remained clear, but the presence of crusts on the wall surface increased. After 90 minutes, a dry seed crystal (A / 2919 / 27 / 3, 30 mg, calculated based on the predicted production rate as 1% w / w) was added. The Lasentec count number rose sharply to 35,000, then began to decline. After 1 hour, a sample was taken and subjected to XRPD analysis, yielding morphology B. Two hours after the addition of the seed crystal, the Lasentec count number had decreased to 15,000, and large crusts were present on the reactor wall surface. The crusts were pushed into the slurry using a spatula, and the Lasentec count number rose to 29,000. These pieces of evidence confirm that crust formation on the reactor wall surface leads to a decrease in product concentration in this system, which can contribute to the difficulty in controlling the seed crystal addition procedure (and also function as self-seed crystal addition).

[0193] Due to the large volume involved, this experiment was continued in a 100 mL reactor. The reactor was rapidly heated to 80°C. During this time, stirring with an anchor was applied at 200 rpm. Approximately 1 mL of solvent was needed to compensate for evaporation. The solution appeared clear, but crust rings were present. The jacket was cooled to 75°C at 0.5 K / min, and after a few minutes, the substance self-crystallized. The contents were heated again to 80°C until complete dissolution was achieved. After about 10 minutes, the temperature was reduced to approximately 74°C [T jacket = 81.5°C], and a dry seed crystal (A / 2919 / 27 / 3, 30 mg, calculated as 1% w / w based on the predicted production rate) was added. The seed crystal did not dissolve within 20 minutes. IPA (13 volume, 52 mL) was added at a rate of 0.3 mL / min (3 hours). During this time, the jacket was maintained at 81.5°C. IPA induced a large amount of precipitate, forming a jelly-like slurry. This content was cooled to 20°C at 0.2 K / min. The following day, a mobile, homogeneous mass was found, and several crusts were observed on the reactor wall surface. This solid was isolated by filtration over a filter funnel (DURAN®, porosity 3). Partial recycling of the mother liquor was necessary to completely recover the product from the reactor. After dewatering and before washing, samples were taken for XRPD analysis, and morphology B was obtained. Washing solution (IPA / water 90 / 10, 10 mL, approximately 1 cake volume) was applied. The solid was dried in a vacuum oven at 40°C for 6 hours. Form B of compound A - Preparation method 3

[0194] Approximately 6 g of compound A was suspended in 6.5 volumes (39 mL; total volume 45 mL, 133 mg / mL) of IPA / water 70:30 in a 100 mL EasyMax reactor equipped with an anchor. The contents were heated to 78°C. A clear solution was obtained. The crust ring was located above the liquid level. The contents were cooled to 74°C at 0.5 K / min. After a few minutes, a dry seed crystal (A / 2919 / 27 / 3, 30 mg, calculated based on the predicted production rate as 0.6% w / w) was added. The seed crystal remained. IPA (13 volumes, 78 mL) was added at a rate of 0.44 mL / min (3 hours). During this time, the contents were maintained at 74°C. After the addition, the contents were cooled to 20°C at 0.2 K / min. Next, this solid is isolated by filtration on a gooch (porosity 3), and this substance is removed from the reactor. To fully recover the material, some recycling of the mother liquor was necessary. A washing solution (IPA / water 90 / 10, 12 mL, 2 volumes) was applied. After washing, a sample was taken for XRPD analysis, and morphology B was obtained. This solid was dried in a vacuum oven for 1 hour, then at 40°C for 5 hours. Form B of compound A - Preparation method 4

[0195] The slurry was prepared by weighing approximately 65 mg of compound A, suspending it in 0.5 mL of methyl isobutyl ketone (MIBK), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form B of compound A - Preparation method 5

[0196] The slurry was prepared by weighing approximately 55 mg of compound A, suspending it in 0.6 mL of methyl t-butyl ether (MTBE), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form B of compound A - Preparation method 6

[0197] The slurry was prepared by weighing approximately 60 mg of compound A, suspending it in 0.8 mL of toluene, and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form B of compound A - Preparation method 7

[0198] The slurry was prepared by weighing approximately 70 mg of compound A, suspending it in 0.7 mL of isopropanol / water (90:10), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was stirred at 20°C for 14 days. The solid was isolated by filtration and vacuum-dried at room temperature for approximately 2 hours. Form B of compound A - Preparation method 8

[0199] The slurry was prepared by weighing approximately 60 mg of compound A, suspending it in 0.8 mL of acetone / water (90:10), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was subjected to a temperature cycle between 20°C and 40°C for a total of 6 cycles of 2 hours each, overnight. The solid was isolated by filtration and dried under vacuum at room temperature for approximately 1-2 hours. Form B of compound A - Preparation method 9

[0200] The slurry was prepared by weighing approximately 70 mg of compound A, suspending it in 0.7 mL of isopropanol / water (90:10), and visually confirming that any excess solid remained undissolved (magnetic stirring at approximately 500-700 rpm was applied). This slurry was subjected to a temperature cycle between 20°C and 40°C for a total of 6 cycles of 2 hours each, overnight. The solid was isolated by filtration and dried under vacuum at room temperature for approximately 1-2 hours. Form B of compound A - Preparation method 10

[0201] Compound A (a mixture of polymorphs), water (2.0V), and IPA (4.0V) were sequentially added to a reaction vessel. The resulting slurry was heated to 75°C to form a solution. Next, while maintaining the temperature at 70-75°C, IPA (8.0V) was slowly added over 90 minutes. During this time, compound A crystallized from the solution. This slurry was cooled to ambient temperature over 3 hours and then aged at ambient temperature for a further 50 hours. The solid was collected by filtration, washed with IPA (2.0V), and dried under vacuum at 40°C to obtain compound A in form B in 82% yield.

[0202] Table 2 above is reproduced below, and the X-ray diffraction peaks observed for compound A in form B are explained. [Table 2-3] [Table 2-4]

[0203] Figure 4 illustrates the XRPD pattern of compound A in form B.

[0204] Figure 5 shows the DSC trace of compound A in form B.

[0205] Figure 6 illustrates the TGA trace of compound A in form B. (Example 3) Preparation of free base form C of compound A [ka] Form C of compound A

[0206] Form C of compound A was prepared as described below. Form C of compound A - Preparation method 1

[0207] Saturated solutions of compound A were prepared in three solvents (water, methanol, and acetone) and filtered through a 0.45 μm PTFE filter. A portion of the prepared solution (approximately 1.5 mL) was placed in a methyl t-butyl ether (MTBE)-rich environment with a solvent selected based on its boiling point difference. The solution was periodically inspected visually for solid formation. The solid was isolated by removing the supernatant and dried under vacuum at room temperature for approximately 1 hour. Form C of compound A - Preparation method 2

[0208] When the drying of compound A in form B, which was produced according to preparation method 1 (form B of compound A), was extended in an oven at 40°C, form C was obtained.

[0209] Table 3 above is reproduced below, and the X-ray diffraction peaks observed for morphology C of compound A are explained. [Table 3-3] [Table 3-4]

[0210] Figure 7 illustrates the XRPD pattern of compound A in form C.

[0211] Figure 8 shows the DSC trace of compound A in form C.

[0212] Figure 9 shows the TGA trace of compound A in form C. (Example 4) - Single crystal study of morphology A of compound 1 [ka] (In the equation, x is approximately 3 / 4).

[0213] Form A of compound 1 was prepared as follows: 40 mg (0.3 mmol) of compound A was dissolved in 5 mL of deionized water, and the solvent was evaporated on a hot plate until needle-like crystals appeared from the hot solution. These crystals were transferred to another vial and sealed.

[0214] These crystals were suitable for X-ray diffraction. The crystals were observed to be thin and long "needle"-like crystals, and X-ray diffraction analysis was performed at room temperature using Cu irradiation. Diffraction was observed, the unit cell was obtained, and the powder pattern was modeled. However, it was observed that there was intensity decay during the measurement at room temperature, and after about 30 minutes, the crystallinity was significantly lost, making it impossible to determine a complete dataset.

[0215] To avoid the loss of crystallinity, new crystals were prepared as described above, and X-ray diffraction analysis of these new crystals was performed at a low temperature (about 250 K, in an inert gas stream). Under these conditions, a complete dataset was determined, and the structure was solved and refined.

[0216] Single crystal investigation of Form A of Compound 1 yielded a chiral monoclinic P2₁ unit cell with the parameters shown in Table 11 below. [Table 11]

[0217] Figure 10 shows an asymmetric unit, whereby chiral centers are found at the carbon atoms labeled as C12, C22, C32 and C42, respectively. The absolute configuration of Form A of Compound 1 was determined to be S for the molecules present in the unit cell.

[0218] The unit cell was observed to be asymmetric, containing 4 independent molecules of Compound A and 3 fully occupied water molecules. The lattice volume is 1880.7(3) Å 3 corresponds to the presence of 8 molecules of Compound A and 6 water molecules in the unit cell. The molecular formula can be written as [C7H 13 F2N1O2] 4. [H2O]3, where the [C7H 13 F2N1O2] entity is a zwitterion.

[0219] The above dataset obtained at low temperature was used together with the above unit cell dataset obtained at room temperature. The unit cell found at room temperature has a=5.90Å, b=30.34Å, c=10.51Å ; and b=90.78°, which is equivalent to the unit cell found at 250K.

[0220] The XRPD pattern shown in Figure 11 was modeled using crystallography software (for example, Mercury Program version 3.10.1 (build 168220)). The above Table 4 is reproduced below to describe the X-ray diffraction peaks related to Form A of Compound 1. [Table 4-3] [Table 4-4]

[0221] While the present inventors have described several embodiments of the present invention, it is apparent that the basic examples of the present inventors may be modified to realize other embodiments utilizing the compounds and methods of the present invention. Therefore, it will be understood that the scope of the present invention is defined by the appended claims rather than by the specific embodiments represented by way of example. The present invention provides, for example, the following items. (Item 1) Compound A of Form A, B or C: [Chemical Formula] . (Item 2) The compound according to Item 1, wherein the compound is crystalline. (Item 3) The compound according to Item 1, wherein the compound is a crystalline solid substantially free of amorphous Compound A. (Item 4) The compound according to Item 1, wherein the compound is substantially free of impurities. (Item 5) The compound described in item 1, having one or more peaks selected from the peaks at approximately 4.4, 16.2, and 17.7 degrees 2θ in its XRPD. (Item 6) The compound described in item 5, having at least two peaks selected from peaks at approximately 4.4, approximately 16.2, and approximately 17.7 degrees 2θ in its XRPD. (Item 7) The compound described in item 6, wherein the aforementioned compound is a compound of form A. (Item 8) The compound described in item 1, having an XRPD substantially similar to the XRPD illustrated in Figure 1. (Item 9) The compound described in item 1, having one or more peaks selected from the peaks at approximately 5.0, 15.2, and 17.5 degrees 2θ in its XRPD. (Item 10) The compound according to item 9, having at least two peaks selected from peaks at approximately 5.0, approximately 15.2, and approximately 17.5 degrees 2θ in its XRPD. (Item 11) The compound described in item 10, wherein the compound is a compound of form B. (Item 12) The compound described in item 1, having an XRPD substantially similar to the XRPD illustrated in Figure 4. (Item 13) The compound described in item 1, having one or more peaks selected from the peaks at approximately 7.0, 16.1, and 16.3 degrees 2θ in its XRPD. (Item 14) The compound according to item 9, having at least two peaks selected from peaks at approximately 7.0, approximately 16.1, and approximately 16.3 degrees 2θ in its XRPD. (Item 15) The compound described in item 10, wherein the compound is a compound of form C. (Item 16) The compound according to item 1, having an XRPD substantially similar to the XRPD illustrated in Figure 7. (Item 17) A composition comprising the compound according to item 1 and a pharmaceutically acceptable carrier or excipient. (Item 18) A method of treating a disease, disorder or condition selected from treatment-resistant depression, lysosomal storage disorders, JNCL, cystinosis, Fabry disease, MLIV, genetic forms of intellectual disability or autism, the method comprising: administering an effective amount of the compound according to item 1 or the composition thereof to a patient in need thereof. (Item 19) A method of activating mTORC1 in a patient, comprising the step of administering an effective amount of the compound according to item 1 or the composition thereof to a patient in need of mTORC1 activation. (Item 20) Compound 1 of Form A:

Chemical Formula

Claims

1. Compound A in form A: 【Chemistry 1】 A method for preparing crystals of, The method comprises one or more steps of adding a solvent to compound A. The method further includes one or more steps of stirring or agitating the obtained preparation, The method further includes one or more steps of removing the solvent from the obtained preparation. The removal includes drying the crystalline compound A in air or under reduced pressure. Morphology A has 10 peaks in its XRPD at 4.4±0.2, 6.1±0.2, 15.6±0.2, 16.2±0.2, 17.3±0.2, 17.5±0.2, 17.7±0.2, 19.4±0.2, 19.6±0.2, and 31.6±0.2 degrees 2θ. The aforementioned solvent a) Acetone; b) Acetonitrile; c) 1-butanol; d) 2-butanone (MEK); e) Ethyl acetate; or f) Isopropanol; A method that is either a mixture of those methods.

2. Compound A in form B: 【Chemistry 2】 A method for preparing crystals of, The method comprises one or more steps of adding a solvent to compound A. The method further includes one or more steps of stirring or agitating the obtained preparation, The method further includes one or more steps of removing the solvent from the obtained preparation. The removal includes drying the crystalline compound A in air or under reduced pressure. Morphology B has 10 peaks in its XRPD at 5.0±0.2, 6.2±0.2, 15.2±0.2, 15.9±0.2, 16.7±0.2, 17.2+0.2, 17.5±0.2, 17.8±0.2, 18.6±±0.2, and 20.5±0.2 degrees 2θ. The aforementioned solvent a) IPA and water (optionally, the ratio of IPA to water may be 70:30 or 90:10); b) Methyl isobutyl ketone (MIBK); c) Methyl t-butyl ether (MTBE); d) Toluene; or e) Acetone and water (optionally, the ratio of acetone to water may be 90:10); A method that is either a mixture of those methods.

3. Compound A in form C: 【Transformation 3】 A method for preparing crystals of, (a) The method comprises one or more steps of adding a solvent to compound A, The method further includes one or more steps of removing the solvent from the obtained preparation. The removal includes drying the crystalline compound A in air or under reduced pressure. The aforementioned solvent (i) Water, which may optionally be combined with methyl t-butyl ether (MTBE); (ii) methanol, which may optionally be combined with methyl t-butyl ether (MTBE); or (iii) Acetone, which may optionally be combined with methyl t-butyl ether (MTBE); or a mixture thereof, method, or (b) The method comprises extending the drying of an isolated solid of form B of compound A, prepared according to claim 2, wherein form B has 10 peaks in its XRPD at 5.0±0.2, 6.2±0.2, 15.2±0.2, 15.9±0.2, 16.7±0.2, 17.2+0.2, 17.5±0.2, 17.8±0.2, 18.6±0.2, and 20.5±0.2 degrees 2θ, Form C is a method having 10 peaks in its XRPD at 7.0±0.2, 15.2±0.2, 16.1±0.2, 16.3±0.2, 18.1±0.2, 18.6±0.2, 19.3±0.2, 19.5±0.2, 21.1±0.2, and 25.1±0.2 degrees 2θ.

4. Compound 1 of form A: 【Chemistry 4】 A method for preparing crystals of, The above method involves compound A: 【Transformation 5】 The process includes one or more steps of adding water to The method further includes drying the obtained crystalline compound 1 in air or under reduced pressure. Method A has 10 peaks in its XRPD at 10.2±0.2, 16.9±0.2, 17.1±0.2, 17.3±0.2, 17.6±0.2, 18.3±0.2, 20.7±0.2, 20.9±0.2, 23.4±0.2, and 26.1±0.2 degrees 2θ, with x being approximately 3 / 4.

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