Composition of 2-(4-chlorophenyl)-n-{[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl]methyl}-2,2-difluoro acetamide, and method of using the same

Abstract

To provide a pharmaceutical composition to be used in a method for treating cancer in a mammal.SOLUTION: A formulation contains the following: based on the overall weight of the formulation, 2-(4-chlorophenyl)-N-{[2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl]methyl}-2,2-difluoro acetamide, or stereoisomer thereof or stereoisomer mixture, pharmaceutically acceptable salt, tautomer, prodrug, solvate, hydrate, cocrystal, clathrate, or polymorph by the amount of approximately 0.01 to approximately 0.15%, and hydroxypropyl β-cyclodextrin or sulfobutyl ether- β-cyclodextrin by the amount of approximately 99.1 to approximately 99.99%.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. Provisional Application No. 62 / 527,744, filed June 30, 2017, U.S. Provisional Application No. 62 / 653,436, filed April 5, 2018, and U.S. Provisional Application No. 62 / 653,436, filed May 17, 2018 This application claims priority to U.S. Provisional Application No. 62 / 673,064, the disclosures of which are incorporated herein by reference in their entirety. No. 6,023,799, filed Dec. 1, 2004, which is incorporated by reference in its entirety.

[0002] The compound provided is 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine]-2-yl]- ... Lysin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Oroacetamide, or a stereoisomer or a mixture of stereoisomers thereof, pharmaceutically acceptable salts, tautomers, prodrugs, solvates, hydrates, co-crystals, clathrates, or polymorphic forms thereof Compositions and dosage forms for treating, managing, and / or preventing cancer Methods of use are also provided herein, namely, methods of treating cancer, The use of these compositions and dosage forms in management and / or prophylaxis.

[0003] Also provided herein is 2-(4-chlorophenyl)-N-{[2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl} 2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers thereof, Isotopic substitutions, pharmaceutically acceptable salts, tautomers, solvates, hydrates, cocrystals, clathrates, or a combination of a polymorph and a second agent for the treatment, prevention, management, and / or management of cancer or amelioration methods. That is, provided herein are methods for use in such methods. 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto Amides, or stereoisomers or mixtures of stereoisomers thereof, isotopically substituted derivatives, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates, or polymorphs that are formed by the action of a second It is a combination of drugs. [Background technology]

[0004] 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidin-3-yl )-1-Oxoisoindolin-5-yl]methyl}-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, or a tautomer thereof , prodrugs, solvates, hydrates, cocrystals, clathrates, or polymorphs have anticancer activity. It has been shown that compound formulations are described in U.S. Patent Application Publication No. 2017 / 0110297, filed January 6, 2017. This is disclosed in patent application Ser. No. 017-0196847.

[0005] 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidin-3-yl )-1-Oxoisoindolin-5-yl]methyl}-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, a pharmaceutically acceptable salt, or a tautomer thereof , prodrugs, solvates, hydrates, cocrystals, clathrates, or polymorphs of the compound, further cancer treatments There is a need for methods and compositions for treating cancer. Summary of the Invention

[0006] Compound 1 used in the formulations and methods herein is disclosed in U.S. Pat. No. 9,499,514 and International Publication No. WO2016 / 007848, the disclosures of which are incorporated herein by reference. Each is incorporated herein by reference in its entirety. Compound 1 may be in the form of crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or non-crystalline form. Crystalline form of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto In one embodiment, Compound 1 is crystalline form C of 2-(4-chlorophenyl)-2-(4-chlorophenyl)-2-(2-methylphenyl)-2-propanol. (phenyl)-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxoisopropyl 2-(4-chloro-2-(4-phenyl-5-yl)methyl)-2,2-difluoroacetamide. 2-(2,6-dioxopiperidin-3-yl)-1-oxophenyl)-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo The polymorphism of {isoindolin-5-yl}methyl}-2,2-difluoroacetamide is As described herein and in U.S. Patent Application Publication No. 2017-0197934, filed January 6, 2017 No. 6,239,999, the disclosure of which is incorporated herein by reference in its entirety.

[0007] In one embodiment, provided herein is a composition comprising, based on the total weight of the formulation, Compound 1 in an amount of about 0.05 to 0.2%, citrate buffer in an amount of about 3% to 6%, and hydroxyl Dipropyl β-cyclodextrin in an amount of about 92-98% and less than about 1% dimethyl In one embodiment, the citrate buffer is anhydrous citrate. Contains citric acid and anhydrous sodium citrate.

[0008] In one embodiment, provided herein is a composition comprising, based on the total weight of the formulation, Compound 1 was added in an amount of about 0.05 to 0.25% and hydroxypropyl β-cyclodextrin was added. The formulation comprises formic acid in an amount of about 99.1 to 99.9% and not more than about 0.5%.

[0009] In one embodiment, provided herein is a method for treating a patient with Compound 1 in an amount of about 0.01 to 0.1 At 5% level, hydroxypropyl β-cyclodextrin is added to approximately 99.1-99.99% It is a formulation containing the following amounts:

[0010] In one embodiment, provided herein is a composition comprising, based on the total weight of the formulation, Compound 1 was added in an amount of about 0.01 to 0.15% and hydroxypropyl β-cyclodextrin was added. The formulation comprises formic acid in an amount of about 99.1 to 99.99% and about 0.5% or less.

[0011] In one embodiment, provided herein is a composition comprising, based on the total weight of the formulation, Compound 1 was added in an amount of about 0.05 to 0.2%, and citrate buffer was added in an amount of about 3 to 6%. ethyl ether-β-cyclodextrin in an amount of about 92-98% and about 1% or less of dimethyl ether-β-cyclodextrin In one embodiment, the formulation contains ethyl sulfoxide. Contains aqueous citric acid and anhydrous sodium citrate.

[0012] In one embodiment, provided herein is a composition comprising, based on the total weight of the formulation, Compound 1 was added in an amount of about 0.05 to 0.25% to sulfobutylether-β-cyclodextrin and about 0.5% or less formic acid.

[0013] In one embodiment, provided herein is a compound comprising Compound 1 in combination with a JAK inhibitor, F LT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RT and administering the compound in combination with one or more second agents selected from K inhibitors. Cancer, including pulmonary and hematological tumors, or one or more of their symptoms or causes The present invention relates to a method for the treatment, prevention, management, and / or amelioration of the causes of a disease, i.e., ... is Compound 1 for use in such a method, the method comprising administering Compound 1 to a JAK inhibitor. Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors. include.

[0014] In one embodiment, the methods provided herein involve administering a formulation of Compound 1 to a JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from an RTK inhibitor. Includes.

[0015] In certain embodiments, the formulations provided herein are solid 2-(4-chloro- (2,6-dioxopiperidin-3-yl)-1-oxophenyl)-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxophenyl [isoindolin-5-yl]methyl}-2,2-difluoroacetamide. In some embodiments, the formulations provided herein comprise an amorphous form of 2-(4-chlorophenoxyethanol). N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoin dulin-5-yl]methyl}-2,2-difluoroacetamide.

[0016] In certain embodiments, provided herein is a unit dosage form comprising the formulation. The formulation comprises Compound 1, a buffer, and a bulking agent.

[0017] In one embodiment, a formulation containing Compound 1 at a therapeutically effective concentration is administered to treat a disease or condition being treated. The amount administered to an individual exhibiting symptoms of a disease or disorder is determined to be one or more of the following: It is effective in ameliorating or eliminating multiple symptoms.

[0018] Also provided is a container or containers filled with one or more of the ingredients of the pharmaceutical composition. or a pharmaceutical pack or kit containing a plurality of such containers. regulated by a government agency with jurisdiction over the manufacture, use, or sale of a drug or biological product. The product may be accompanied by instructions in a prescribed format, which instructions may include instructions for manufacture, administration, and / or administration to humans. The pack or kit contains: Labels containing information regarding the mode of administration, order of drug administration (e.g., separate, sequential, or simultaneous), etc. You can add a rule.

[0019] These and other aspects of the patented subject matter described herein are discussed in greater detail below with reference to the detailed description. It will become clearer with the light. [Brief explanation of the drawings]

[0020] [Figure 1] 1 shows a stacked plot of powder X-ray diffraction patterns of Forms A, B, C, D, and E of Compound 1.

[0021] [Figure 2] 1 shows an X-ray powder diffraction diagram (XRPD) plot of Compound 1 Form A.

[0022] [Figure 3] 1 shows an SEM image of Form A of Compound 1.

[0023] [Figure 4] 1 shows a thermogravimetric analysis (TGA) plot of Form A of Compound 1.

[0024] [Figure 5] 1 shows a differential scanning calorimetry (DSC) plot of Form A of Compound 1.

[0025] [Figure 6] 1 presents a dynamic vapor sorption (DVS) isotherm plot of Form A of compound 1.

[0026] [Figure 7] 1H NMR spectrum of Form A of Compound 1 is presented.

[0027] [Figure 8] 1 shows a comparison of powder X-ray diffraction diagram plots of Compound 1 Form A before (a) and after (b) compression.

[0028] [Figure 9] 1 shows an XRPD plot of Compound 1 Form B.

[0029] [Figure 10] 1 shows an SEM image of Form B of Compound 1.

[0030] [Figure 11] 1 shows the TGA thermogram plot of Compound 1 Form B.

[0031] [Figure 12] 1 shows the DSC thermogram plot of Compound 1 Form B.

[0032] [Figure 13] 1 presents the DVS isotherm plot of Form B of Compound 1.

[0033] [Figure 14] 1H NMR spectrum of Form B of Compound 1 is presented.

[0034] [Figure 15] 1 shows a comparison of powder X-ray diffraction diagram plots of Compound 1 Form B before (a) and after (b) compression.

[0035] [Figure 16] 1 shows an XRPD plot of Compound 1 Form C.

[0036] [Figure 17] 1 shows an SEM image of Form C of Compound 1.

[0037] [Figure 18] 1 shows the TGA thermogram plot of Compound 1 Form C.

[0038] [Figure 19] 1 shows the DSC thermogram plot of Compound 1 Form C.

[0039] [Figure 20] 1 presents a DVS isotherm plot of Form C of Compound 1.

[0040] [Figure 21] 1H NMR spectrum of Form C of compound 1 is presented.

[0041] [Figure 22] 1 shows a comparison of powder X-ray diffraction diagram plots of Compound 1 Form C before (a) and after (b) compression.

[0042] [Figure 23] 1 shows an XRPD plot of Compound 1 Form D.

[0043] [Figure 24] 1 shows the TGA thermogram plot of Compound 1 Form D.

[0044] [Figure 25] 1 shows an XRPD plot of Form E of Compound 1.

[0045] [Figure 26] 1 shows the TGA thermogram plot of Form E of Compound 1.

[0046] [Figure 27] 1 shows a modulated DSC thermogram plot of amorphous Compound 1.

[0047] [Figure 28] 1 shows an XRPD plot of amorphous Compound 1.

[0048] [Figure 29] 1 shows the H NMR spectrum of amorphous Compound 1.

[0049] [Figure 30] The solubility of each type of Compound 1, the brand and percentage of cyclodextrin, along with various solvents and solvent to cyclodextrin ratios are presented.

[0050] [Figure 31] The final pH of the bulk solution is presented relative to the citrate buffer pH and strength.

[0051] [Figure 32] 1 presents the lyophilization profile of the first scale-up batch of Formulation Ib.

[0052] [Figure 33] Residual solvent is presented as a function of lyophilization processing time for formulation Ib.

[0053] [Figure 34]1 presents the lyophilization profile of a second scaled-up batch of Formulation Ib.

[0054] [Figure 35] 1 presents a process diagram for formulation Ia.

[0055] [Figure 36] 1 presents a process diagram for formulation Ib.

[0056] [Figure 37] The increase in solubility of Compound 1 at 25° C. is shown as a function of kleptose concentration (ascending).

[0057] [Figure 38] 1 shows the effect of increasing concentrations of kleptose on Compound 1 precipitation.

[0058] [Figure 39] 1 shows Compound 1 precipitation in kleptose solution under refrigerated conditions.

[0059] [Figure 40] 1 shows a delineation of the design space for compound 1 and kleptose formulations.

[0060] [Figure 41] 1 shows that formic acid removal decreases with increasing amounts of kleptose in the same freeze-drying cycle.

[0061] [Figure 42] 1 shows the effect of cake thickness on residual formic acid levels.

[0062] [Figure 43] 1 shows the residual formic acid vs. kleptose concentration per mg dose in a trial run of Formulation Ic.

[0063] [Figure 44] 1 shows that the osmolality of the reconstituted solution correlates linearly with the kleptose concentration.

[0064] [Figure 45] 1 presents the product temperature profile for lab-scale freeze-drying of Batch 1 of Formulation Ic.

[0065] [Figure 46] 1 presents the product temperature profile for lab-scale freeze-drying of Batch 2 of Formulation Ic.

[0066] [Figure 47] 1 presents the product temperature profile for the lyophilization of development batch Ic-1 of formulation Ic.

[0067] [Figure 48] 1 presents the product temperature profile for the lyophilization of development batch Ic-2 of formulation Ic.

[0068] [Figure 49] 1 presents the product temperature profile for the lyophilization of development batch Ic-3 of formulation Ic.

[0069] [Figure 50] 1 presents a plot of residual moisture as a function of lyophilization cycles for development batches Ic-1-F1, Ic-1-F2, Ic-2-F1, and Ic-2-F2 of formulation Ic.

[0070] [Figure 51] 1 presents a plot of residual formic acid as a function of secondary drying time for development batches Ic-1-F1, Ic-1-F2, Ic-2-F1, Ic-2-F2, Ic-3-F1, and Ic-3-F2 of formulation Ic.

[0071] [Figure 52] 1 presents the product temperature profile for the lyophilization of batch C1 of formulation Ic.

[0072] [Figure 53]1 presents the product temperature profile for the lyophilization of batch C2 of formulation Ic.

[0073] [Figure 54] Figure 1 shows the lyophilized cake appearance of batches C1 and C2 of formulation Ic.

[0074] [Figure 55] 1 presents a process diagram for the preparation of formulation Ic.

[0075] [Figure 56] The cell proliferation dose response (EC50) of Compound 1 in the presence of various concentrations of a second agent is presented. The data demonstrate that the EC50 shifts toward lower values ​​in the presence of a second agent, indicating synergistic activity between Compound 1 and the second agent. Synergism was confirmed by Bliss analysis.

[0076] [Figure 57] 1 presents cell proliferation dose-response curves for the combination of Compound 1 with midostaurin and ruxolitinib in MOLM-13 cell lines.

[0077] [Figure 58] A summary of the synergy observed with Compound 1 when combined with everolimus or temsirolimus, as measured by EC50 shift and by Bliss analysis in solid tumor cell lines, is presented.

[0078] [Figure 59] 1 presents cell proliferation dose-response curves for the combination of Compound 1 and everolimus in various solid tumor cell lines.

[0079] [Figure 60] The effect of Compound 1 alone and in combination with everolimus (RAD, 2 nM, 20 nM, and 200 nM) on BON cell proliferation after 24 hours of treatment is presented.

[0080] [Figure 61] The effect of compound 1 alone and in combination with everolimus (RAD, 2 nM, 20 nM, and 200 nM) on BON cell proliferation after 120 hours of treatment on 2D plates is presented.

[0081] [Figure 62] The effect of Compound 1 alone and in combination with everolimus (RAD, 2 nM, 20 nM, and 200 nM) on BON cell proliferation after 120 hours of treatment is presented.

[0082] [Figure 63] The effect of compound 1 alone and in combination with everolimus (RAD, 2 nM, 20 nM, and 200 nM) on BON cell proliferation after 96 hours of treatment on 3D plates is presented.

[0083] [Figure 64] Figures 64A and 64B present the effect of compound 1 alone and in combination with everolimus (RAD, 2 nM, 20 nM, and 200 nM) on BON cell proliferation after 120 hours of treatment on 3D plates.

[0084] [Figure 65] Figures 65A and 65B present the dose response of Compound 1 and everolimus in a 3D ex-vivo proliferation assay, showing the IC50 and maximum inhibition of the compounds in the GA0087 model in replicate experiments.

[0085] [Figure 66] Dose-dependent response of cisplatin (reference compound) in a 3D ex-vivo GA0087 proliferation assay is presented, showing the IC50 and maximum inhibition of the cisplatin model (replicate experiments).

[0086] [Figure 67] Figures 67A and 67B present the effect of Compound 1 in a matrix combination assay with everolimus in a 3D GA0087 cell proliferation model (replicate experiment).

[0087] [Figure 68] Figures 68A and 68B present the composite index of Compound 1 and everolimus as calculated by the Chou and Talalay method in a 3D GA0087 cell proliferation model (replicate experiments).

[0088] [Figure 69] 1 presents the effect of Compound 1 and everolimus alone and in combination on tumor volume in the GA0087 model.

[0089] [Figure 70] 1 presents the effect of Compound 1 on colony number in samples from myelofibrosis patients in a colony formation assay.

[0090] [Figure 71] 1 presents the effect of Compound 1 on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0091] [Figure 72] 1 presents the effect of ruxolitinib on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0092] [Figure 73] The effect of NS-18 on cell viability of BaF3 cells expressing hCRBN, hCRBN and wild-type JAK2, or hCRBN and JAK2-V617F is presented.

[0093] [Figure 74] 1 shows the effect of momelotinib on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0094] [Figure 75] 1 shows the effect of pacritinib on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0095] [Figure 76] 1 shows the effect of fedratinib on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0096] [Figure 77] 1 shows the effect of everolimus on cell viability of BaF3 cells expressing hCRBN, hCRBN, and wild-type JAK2, or hCRBN and JAK2-V617F.

[0097] [Figure 78] 1 presents the effect of the combination of Compound 1 and NS-018 on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0098] [Figure 79] 1 presents the effect of the combination of Compound 1 and low dose NS-018 on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0099] [Figure 80] 1 presents the effect of the combination of Compound 1 and ruxolitinib on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent and JAK2-V617F cell lines; and IL3-independent BaF cell line cell lines.

[0100] [Figure 81]1 presents the effect of the combination of Compound 1 and low-dose ruxolitinib on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0101] [Figure 82] 1 presents the effect of the combination of Compound 1 and momelotinib on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0102] [Figure 83] 1 presents the effect of the combination of Compound 1 and pacritinib on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0103] [Figure 84] 1 presents the effect of the combination of Compound 1 and fedratinib on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0104] [Figure 85] 1 presents the effect of the combination of Compound 1 and everolimus on cell viability of hCRBN, JAK2, JAK2-V617F newly transduced cell lines; IL3-dependent, and JAK2-V617F cell lines; IL3-independent BaF cell lines.

[0105] [Figure 86] The effects of NS-018 and ruxolitinib as single agents on cell viability of JAK2V617F AML cell lines are presented.

[0106] [Figure 87]1 presents the effect of the combination of Compound 1 and NS-018 on cell viability of JAK2 V617F-positive HEL, SET-2, and MUTZ-8 AML cell lines.

[0107] [Figure 88] 1 presents the effect of the combination of Compound 1 and ruxolitinib on cell viability of JAK2 V617F-positive HEL, SET-2, and MUTZ-8 AML cell lines.

[0108] [Figure 89] 1 presents the effect of the combination of Compound 1 and everolimus on cell viability of HEL, SET-2, and MUTZ-8 AML cells.

[0109] [Figure 90] A summary of the effects of JAK2 inhibitors in combination with Compound 1 in JAK2 V617F cells is presented, and synergy was scored by EC50 shift and the Bliss method.

[0110] [Figure 91] 1 presents a dosing schedule for the combination of Compound 1 and the IDH2 inhibitor enasidenib (AG-221).

[0111] [Figure 92] The results of quantitative analysis of phenotypes in flow cytometry assays are presented.

[0112] [Figure 93] Scatter plots are presented showing the differentiation effects of the combination of Compound 1 and enasidenib (AG-221) on TF-1:IDH2R140Q stem and progenitor cells (CD34+) and CD34- / CD235+ erythroid cells according to Schedule A.

[0113] [Figure 94]The differentiation effects of Compound 1 and enasidenib on TF-1:IDH2R140Q stem and progenitor cells (CD34+ / CD38+), and HSCs (CD34+ / CD38-), and non-stem / progenitor CD34- / CD38- cells are presented using Schedules A, B, or C.

[0114] [Figure 95] 1 presents the differentiation effects of Compound 1 and enasidenib on CD235a+ (glycophorin A) erythroblasts.

[0115] [Figure 96] 1 presents the effects of Compound 1 and enasidenib on GSPT1 degradation in multiple cell subsets in a TF1 assay.

[0116] [Figure 97] 1 presents the effects of Compound 1 and enasidenib on GSPT1 degradation in multiple cell subsets in a TF1 assay.

[0117] [Figure 98] The effects of Compound 1 and enasidenib on cell proliferation, as measured by total cell number and undifferentiated HSC (CD34+ / CD38-) and progenitor (CD34+ / CD38+) cell number, are presented.

[0118] [Figure 99] Figure 1 shows that the combination of Compound 1 and RAD resulted in a significant decrease in GSPT1 protein and changes in phosphorylated proteins that regulate translation and metabolism. Western blot analysis was performed on BON cell lysates treated with the indicated concentrations of vehicle, RAD, and / or Compound 1 for 120 hours and probed with the indicated antibodies. Actin was used as a loading control.

[0119] [Figure 100]Figures 100A-100E show the combined effects of treatment with compound 1 and inhibitors targeting mTOR, FLT3, JAK2, or JAK3 on cell proliferation of U937 AML cells. Figure 100A shows the combination of compound 1 with the mTOR inhibitor everolimus; Figure 100B shows the combination of compound 1 with the FLT3 inhibitor quizartinib; Figure 100C shows the combination of compound 1 with the JAK2 inhibitor ruxolitinib; Figure 100D shows the combination of compound 1 with the JAK2 inhibitor AZD1480; and Figure 100E shows the combination of compound 1 with the JAK3 inhibitor tofacitinib.

[0120] [Figure 101] 1 shows the combined effects of treatment with Compound 1 and mTOR, FLT3, JAK2, or JAK3 inhibitors on GSPT1 expression, mTOR activation, ATF4 induction, and caspase-3 cleavage in U937 AML cells.

[0121] [Figure 102] Figures 102A-102G show the effect of Compound 1, at the indicated concentrations, with and without venetoclax, incubated for 48 hours on the proliferation of AML cell lines.

[0122] [Figure 103] Relative ATP levels are shown as a measure of viability in response to multiple dose combinations of Compound 1 and venetoclax.

[0123] [Figure 104] 1 shows Western blot analysis measuring GSPT1, Mcl-1, Bcl-2, cleaved caspase 3, and GAPDH protein levels in KG-1 cells 16 hours after treatment with multiple dose sets of compound 1, venetoclax, and the combination of compound 1 and venetoclax.

[0124] [Figure 105]Figures 105A and 105B show live cell analysis of KG-1 confluency (Figure 105A) and number of apoptotic events (Figure 105B) after treatment with Compound 1, venetoclax, and a combination of Compound 1 and venetoclax.

[0125] [Figure 106] 1 shows the combined effects of treatment with Compound 1 and everolimus on GSPT1 expression, mTOR activation, Mcl-1 expression, and caspase-3 cleavage.

[0126] [Figure 107] Figure 1 shows the effect of Compound 1 on bone marrow mononuclear cells or isolated CD34+ blasts from two different patients with myelodysplastic syndrome, assayed in liquid culture.

[0127] [Figure 108] 1 shows the effect of Compound 1 on bone marrow mononuclear cells from patients with myelodysplastic syndrome, assayed by liquid culture (A) or colony formation assay (B).

[0128] [Figure 109] 1 shows the effects of Compound 1 on caspase-3 activation and GSPT1 degradation in bone marrow mononuclear cells from myelodysplastic syndrome patients, tested as a single agent or in combination with 111 nM everolimus, after 24 hours of compound(s) exposure. DETAILED DESCRIPTION OF THE INVENTION

[0129] definition Generally, the nomenclature used herein, as well as the organic chemistry, pharmaceutical Laboratory procedures in chemistry and pharmacology are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally refer to It has the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains. The technical teachings of one embodiment may be combined with those disclosed in other embodiments provided herein. It can be adjusted.

[0130] The use of the words "a" or "an" in the claims and / or specification means When used with the word "comprising," it means "one" Although it is possible to use "one or more," "at least one," and "one or more" This is consistent with the meaning of "one or more than one."

[0131] As used herein, "comprising" and "including" The term "comprising" can be used interchangeably. The terms "including" and "including" mean that the stated feature or component is should be construed to specify the presence of one or more It does not preclude the presence or addition of features, components, or groups thereof. The terms "comprising" and "including" "consisting of" includes examples encompassed by the term "consisting of" Therefore, the term "consisting of" is used in To provide more specific embodiments of the invention, the terms "comprising" and "i It can be used instead of the term "including."

[0132] The term "consisting of" means that an object is made up of At least 90%, 95%, 97%, 98%, or In another embodiment, "consisting of ( The term "comprising" shall not be construed as a substitute for any other specific term in any subsequent description. It also excludes any length or component that is not essential to the technical effect to be achieved. The following are exceptions.

[0133] As used herein, the term "or" means any one or any combination. Therefore, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, or C." Exceptions to this definition are combinations of elements, functions, steps, or acts. This only occurs when the two are, in some way, inherently opposed to each other. "Prevent, or manage" or similar enumeration means: "treat; prevent Prevent; Manage; Treat and Prevent; Treat and Manage; Prevent and Manage treat, prevent, and control'.

[0134] The term "Compound 1" refers to "2-(4-chlorophenyl)-N- {[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- {2,2-difluoroacetamide}: [ka] and its stereoisomers or stereoisomeric mixtures, pharmaceutically acceptable salts, tautomers, prodrugs, In certain embodiments, the compound may be a globular compound, a solvate, a hydrate, a co-crystal, a clathrate, or a polymorph. In the above, compound 1 is 2-(4-chlorophenyl)-N-{[2-(2,6-dioxo Piperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-di Fluoroacetamide and its tautomers are shown. In certain embodiments, the compound 1 is a polymorphic form of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Cetoamide, e.g., Form A, B, C, D, or E crystalline forms, or mixtures thereof In certain embodiments, Compound 1 is in the C-type crystalline form of 2-(4-chloro-2-methyl-2-methyl-2-propanol). 2-(2,6-dioxopiperidin-3-yl)-1-oxophenyl)-N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo isoindolin-5-yl]methyl}-2,2-difluoroacetamide. In certain embodiments, Compound 1 is 2-(4-chlorophenyl)-N-{[ 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl ]methyl}-2,2-difluoroacetamide. The isomers are enantiomers.

[0135] Unless otherwise specifically stated, compounds may be in the form of alternative tautomers, regioisomers, and / or isomers. Where isomeric forms are possible, all alternative isomers are encompassed within the scope of the claimed subject matter. For example, if a compound can exist in one of two tautomeric forms, both are intended to be included herein.

[0136] Thus, the compounds herein may be enantiomerically pure or stereoisomerically pure. or a diastereomeric mixture. Unless otherwise specified, the term "stereomerically pure" refers to one stereoisomer of a compound. It means a composition that contains a compound and is substantially free of other stereoisomers of that compound. A stereomerically pure composition of a compound having one chiral center is a stereomerically pure composition of that compound. A compound having two chiral centers is substantially free of the opposite enantiomer. A stereomerically pure composition of a compound is substantially free of other diastereomers of the compound. A typical stereomerically pure compound is one stereoisomer of the compound. More than about 80% by weight of one stereoisomer and less than about 20% by weight of the other stereoisomer of the compound, more preferably or more than about 90% by weight of one stereoisomer of the compound and other stereoisomers of the compound and even more preferably less than about 95% by weight of one stereoisomer of the compound. % by weight of the compound and less than about 5% by weight of other stereoisomers of the compound, particularly preferably one of the compounds containing greater than about 97% by weight of one stereoisomer and less than about 3% by weight of other stereoisomers of that compound As used herein, a stereomerically pure compound refers to one form of that compound. More than about 80% by weight of one stereoisomer of the compound, more preferably more than about 90% by weight of one stereoisomer of the compound. More preferably, the compound is present in an amount of more than about 95% by weight of one stereoisomer of the compound, and even more preferably, the compound is present in an amount of more than about 95% by weight of one stereoisomer of the compound. Preferably, the compound contains greater than about 97% by weight of one stereoisomer. In some cases, and unless otherwise specified, the term "stereoisomerically enriched" refers to a compound More than about 60% by weight, preferably more than about 70% by weight, more preferably more than about 60% by weight, of one stereoisomer of the mixture. As used herein, "stereoisomer" refers to a composition that contains greater than about 80% by weight of one stereoisomer of a compound. When used and unless otherwise specified, the term "enantiomerically pure" refers to one It means an enantiomerically pure composition of a compound having a chiral center. The term "enantiomerically enriched" refers to stereoisomers of a compound with one chiral center. As used herein, the term "stereoisomer" refers to a composition enriched as a A stereomeric mixture refers to a composition containing more than one stereoisomer of a compound. A typical stereoisomeric mixture of a compound will contain about 50% by weight of one stereoisomer of the compound. and about 50% by weight of other stereoisomers of that compound, or one stereoisomer of that compound greater than about 50% by weight of one stereoisomer and less than about 50% by weight of the other stereoisomer of that compound; or A compound that is greater than about 45% by weight of one stereoisomer of the compound and about 5% by weight of another stereoisomer of the compound. Contains less than 5% by weight of one stereoisomer of the compound, or more than about 40% by weight of the compound containing less than about 60% by weight of one stereoisomer of the compound, or More than 35% by weight and less than about 65% by weight of other stereoisomers of the compound.

[0137] As used herein, API refers to Compound 1. In certain embodiments , the API is 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro This shows cetoamide.

[0138] As used herein, what are the abbreviations for protecting groups, amino acids, and other compounds? Unless otherwise noted, their common usage, recognized abbreviations, or IUP In accordance with the AC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11:9 42-944).

[0139] As used herein, and unless otherwise specified, the term "lyophilized" , refers to a process for isolating a solid material from a solution and / or removing a solvent. This can be achieved by a variety of techniques known to those skilled in the art, including: and / or by evaporation (e.g., in a vacuum, e.g., by freeze-drying) (e.g., freezing the solution and evaporating the frozen solvent under vacuum or reduced pressure) can be.

[0140] As used herein, the term "co-solvent" refers to the Co-solvents are solvents that aid in the solubilization of the active agent in water during manufacturing. Co-solvents are possible that also provide sufficient stability of the product. or can be reduced to an acceptable level. Nitriles, chloroform, tert-butanol, methanol, tetrahydrofuran, gypsum Acid, acetic acid, acetone, anisole, butanol, butyl acetate, tert-butylmethyl ether ether, ethanol, ethyl acetate, ethyl ether, ethyl formate, heptane, isobutyl acetate ethyl acetate, isopropyl acetate, methyl acetate, 3-methyl-butanol, methyl ethyl ketone, Methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol , 1-propanol, 2-propanol, and propyl acetate.

[0141] As used herein, and unless otherwise specified, the term "substantially free" The term "contains" means "contains no more than an insignificant amount." In some embodiments, a composition or the formulation contains less than 5%, 4%, 3%, 2%, or 1% by weight of the referenced element. In some embodiments, the composition is "substantially free" of an element when it contains The composition or preparation may contain the mentioned element at 0.9%, 0.8%, 0.7%, 0.6%, 0. In some embodiments, the content is 5%, 0.4%, 0.3%, 0.2%, or 0.1% or less. The composition or preparation contains the recited element in an undetectable amount.

[0142] As used herein, a "reconstituted aqueous solution" or "reconstituted aqueous composition" refers to a " or "reconstituted aqueous formulation" refers to the lyophilized formulations provided herein. It refers to an aqueous solution obtained by dissolving in an aqueous solvent.

[0143] As used herein, the term "aqueous diluent" refers to a liquid that may be included in a parenteral formulation. Such aqueous diluents include, for example, water, saline, and, if desired, 1 / 2 normal saline or dextrose, as well as those commonly found as part of parenteral formulations Examples of aqueous diluents include any of the known auxiliary preservatives or excipients used in pharmaceutical preparations. , water, 5% glucose solution, etc.

[0144] As used herein, and unless otherwise specified, the term "parenteral" includes subcutaneous , intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial Includes injection or infusion techniques.

[0145] As used herein, and unless otherwise specified, the expression "unit dose" refers to a therapeutic Refers to a formulation of physically discrete units (e.g., single doses) appropriate for the intended subject; each unit The position is a predetermined amount of active agent (of course) selected to produce the desired therapeutic effect. (and multiple doses may be required to achieve the desired or optimal effect) Optionally, with a pharmaceutically acceptable carrier, where the carrier is provided in a predetermined amount. A unit dose can be, for example, a volume containing a predetermined amount of one or more therapeutic agents. a liquid (e.g., an acceptable carrier), a predetermined amount of one or more solid therapeutic agents, a predetermined amount of May be a sustained-release formulation or drug delivery device containing one or more therapeutic agents Of course, a unit dose may contain various ingredients in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, Stabilizers, buffers, preservatives, etc. may be included as described below. It will be understood that the total daily usage of the disclosed combinations may be adjusted within the scope of reasonable medical judgment. The specific use for a particular subject or organism will be determined by the attending physician. The level of quantity may depend on a variety of factors, whatever the subject or organism, Such factors include the disorder being treated and the severity of the disorder; the particular activating agent being used; the activity of the substance; the specific composition used; the age, weight, general health, sex, and diet of the subject the time of administration, the rate of excretion of the specific active compound used; the duration of treatment; Drugs and / or additional therapies used in combination or concurrently with the therapeutic compound(s), and and similar factors well known in the medical field.

[0146] As used herein, the term "solid" refers to 2-(4-chlorophenyl)-N -{[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5 -yl]methyl}-2,2-difluoroacetamide or its stereoisomer or stereoisomer Isomer mixtures, pharmaceutically acceptable salts, tautomers, prodrugs, solvates, hydrates, co-forms It refers to crystalline, clathrate, or polymorphic, crystalline or amorphous forms or mixtures thereof.

[0147] As used herein, unless otherwise specified, "pharmaceutically acceptable salt(s)" refers to The term as used herein includes salts of the acidic or basic moieties of Compound 1. The basic moiety forms a wide variety of salts with various inorganic and organic acids, including, but not limited to, It can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds. Acceptable acids include non-toxic acid addition salts, for example, salts containing pharmacologically acceptable anions. Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, Succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, Acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, oleic acid, tannic acid, asparagine Acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucuronolic acid Saccharinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid benzenesulfonic acid, benzenesulfonic acid, or pamoic acid (e.g., 1,1'-methylene-bis(2-methyl-2-methyl-2-propanol) Examples of suitable hydroxybenzoates include, but are not limited to, bis-(2-hydroxy-3-naphthoic acid). Suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids. In addition to the above-mentioned acids, compounds having an amine moiety include, but are not limited to, various It can form pharmaceutically acceptable salts with various amino acids. can form base salts with various pharmacologically acceptable cations. Examples of salts include alkali metal or alkaline earth metal salts, particularly calcium salts, malic acid salts, and the like. There are magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts, or iron salts.

[0148] As used herein, and unless otherwise specified, the term "solvate" refers to a compound of the present invention. The compounds provided herein or salts thereof may further comprise stoichiometric or non-stoichiometric amounts of the compound. The term "solvent" refers to a substance that contains a solvent through intermolecular forces due to non-covalent bonds. , solvates are hydrates.

[0149] As used herein, and unless otherwise specified, the term "prodrug" refers to , under biological conditions (in vitro or in vivo), hydrolysis, oxidation, or is a derivative of a compound that can react in any way to give a compound. Examples of prodrugs include biohydrolyzable amides, biohydrolyzable esters, Biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and bio The compounds described herein having biohydrolyzable moieties, such as hydrolyzable phosphate analogs, Examples of compounds include, but are not limited to, derivatives of the compound (e.g., Compound 1).

[0150] A "pharmaceutically acceptable excipient" is an excipient that acts to, for example, modify the stability of an active agent. or by modifying the absorption by the subject upon administration, thereby facilitating the administration of an active agent to the subject. Pharmaceutically acceptable excipients typically do not pose significant toxicity to the patient. Examples of pharmaceutically acceptable excipients include water, NaCl ( saline solution), normal saline, half normal saline, sucrose, glucose, bulking agents , buffering agents, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, alcohols Carbohydrates such as alcohol, oil, gelatin, amylose or starch, fatty acid esters, hydrolyzed sugars, Examples of the additives include hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Other pharmaceutical excipients known in the art may be found to be useful in the present invention. Such pharmaceutical excipients are, for example, those listed in The Handbook of Pharmaceutical Excipients, Rowe RC, Shes ky PJ, and Quinn ME,6 th Ed., The Pharm Listed in aceutical Press, RPS Publishing (2009) The terms "bulking agent" and "buffering agent" are used in the art and are understood to be of ordinary skill in the art. Used according to its ordinary meaning.

[0151] As used herein, and unless otherwise specified, the term "about" means to refer to a composition or When used in reference to a dose, amount, or weight percent of an ingredient in a dosage form, the specified To produce a pharmacological effect equivalent to that obtained from a dose, amount, or weight percentage is meant to encompass dosages, amounts, or weight percents recognized by those of skill in the art. Specifically, the term "about" refers to a percentage of a specified dose, amount, or weight. Dosage, volume, or weight percentage within 0%, 25%, 20%, 15%, 10%, or 5% This document is intended to include all content.

[0152] As used herein, and unless otherwise specified, the term "stable" means a liquid When used with respect to a formulation or dosage form, the active ingredient of the formulation or dosage form is It remains dissolved for a length of time and does not significantly decompose, aggregate, or otherwise change. This means that the sample is not broken down (for example, when measured by HPLC). Depending on the form, more than about 70%, more than about 80%, or more than about 90% of the compound may be in the specified form. The stability is determined by the pharmaceutically acceptable excipients described herein. The compatibility of the excipients is also indicated. Thus, the dosage form is a combination of pharmaceutically acceptable excipients and The active agent(s) described herein do not degrade or Does not modify in any way the efficacy or therapeutic value of the active agent (e.g., does not interact with the active agent) It can be considered stable if the reaction is stable (no reaction).

[0153] As used herein, and unless otherwise specified, the term "stable" refers to a solid When used with respect to a formulation or dosage form, the active ingredient of the formulation or dosage form is significantly degraded. , decomposition, or in any way altered (e.g., as measured by HPLC) In some embodiments, the active ingredient is about 85% or more, or about 90% or more. At least about 95%, or at least about 98% of the solubility of the compound remains unchanged after a specified period of time. The compatibility of the pharmaceutically acceptable excipients described herein is also demonstrated. The combined pharmaceutically acceptable excipient and active agent(s) described herein does not degrade or otherwise impair the efficacy or therapeutic value of the active agents described herein. A compound can be considered stable if it is not modified in any way (e.g., does not react with an active agent). do.

[0154] As used herein, "administer" or "administration" refers to administering to an organism that is external to the subject. Administration refers to the act of physically delivering a substance into a subject. All known forms are included, such as topical, transmucosal, injectable, intradermal, and intravenous. intramuscular, intramuscular, or other physical means as described herein or known in the art. Delivery methods (e.g., placement of a sustained-release device such as a mini-osmotic pump in the subject; liposomal formulation; buccal ; sublingual; palatal; gingival; nasal; vaginal; rectal; intraarteriolar; intraperitoneal; intraventricular; intracranial; or Skin).

[0155] "Anti-cancer drugs" include antimetabolites (e.g., 5-fluorouracil, methotrexate, fludarabine), anti-microtubule agents (e.g., vincarcinomas such as vincristine and vinblastine), cyclopropyl methyl ... Cyclophosphamide, melphalan, carmustine, bischloroethylnitrosourea and nitrosoureas such as hydroxyurea), platinum-active agents (e.g., cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), Lacyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., Mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase enzyme inhibitors (e.g., etoposide, camptothecin), antiangiogenic agents (e.g., Sutent trademark), sunitinib malate, and bevacizumab), or any other cytotoxic drugs (estramustine phosphate, prednimustine), hormones or hormone analogs agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors , checkpoint inhibitors, and radiation therapy.

[0156] "Co-administration" refers to the administration of one or more compounds, compositions, or agents described herein in combination with one or more other compounds. Concurrent administration of multiple additional compounds, compositions, or agents, such as anti-cancer agents, Co-administration means administration of a compound, composition, or The agents may be administered individually or in combination (more than one compound or agent) simultaneously or Sequential administration is meant to include sequential administration. Co-administration is the administration of two compounds, compositions, or agents simultaneously. The active ingredients are administered simultaneously or at about the same time (e.g., about 1, 5, 10, 15, 20, or Within 30 minutes of each other), or sequentially in any order. One active agent (e.g., a compound described herein) is added to 0.5 of a second active agent. , should be administered within 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours. Simultaneous administration can include co-formulations, e.g., single dosage forms containing both active agents. This can also be achieved by preparing the active agents separately. In such cases, the active agents are mixed and included together in the final dosage unit. Alternatively, co-administration as described herein may be achieved by administering at least two distinct active ingredients. two separate, separate, and separate active agents (e.g., Compound 1 and a second active agent, as described herein). The method can include administering a dosage form.

[0157] As used herein, the term "daily" refers to a period in which a therapeutic compound, such as Compound 1, is administered daily. "Concurrent" shall mean administered once or more than once daily for a period of time. The term "continued" refers to a therapeutic compound, such as Compound 1, that has been in use for at least 10 days to 52 weeks. "Intermittent" or "intermittent" shall mean administered daily for an uninterrupted period. The term "at" as used herein means at either regular or irregular intervals. For example, intermittent administration of Compound 1 means stopping and starting the 1-6 days per cycle, cycle administration (e.g., 1-6 consecutive days in a 28-day cycle) daily for the first 10 days of the 28-day cycle, followed by a rest period without dosing for the remainder of the 28-day cycle; or Daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to 1 week without administration), or The term "in cycles" as used herein refers to the administration of Compound 1. The therapeutic compound, such as, is administered daily or continuously, but with rest periods. means:

[0158] "Cycling therapy" refers to a combination of administration periods as described herein and This indicates a regimen or treatment, including rest periods as indicated.

[0159] The term "administration period," as used herein, refers to the period during which a subject is administered the It refers to the period of time during which a compound or composition is administered continuously or actively.

[0160] The term "rest period," as used herein, refers to a period in which a subject is given any of the treatments described herein. indicates a period during which the compound or composition is not administered (e.g., treatment is discontinued), and follows the administration period. In certain embodiments, a "rest period" is a period in which a subject is not administered a single agent. It refers to a period during which no treatment is administered or during which treatment with a particular compound is discontinued. In embodiments, a second therapeutic agent (e.g., a compound or composition administered in a preceding administration period) A different agent than the agent can be administered to the subject.

[0161] An "effective amount" is a dose that produces the desired effect (e.g., treats a disease or alleviates a disease) for which it is administered. or a reduction in one or more symptoms of the condition. That is, administering to a subject an "amount" of a compound described herein may produce a desired therapeutic result. Therefore, for purposes herein, A "therapeutically effective amount" of a compound described herein for a The term "therapeutically effective amount" of a compound described herein is determined by consideration of the following: When administered, the compounds described herein can be used to treat diseases such as cancer, e.g., AML, MD, a composition sufficient to treat one or more symptoms of a tumor (e.g., a pulmonary necrosis factor (MPN), or solid tumor) The administration of the compounds described herein may be performed, for example, depending on the stage of the disease, the individual's The therapeutically effective amount of Compound 1 can be determined according to factors such as age, sex, and body weight. It also demonstrates that any toxic or adverse effects are outweighed by the therapeutically beneficial effects.

[0162] As used herein, and unless otherwise specified, "treat" means The terms "treating" and "treatment" , the root cause of a disease or disorder, or of one or more symptoms associated with a disease or disorder In certain embodiments, these terms refer to the complete or complete remission of a disease or disorder. The disease or condition that results from the administration of one or more prophylactic or therapeutic agents to a patient. In some embodiments, these terms refer to minimizing the spread or worsening of the disorder. , with or without other additional active agents, after the onset of symptoms of a particular disease, as described herein. In one embodiment, the disease is leukemia. Leukemia includes chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute myeloid leukemia (ACML), and lymphoblastic leukemia (ALL), acute myeloid leukemia, or acute myeloblastic leukemia (AM) In one embodiment, the leukemia includes, but is not limited to, at least Cancer may be relapsed, refractory, or resistant to at least one anti-cancer therapy. In one embodiment, the disease is AML, including the AML described herein. In one embodiment, the disease is myelodysplastic syndrome (MDS). There are various types of MDS, including the subtypes of MDS described herein.

[0163] As used herein, and unless otherwise specified, "prevent" ", "preventing," and "prevention." The term "prostate cancer" refers to the onset, recurrence, or progression of a disease or disorder or one or more symptoms thereof. In certain embodiments, these terms refer to preventing the onset of symptoms. Other follow-up studies may be conducted before death, particularly for patients at risk for the diseases or disorders provided herein. The compounds provided herein may be used with or without an additive agent. These terms refer to the administration of a compound or compound to treat a particular disease. Patients with a family history of the disease may be particularly susceptible to prophylactic regimens in certain embodiments. Patients with a history of recurrent symptoms may also be candidates for prophylaxis. In this regard, the term "prevention" is used interchangeably with "preventive treatment." In one embodiment, the disease is leukemia, and as leukemia Chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia These include, but are not limited to, acute myeloblastic leukemia and acute myeloblastic leukemia. In this study, the leukemia was relapsed, refractory, or resistant to at least one anticancer therapy. In one embodiment, the disease is AML, which may include The subtypes of AML described herein are included. In one embodiment, the disease is: MDS, including the subtypes of MDS described herein.

[0164] As used herein, and unless otherwise specified, "manage" The words "managing" and "management" The term refers to the progression, spread, or progression of a disease or disorder, or of one or more of its symptoms. In many cases, patients are given prophylactic and / or therapeutic medications. The beneficial effects of a therapeutic agent do not necessarily result in a cure of the disease or disorder. In this context, the term "managing" refers to the process of managing a person who has a particular disease. Treating a patient to prevent or minimize the recurrence of their disease, and In one embodiment, the disease is Leukemia, including chronic lymphocytic leukemia, chronic myeloid leukemia, and acute lymphoblastic leukemia leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. In one embodiment, the leukemia is resistant to at least one anti-cancer therapy. It may be relapsed, refractory, or resistant. In one embodiment, the disease is A AML, including the subtypes of AML described herein. In embodiments, the disease is MDS, including the subtypes of MDS described herein. Type included.

[0165] As used herein, "induction therapy" refers to the initial treatment given because of a disease such as cancer. refers to the treatment of a disease or the first treatment given with the intent of inducing complete remission of the disease. When used in a setting, induction therapy is that recognized as best treatment. For example, AM Induction therapy for L consisted of 7 days of cytarabine plus 3 days of anthracycline Treatment with daunorubicin or idarubicin is also included. If the patient is diagnosed with induction therapy, the patient is treated with another course of chemotherapy, called reinduction. If the patient is later in complete remission, additional treatments may be administered to prolong the patient's remission or potentially cure them. Consolidation and / or maintenance therapy is given.

[0166] As used herein, "consolidation therapy" refers to treatment to address the disease after remission is initially achieved. For example, cancer consolidation therapy refers to treatment given after the initial treatment has made the cancer disappear. Consolidation therapy may include radiation therapy, stem cell transplant, or cancer drugs. Consolidation therapy includes both intensive therapy and post-remission therapy. It is called.

[0167] As used herein, "maintenance therapy" refers to treatment after remission or optimal response has been achieved. Refers to treatment given because of a disease with the aim of preventing or delaying recurrence. , chemotherapy, hormone therapy, or targeted therapy.

[0168] "Remission," as used herein, refers to the improvement of symptoms and symptoms of cancer, e.g., multiple myeloma. A partial remission is the disappearance of some of the signs and symptoms of cancer. In a complete remission, all signs and symptoms of cancer disappear, but the cancer is still present. may be present in the body as

[0169] The terms "subject," "patient," "subject in need," and "patient in need" are used. The terms are used interchangeably herein and are treatable by administration of the compositions described herein. an organism suffering from one or more of the diseases described herein (e.g., AML) Examples of living organisms include, but are not limited to, humans, other mammals, cows, rats, mice, and dogs. , monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the subject is a human. The human subject is typically between about 1 year and about 100 years old. In embodiments, the subject herein is a patient characterized by the disease being treated. It is possible to group the target groups into groups (e.g., "AML target," "cancer target," or "leukemia target"). ").

[0170] As used herein, the term "tumor" refers to any neoplastic disease, whether malignant or benign. "Neoplastic" refers to cell growth and proliferation, and all pre-cancerous and cancerous cells and tissues. As used herein, any form of abnormal tissue growth, whether benign or malignant, is included. exhibits dysregulated or uncontrolled cell proliferation. Includes malignant and benign cells that undergo uncontrolled cell proliferation.

[0171] As used herein, a "hematologic malignancy" refers to a tumor that affects the body's blood-forming and immune systems—bone marrow and lymph nodes. This refers to cancer of the lymphatic system. Such cancers include leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma), and myeloma. In some embodiments, the myeloma is multiple myeloma. In some embodiments, the leukemia is, for example, acute myeloma. Myeloid leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia lymphocytic leukemia (CLL), hairy cell leukemia, myelodysplastic syndromes, myeloproliferative disorders or bone marrow leukemia Myeloproliferative neoplasms (MPN), chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS), Human lymphotropic virus type 1 (HTLV-1) leukemia, mastocytosis, or B-cell acute lymphoblastic leukemia In some embodiments, the lymphoma is, for example, diffuse large cell lymphoma. B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-dividing cell lymphoma, Human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma , peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell Lymphoma (MCL), Hodgkin's lymphoma (HL), Non-Hodgkin's lymphoma (NHL), AI DS-associated lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocytic lymphoma Follicular B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, Splenic marginal zone lymphoma, Richter transformation, nodal marginal zone lymphoma, or ALK-positive large cell In one embodiment, the hematological cancer is an indolent B-cell lymphoma. , low-grade lymphomas, such as DLBCL, follicular lymphoma, or marginal zone lymphoma In one embodiment, the hematological malignancy is AML. In some embodiments, the hematological malignancy is MDS.

[0172] The term "leukemia" refers to a malignant tumor of the blood-forming tissues. Leukemia includes chronic lymphocytic leukemia, Hemophilia, chronic myeloid leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia Leukemia includes, but is not limited to, myeloid leukemia. It may be relapsed, refractory, or resistant to therapy.

[0173] In one embodiment, the subject has AML, including, for example, the following subtypes of AML: The term "acute myeloid or myeloid leukemia" refers to a disease that affects primarily undifferentiated cells in the bone marrow. a hematological condition characterized by the proliferation and accumulation of differentiated or minimally differentiated bone marrow cells, This term includes either the FAB (French, American, British) or WHO classification systems. As described herein, AML includes subtypes classified by FA. Based on the B classification, the following subtypes are included: M0 (mostly undifferentiated AML); M1 (least differentiated AML); differentiated AML); M2 (differentiated AML); M3 (acute promyelocytic leukemia); M4 (acute myeloid leukemia); monocytic leukemia); M4 (eos acute myelomonocytic leukemia with eosinophilia); M5 (acute monocytic leukemia); M6 (acute erythroleukemia); and M7 (acute megakaryoblastic leukemia). As described in [2], AML includes the following subtypes based on the WHO classification: recurrent AML; AML with genetic abnormalities (AML with translocation between chromosomes 8 and 21); AML with chromosomal translocations or inversions; AM with a translocation between chromosomes 9 and 11 L: APL with a translocation between chromosomes 15 and 17 (M3); AML with translocations between chromosomes; AML with translocations or inversions on chromosome 3; AML with translocations or inversions on chromosome 1 AML (megakaryoblastic) with translocation between chromosomes 21 and 22; associated with myelodysplasia-associated changes AML; AML associated with previous chemotherapy or radiation (alkylating agent-associated AML; Topoisomerase II inhibitor-associated AML; AML of unknown lineage (not falling under the above categories) AML, namely, minimally differentiated AML (M0); minimally differentiated AML (M1); and differentiated AML (M2). ML (M2); acute myelomonocytic leukemia (M4); acute monocytic leukemia (M5); acute erythroleukemia acute megakaryoblastic leukemia (M6); acute megakaryoblastic leukemia (M7); acute basophilic leukemia; acute with fibrosis panmyelosis); myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma) and undifferentiated and biphenotypic acute leukemia (also known as mixed phenotypic acute leukemia). (https: / / www.cancer.org / cancer / acute -myeloid-leukemia / detection-diagnosis-st aging / how-classified.html, last accessed 201 May 25, 2017).

[0174] In certain embodiments, cytogenetic-based AML risk groups are described below. As shown: [Table 1] a The molecular disorders included in this table are available for analysis by standardized, commercial laboratory-validated methods. The figures reflect what is available. b New data suggest that t(8;21) and, to a lesser extent, inv(16) may be involved in the The presence of KIT has been shown to be associated with a higher risk of recurrence in these patients. Patients are considered to be at intermediate risk and, if possible, undergo hematopoietic stem cell transplantation (HSCT) or clinical trials. If these findings are accompanied by other cytogenetic abnormalities, patients should be considered for inclusion in a clinical trial. If the risk is not met, the risk situation will not change. c Paschka P,et al.Blood 2013;121:170-177. d These findings, along with other cytogenetic abnormalities, suggest a favorable risk status. It will never change. e Philadelphia + acute myeloid leukemia (AML) t(9;22) - tyrosine kinase Addition of an enzyme inhibitor is used to manage myeloid blast crisis in a manner similar to that of chronic myeloid leukemia (CML). do.

[0175] In one embodiment, the subject has a subtype of MDS, including, for example, the following subtypes: The term "myelodysplastic syndrome" refers to the development of a disorder in one or more cells of the blood. Components (red blood cells, white blood cells (excluding lymphocytes), and platelets (or their precursor cells, megakaryocytes)) MDS refers to a hematological condition characterized by abnormalities in the production of bone marrow (B The ineffective hematopoiesis and peripheral blood cytopenias of M) are clinically manifested as anemia of varying frequency and severity, Anemia manifests as neutropenia and / or thrombocytopenia. This is a finding that often progresses to red blood cell (RBC) transfusion dependence. Other less common associated clinical signs include increased risk of infection and and / or increased bleeding symptoms and a tendency to progress to acute myeloid leukemia (AML) (C atenacci,et al.Blood Rev 2005;19:301-319 ).

[0176] MDS includes the following disorders: refractory anemia (RA); RA with ringed sideroblasts; (RARS); RA with excess blasts (RAEB); refractory cytopenia with multilineage dysplasia Refractory cytopenia with monolineage dysplasia (RCMD); refractory cytopenia with monolineage dysplasia (RCUD); unclassifiable Myelodysplastic syndrome (MDS-U), a myelopathic disorder associated with isolated del(5q) chromosomal abnormality MDS is a group of diseases that affect the immune system, including: myeloma, myeloma-associated myeloma, myeloma-associated myeloma, and chronic myelomonocytic leukemia (CMML). As used herein, very low risk, low risk, medium risk, high risk, and very high risk In some embodiments, the MDS is primary or de novo MDS. In other embodiments, the MDS is secondary.

[0177] In certain embodiments, MDS is classified as: and classified as described below: WHO classification of MDS [Table 2] TIFF2023113681000005.tif194170 a Cytopenias were defined as follows: hemoglobin, <10 g / dL; platelet count, < 100×10 9 / L; and absolute neutrophil count, <1.8 × 10 9 / L. Rarely, MDS may Peripheral blood mononuclear cells (PBMCs) exceeding these levels may indicate mild anemia or thrombocytopenia. <1×10 9 Must be / L. b Cases with ≥15% ringed sideroblasts and significant erythroid dysplasia by definition are classified as M It is classified as DS-RS-SLD. c 1 percent PB blasts must be recorded on at least two separate occasions . d Abnormalities are demonstrated by conventional karyotyping, not by FISH or sequencing The presence of del(20q) +8, -Y is a morphological diagnosis of MDS. The absence of features is not considered to confirm MDS. ood 2016;127(20):2391-2405, and Vardiman,et. al.Blood.2009;114(5):937-51.

[0178] As used herein, "promyelocytic leukemia" or "acute promyelocytic leukemia" refers to There is a deficiency of mature blood cells in the myeloid cell lineage and an excess of immature cells called promyelocytes. This refers to a malignant tumor of the bone marrow, usually involving a region exchange between chromosomes 15 and 17. It is characterized by:

[0179] As used herein, "acute lymphocytic leukemia (ALL)" or "acute lymphoma" refers to Also known as "blastic leukemia," this is an abnormal development of early nongranular white blood cells or lymphocytes. It refers to a malignant disease caused by growth and development.

[0180] As used herein, "T-cell leukemia" refers to a type of leukemia that is caused by T lymphocytes or T cells. This refers to a disease in which certain cells in the lymphatic system become malignant. T cells are usually responsible for the proliferation of virus-infected cells. Produce substances that can attack foreign cells and cancer cells and regulate the immune response These are white blood cells that can

[0181] The term "relapsed" refers to a patient whose leukemia went into remission after treatment, but whose leukemia cells return to the bone marrow. This results in a decrease in normal blood cells.

[0182] The term "refractory or resistant" refers to the condition in which a patient develops persistent leukemia in their bone marrow, even after intensive treatment. This shows a situation with leukemia cells.

[0183] The term "drug resistance" refers to a disease that does not respond to treatment with a particular drug or drugs. Drug resistance can be either intrinsic or acquired. Intrinsic resistance refers to the This means that the patient has never had a reaction to a particular drug or drugs. Acquired means that the disease no longer responds to one or more specific drugs to which it previously responded. In certain embodiments, the drug resistance is intrinsic. In certain embodiments, the drug resistance is acquired.

[0184] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound , which provides a therapeutic benefit in the treatment or management of a disease or disorder, or which is associated with a disease or disorder The compound is an amount sufficient to delay or minimize one or more of the associated symptoms. A therapeutically effective amount of a substance is one in which a therapeutic agent, alone or in combination with other treatments, is effective to treat a disease or disorder. The term "therapeutically effective amount" means an amount that provides a therapeutic effect in the treatment or management of improve overall treatment, reduce or avoid the symptoms or causes of a disease or disorder, or Alternatively, it may include an amount that enhances the therapeutic effect of another therapeutic agent.

[0185] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound , an amount sufficient to prevent a disease or disorder or to prevent its recurrence. A prophylactically effective amount of a therapeutic agent, alone or in combination with other agents, is a prophylactically effective amount of a therapeutic agent that is effective in preventing a disease. The term "prophylactically effective amount" refers to an amount that provides a prophylactic benefit. or an amount that enhances the prophylactic effectiveness of another prophylactic agent.

[0186] As used herein, ECOG status refers to the Eastern Cooperative Oncology Group (ECOG) status as follows: The European Commission of Group (ECOG) performance status is shown (Oken M, et al Toxicity and response criteria of the Ea stern Cooperative Oncology Group.Am J Cl in Oncol 1982;5(6):649-655): [Table 3]

[0187] In the context of cancer, treating or inhibiting can mean, inter alia, inhibiting disease progression, inhibiting tumor growth, , reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, primary or secondary tumors delayed appearance of tumors, slowed growth of primary or secondary tumors, development of primary or secondary tumors reduction in the severity of the disease, delay in secondary effects of the disease or reduction in their severity, cessation of tumor growth and tumor regression , prolongation of time to progression (TTP), prolongation of progression-free survival (PFS), and overall survival ( OS, as used herein, can be evaluated by the prolongation of treatment duration (OS). TTP means the time from the onset of disease to death from any cause. If present, TTP refers to the time from the start of treatment to tumor progression; TTP does not include death. Time to remission (TTR), as used herein, is the time from initiation of treatment to the end of remission, e.g., complete remission. PFS means the time to complete or partial remission. As used herein, PFS refers to the time to complete or partial remission. In one embodiment, the time from the start of treatment to tumor progression or death. PFS rates will be computed using the Kaplan-Meier method. Event-free survival The extended free survival (EFS) period is measured from study enrollment until disease progression, treatment discontinuation for any reason, or death. Recurrence-free survival (RFS) is the time to any treatment failure. This refers to the length of time a patient lives without any signs or symptoms of their cancer after completion of treatment. Objective response rate (ORR) refers to the combined percentage of patients who achieved a complete response and a partial response. The complete remission rate (CRR) is the percentage of patients who achieved a complete remission (CR). Duration of response (DoR) is the time from achieving response to relapse or disease progression. A remission period is a period of time during which remission, e.g., complete or partial remission, is achieved followed by relapse. In extreme cases, complete inhibition is referred to herein as prevention or chemoprevention. In this context, the term "prevention" refers to the complete prevention of clinically evident cancer development. This definition includes either preventing cancer from occurring at a preclinical stage or preventing cancer from occurring at a preclinical stage. Also intended to be included are the prevention of transformation of malignant cells or the reduction of premalignant cells. The progression of cytoplasmic cells to malignant cells is halted or reversed. This includes preventive treatment of

[0188] In the case of leukemia, specifically AML, response to treatment is measured by the International Working Group on AML Response Measures. It can be evaluated based on the criteria (Cheson et al. J Clin Onc ol 2003;21(24):4642-9).

[0189] Hematological response according to IWG AML criteria: [Table 4]

[0190] Important abbreviations: CR = complete remission; EMD = extramedullary disease; IWG = international working group; NA = not applicable.

[0191] Treatment of lymphoma should be based on the NH International Working Group's definitions of response and endpoints, as outlined below. It can be evaluated by the IWC criteria (Cheson BD, et al. See J. Clin. Oncol: 2007:(25)579-586): [Table 5] TIFF2023113681000009.tif70170Abbreviations: CR, complete remission; FDG, [ 18 F]fluorodeoxyglucose; PET, positive tron tomography; CT, computed tomography; PR, partial response; SPD, sum of product diameters ;SD, stable;PD, progressive. [Table 6] Abbreviations: Abbreviations: CR: complete remission; PR: partial remission.

[0192] In one embodiment, the endpoint for lymphoma is the outcome of clinical benefit. Clinical benefit is measured by improvement in quality of life or reduction in patient symptoms, transfusion requirements, and frequency. This may be reflected in a decrease in the incidence of lymphoma-related symptoms or other parameters. Time to onset or progression can also be used for this endpoint.

[0193] Treatment of CLL is based on the response and endpoints outlined in the International Study Group CLL Guidelines. Using the definition of the point, the guidelines (Hallek M, et al. Blood ,2008;(111)12:5446-5456), In detail: [Table 7]

[0194] Group A criteria define tumor burden; Group B criteria define hematopoietic (or CR (Complete Response): All criteria must be met and Patients must have no disease-related constitutional symptoms; PR (partial response): Group A At least two of the criteria + at least one of the criteria for Group B must be met SD is defined as the absence of progressive disease (PD) and the achievement of at least PR. PD: At least one of the criteria for Group A or Group B must be met. The sum of multiple lymph nodes (as determined by CT scan in clinical trials or by comprehensive diagnostic testing) These parameters may vary depending on the response category. It may be irrelevant.

[0195] Treatment of MM is assessed by the National Institutes of Multiple Myeloma using the response and endpoint definitions below. International Uniform Effectiveness Criteria (IURC) (Durie et al. Leukemia, 200 6;(10) 10:10:1-7) can be evaluated by: [Table 8] Abbreviations: Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR , stringent complete response;VGPR, very good partial response; a All response categories were based on any new Requires two consecutive assessments performed at any time before administering any new treatment; The risk is that if radiographic examination is performed, there is no evidence of progression or new bone lesions. Radiographic studies are not required to meet these response requirements; b Confirmation with repeat bone marrow biopsy is not necessary; c The presence or absence of clonal cells is determined by κ / λ Ratio-based. Abnormalities in the kappa / lambda ratio are analyzed by immunohistochemistry and / or immunofluorescence. A minimum of 100 plasma cells is required for the detection of abnormal clones. The usual ratios are κ / λ >4:1 or <1:2. d Measurable disease means the following measurements: Defined by at least one of the following values: bone marrow plasma cells ≥ 30%; serum M protein ≥ 1g / dl (≥ 10 gm / l) [10 g / l]; urinary M protein ≥ 200 mg / 24 h; blood Serum FLC assay: Involved FLC levels ≥ 10 mg / dl (≥ 100 mg / l); but if serum FLC ratio is abnormal.

[0196] Cancer treatments should be evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Thereasse P., et al. J. of the Nationa l Cancer Institute;2000;(92)205-216 and Eis enhauer et al.European J.Cancer;2009;(45 )228-247). Target and non-target lesions with or without the appearance of new lesions. The overall efficacy for all possible combinations of tumor responses in the study is as follows: [Table 9] CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.

[0197] Regarding the evaluation of target lesions, a complete response (CR) is the disappearance of all target lesions, and a partial response is the disappearance of all target lesions. A response (PR) was defined as a reduction of at least 3x the sum of the longest diameters of target lesions compared to the baseline sum of the longest diameters. Progression (PD) was defined as the smallest sum of the longest diameters recorded since the start of treatment. At least a 20% increase in the sum of the longest diameters of the target lesions or one or more new The appearance of lesions, and stable disease (SD) is defined as the minimum sum of the longest diameters since the start of treatment. There is neither enough shrinkage to qualify as a minute response nor enough growth to qualify as a progression.

[0198] Regarding the evaluation of non-target lesions, a complete response was defined as the disappearance of all non-target lesions and tumor markers. normalization of levels; incomplete response / stable disease is defined as one or more non-target lesion(s). and / or tumor marker levels remain above the upper limit of normal, indicating progressive disease (PD) This is defined as the appearance of one or more new lesions and / or a clear worsening of existing non-target lesions. be.

[0199] Treatment for MDS is evaluated according to the International Working Group (IWG) Myelodysplastic Response Criteria. It is possible to price it. Revised IWG Response Criteria for MDS [Table 10] TIFF2023113681000015.tif188170BM=bone marrow;CR=complete remission;FAB=France-US-UK;Hgb=hemoglobin Robin; HI = Hematologic Improvement; IWG = International Working Group; MDS = Myelodysplastic Syndrome; PB = peripheral blood; PD = progressive disease; PR = partial response; RBC = red blood cells. a Dysplastic changes should be considered as dysplastic changes within the normal range (segmental changes). b Revised IWG response criteria. c In some circumstances, protocol treatment may be initiated prior to a 4-week period with further treatment (e.g., consolidation). Such patients may need to be treated immediately after treatment is initiated. Once the patient has completed the course of chemotherapy, they can be included in the appropriate response category. Transient cytopenias during treatment are considered to be prolonged as long as they return to the previous course. should not be considered a disruption of d Sponsor revision of IWG criteria. Source: Cheson, 2006 and Vardiman, 2008. RBC and platelet transfusion independence [Table 11] RBC = red blood cells; Hgb = hemoglobin. a RBC transfusion independence and RBC transfusion dependence are defined by the revised IWG criteria. b Platelet transfusion independence and platelet transfusion dependence will be defined by the sponsor. Source:Cheson,et al.Blood.2006;108(2):419-25 .

[0200] The following revised international prognostic scoring system is used for prognosis in MDS: IPSS-R Cytogenetic Risk Groups [Table 12] Source: Greenburg, et al. Blood. 2012;120(12):24 54-65. Value of the IPSS-R prognostic score [Table 13] Source: Greenburg, et al. Blood. 2012;120(12):24 54-65.

[0201] The total IPSS-R score is based on cytogenetics, bone marrow blast percentage, hemoglobin, and blood It is calculated as the sum of the scores for platelet count, platelet count, and ANC. IPSS-R prognostic risk category / score [Table 14] Source: Greenburg, et al. Blood. 2012;120(12):24 54-65. IPSS-R: Prognostic Risk Category Treatment Results [Table 15] Source: Greenburg, et al. Blood. 2012;120(12):24 54-65.

[0202] compound Compounds suitable for use in the methods and formulations provided herein have the structure: Compound 1: 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidinyl] 1-oxoisoindolin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Acetamide: [ka] or a stereoisomer or a mixture of stereoisomers thereof, an isotope-substituted derivative, or a pharmaceutically acceptable salt thereof, It may be a tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph. In this embodiment, compound 1 is 2-(4-chlorophenyl)-N-{[2-(2,6-dioxophenyl)-N-(4-chloro ... 2,2-isopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl Difluoroacetamide is shown.

[0203] Compound 1 can be prepared according to the methods described in the Examples provided herein or by methods described in U.S. Pat. 9,499,514, and can be prepared as described in U.S. Pat. No. 9,514 is incorporated herein by reference in its entirety. Based on the teachings of the present invention, other methods that will be apparent to those skilled in the art can also be used for synthesis.

[0204] In certain embodiments, Compound 1 is a solid. In certain embodiments, Compound 1 is a solvated form. In certain embodiments, Compound 1 is an anhydrate.

[0205] In certain embodiments, Compound 1 is amorphous. In certain embodiments, Compound 1 is crystalline. The crystalline form is described in U.S. Patent Application Publication No. 2017-0197934, filed on June 6, , the disclosure of which is incorporated herein by reference in its entirety. Representative solid forms include It is described on pages 86-101.

[0206] The solid form of Compound 1 is disclosed in U.S. Patent Application Publication No. 2017-019793, filed January 6, 2017. It can be prepared according to the method described in the disclosure of No. 4, pp. 86-101. Compound 1 of the formula (I) can also be prepared according to other methods apparent to those skilled in the art.

[0207] In one embodiment, Compound 1 is present in the form of a Type A crystal, a Type B crystal, a Type C crystal, a Type D crystal, or a Type E crystal. 2-(4-chlorophenyl)-N-{[2-(2, 6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl} -2,2-difluoroacetamide. (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]me The polymorphism of {ethyl}-2,2-difluoroacetamide is briefly described herein. .

[0208] Form A of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto amide In certain embodiments, the formulations provided herein are prepared from Form A of Compound 1. It is manufactured.

[0209] In one embodiment, Form A is the anhydrous form of Compound 1. Form A of Compound 1 is crystalline.

[0210] In certain embodiments, Form A is prepared in a particular solvent system, for example, one of the following solvents: or by crystallization at room temperature from a solvent system containing: acetone, and a solvent mixture of isopropanol and water. In certain embodiments, Form A can be prepared by high temperature For example, at about 50° C., ethanol / water (1:1), acetone, or acetonitrile It is an intermediate solid form obtained from a slurry.

[0211] In certain embodiments, Form A is, for example, as shown by powder X-ray diffraction measurements. In one embodiment, Form A of Compound 1 is substantially crystalline. It has the powder X-ray diffraction pattern shown in

[0212] In one embodiment, Form A of Compound 1 has a pH of about 11.5, 15.6, or 16.5 as shown in FIG. , 16.6, 17.2, 18.1, 19.0, 19.6, 21.1, 23.2, or 2 It has one or more characteristic powder X-ray diffraction peaks at a 2θ angle of 4.8° 2θ. In embodiments, Form A of Compound 1 has an NA of about 15.6, 16.6, 17.2, or 24.8 Possessing one, two, three, or four characteristic powder X-ray diffraction peaks at 2θ angles of 20° In another embodiment, Form A of Compound 1 has the characteristic powder form as set forth in Table A. The compound has one, two, three, four, five, six, or seven X-ray diffraction peaks. In this embodiment, Form A of Compound 1 exhibits the characteristic X-ray powder diffraction peaks as set forth in Table A. have one, two, or three. Table A [Table 16] TIFF2023113681000023.tif77170

[0213] In one embodiment, Form A of Compound 1 has an SEM image as shown in FIG. .

[0214] In one embodiment, the crystalline form of Compound 1 is obtained at a representative TGA temperature as shown in FIG. A thermogravimetric analysis (TGA) thermograph substantially corresponds to a temperature record. In terms of morphology, no TGA weight loss is observed for Form A.

[0215] In one embodiment, crystalline Form A of Compound 1 has a DSC spectrum substantially as shown in FIG. In one particular embodiment, Form A has an onset temperature of 229°C and a heat of fusion of It is characterized by a DSC plot containing a melting event of 118 J / g.

[0216] In certain embodiments, Form A is characterized by dynamic vapor sorption analysis. A representative dynamic vapor sorption (DVS) isotherm plot is shown in Figure 6. In certain embodiments, When the relative humidity ("RH") increases from about 0% to about 90% RH, Type A has a 1.5% exhibits a water uptake of less than, less than 1.2%, or about 1.2% w / w. In the case of Type A, a coulometric Karl Fischer (KF) titrator is used with an oven set to 225°C. Contains less than 0.1% water when measured with a sample processor.

[0217] In certain embodiments, for Form A, significant degradation or residual solvent is 1 HN Not observed by MR (Fig. 7).

[0218] In certain embodiments, Form A of Compound 1 is characterized by its stability profile upon compression. In certain embodiments, Form A is stable, e.g., characterized by When a pressure of 2000 psi was applied for approximately 1 minute, the XRPD pattern showed a broad diffraction peak. The resulting product remains essentially unchanged (Figure 8).

[0219] In yet another embodiment, Form A of Compound 1 is substantially pure. In embodiments, substantially pure Form A of Compound 1 may be present in other solid forms, such as amorphous forms. In certain embodiments, the purity of substantially pure Form A of Compound 1 is is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 9 8.5% or more pure, approximately 99% or more pure, approximately 99.5% or more pure, or approximately 99.8% or more pure It is pure.

[0220] In certain embodiments, Form A of Compound 1 is substantially pure. In this embodiment, Form A of Compound 1 may be used in combination with other solid forms of Compound 1, such as Substantially free of Forms B, C, D, E, and / or amorphous solids that make up Compound 1 In certain embodiments, Form A is a mixture of solid forms comprising Compound 1, The mixtures include, for example, mixtures containing one or more of the following: Forms B, C, D, E and amorphous solids.

[0221] Form B of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto amide In certain embodiments, the formulations provided herein comprise anhydrous Form B of Compound 1. It is prepared from

[0222] In certain embodiments, Form B is prepared in a particular solvent system, for example, one of the following solvents: or by anti-solvent crystallization from solvent systems containing: methanol / water, DMSO / Isopropanol, DMSO / toluene, and DMSO / water. In certain embodiments Form B can be obtained by cooling recrystallization from THF / water (1:1).

[0223] In certain embodiments, Form B is, for example, as shown by powder X-ray diffraction measurements. In one embodiment, Form B of Compound 1 is substantially as shown in FIG. It has the powder X-ray diffraction pattern shown below.

[0224] In one embodiment, Form B of Compound 1 has a pH of about 15.4, 16.3, or 17.4 as shown in FIG. , characteristic at 2θ angles of 16.7, 17.7, 20.4, 25.6, or 27.5°2θ In another embodiment, Form B of Compound 1 has one or more powder X-ray diffraction peaks. are one, two, and at 2θ angles of approximately 16.7, 25.6, 15.4, or 16.3°2θ. In another embodiment, Form B has three or four characteristic powder X-ray diffraction peaks. Compound 1 has one, two, three characteristic powder X-ray diffraction peaks as listed in Table B. In another embodiment, Form B of Compound 1 has one, four, five, six, or seven. having one, two, or three characteristic powder X-ray diffraction peaks as set forth in Table B . Table B [Table 17] TIFF2023113681000025.tif143170

[0225] In one embodiment, Form B of Compound 1 has an SEM image as shown in FIG. In one embodiment, the crystalline form of Compound 1 is a representative TG as shown in FIG. A thermogravimetric analysis (TGA) thermograph substantially corresponding to a temperature record. In embodiments, Form B exhibits no TGA weight loss below 170° C. In an embodiment, Form B exhibits a TGA weight loss of 0.4% between 170 and 230°C.

[0226] In one embodiment, the B-type crystals of Compound 1 have a DS substantially as shown in FIG. In certain embodiments, Form B has a melting point of 219-224°C. The DSC plots show the recrystallization event and the main melting event at a peak temperature of 231°C. Sex is determined.

[0227] In certain embodiments, Form B is characterized by dynamic vapor sorption analysis. A typical dynamic vapor sorption (DVS) isotherm plot is shown in Figure 13. When the relative humidity ("RH") increases from about 0% to about 90% RH, Type B increases by about 1. In certain embodiments, Form B exhibits a water uptake of 4% w / w. Measurements were performed using a KF titrator equipped with an oven sample processor set at 225°C. Contains less than 0.1% water when heated.

[0228] In certain embodiments, Form B has no significant degradation or residual solvent. 1 H NMR This is less evident (Figure 14).

[0229] In certain embodiments, Form B of Compound 1 is In certain embodiments, Form B is stable, e.g., 2 When a pressure of 1000 psi was applied for approximately 1 minute, the XRPD pattern showed a broadening of the diffraction peaks. Although the α-glucan is slightly oxidized, it remains essentially unchanged (Figure 15).

[0230] In yet another embodiment, Form B of Compound 1 is substantially pure. In embodiments, substantially pure Form B of Compound 1 may be present in other solid forms, such as amorphous forms. In certain embodiments, the purity of substantially pure Form B of Compound 1 is is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 9 8.5% or more pure, approximately 99% or more pure, approximately 99.5% or more pure, or approximately 99.8% or more pure It is pure.

[0231] In certain embodiments, Form B of Compound 1 is substantially pure. In this embodiment, Form B of Compound 1 may be used in combination with other solid forms of Compound 1, such as Substantially free of Forms A, C, D, E, and / or amorphous solids that make up Compound 1 In certain embodiments, Form B is a mixture of solid forms comprising Compound 1, The mixture may include, for example, a mixture comprising one or more of the following: Compound 1 Forms A, C, D, E, and amorphous solids.

[0232] C-type 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto amide In certain embodiments, the formulations provided herein are prepared from anhydrous Form C of Compound 1. In certain embodiments, Form C is the most thermodynamically efficient crystalline form of Compound 1. It is a chemically stable anhydrate.

[0233] In certain embodiments, Form C can be prepared by dissolving Compound 1 in certain solvent systems, such as and a solvent system containing one or more of the solvents : Acetonitrile / water, acetone, or ethanol / water.

[0234] In certain embodiments, Form C can be prepared by adding Form B (1× weight) to acetone (30× volume). and then slurried at high temperature, for example, 60-80°C or 70-75°C for at least 24 hours. and then cooling the mixture to room temperature. The annealing is carried out under nitrogen pressure of 50-55 psi at 70-75°C. In embodiments, the mixture is cooled to room temperature over a period of at least 6 hours.

[0235] In certain embodiments, Form C is, for example, as shown by powder X-ray diffraction measurements. In one embodiment, Form C of Compound 1 is substantially as shown in FIG. The powder X-ray diffraction pattern is as follows:

[0236] In one embodiment, Form C of Compound 1 has a pH of about 7.4, 11.5, as shown in FIG. , 15.8, 16.7, 16.9, 17.7, 18.4, 19.2, 19.5, 21.1 , characteristic powder X-ray diffraction peaks at 2θ angles of 23.4, 24.7, or 29.9°2θ In another embodiment, Form C of Compound 1 has one or more of about 16.7, 16 One, two, three, or four features at 2θ angles of 0.9, 17.7, or 24.7°2θ In another embodiment, Form C of Compound 1 has the characteristic powder X-ray diffraction peaks shown in Table C. One, two, three, four, five, six characteristic powder X-ray diffraction peaks as listed In another embodiment, Form C of Compound 1 is as set forth in Table C. They have one, two, or three characteristic powder X-ray diffraction peaks. Table C [Table 18]

[0237] In one embodiment, Form C of Compound 1 has an SEM image as shown in FIG. In one embodiment, the crystalline form of Compound 1 is a representative TG as shown in FIG. A thermogravimetric analysis (TGA) thermograph substantially corresponding to a temperature record. In embodiments, Form C exhibits no TGA weight loss.

[0238] In one embodiment, crystalline Form C of Compound 1 has a D In one particular embodiment, Form C has an onset temperature of 232°C and a melting point of 100°C. It is characterized by a DSC plot containing a melting event with a heat release of 126 J / g.

[0239] In certain embodiments, Form C is characterized by dynamic vapor sorption analysis. A typical dynamic vapor sorption (DVS) isotherm plot is shown in Figure 20. When the relative humidity ("RH") increases from about 0% to about 90% RH, Type C will drop to about 0. In certain embodiments, Form C exhibits a water uptake of 6% w / w. Measurements were performed using a KF titrator equipped with an oven sample processor set at 225°C. Contains less than 0.1% water when heated.

[0240] In certain embodiments, Form C has no significant decomposition or residual solvent. 1 H NMR This is not shown in Figure 21.

[0241] In certain embodiments, Form C of Compound 1 is In certain embodiments, Form C is stable, e.g., 2 When a pressure of 1000 psi was applied for approximately 1 minute, the XRPD pattern showed a broadening of the diffraction peaks. Although the α-glucan is slightly oxidized, it remains essentially unchanged (Figure 22).

[0242] In yet another embodiment, Form C of Compound 1 is substantially pure. In embodiments, substantially pure Form C of Compound 1 may be present in other solid forms, such as amorphous forms. In certain embodiments, the purity of substantially pure Form C of Compound 1 is is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 9 8.5% or more pure, approximately 99% or more pure, approximately 99.5% or more pure, or approximately 99.8% or more pure It is pure.

[0243] In certain embodiments, Form C of Compound 1 is substantially pure. In the present invention, Form C of Compound 1 is a compound that can be used in other solid forms of Compound 1, such as Forms A, B, D, E, and / or amorphous solids are substantially free of the In this embodiment, Form C is a mixture of solid forms that comprise Compound 1, and as a mixture Examples of suitable compounds include mixtures containing one or more of the following: Type A constituting Compound 1; , Form B, Form D, Form E, and amorphous solid.

[0244] D-form of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto amide In certain embodiments, the formulations provided herein are prepared from the D form of Compound 1. In certain embodiments, Form D of Compound 1 is a DMSO solvate.

[0245] In certain embodiments, Form D can be prepared by reacting Form B in DMSO / methyl isobutyl ketone. This is achieved by heating and cooling the solution.

[0246] In certain embodiments, Form D is, for example, as shown by powder X-ray diffraction measurements. In one embodiment, Form D of Compound 1 is substantially as shown in FIG. The powder X-ray diffraction pattern is as follows:

[0247] In one embodiment, the D form of Compound 1 has an average molecular weight of about 14.1, 14.1 as shown in FIG. Characteristic powder X at 2θ angles of 3, 18.8, 19.1, 23.6, or 24.0°2θ In another embodiment, Form D of Compound 1 has one or more X-ray diffraction peaks of about 1 One, two, three, or four 2θ angles of 4.1, 14.3, 18.8, or 19.1° 2θ In another embodiment, Form D of Compound D has four characteristic X-ray powder diffraction peaks. 1 has one, two, three, or four characteristic powder X-ray diffraction peaks as listed in Table D. In another embodiment, Form D of Compound 1 has one of the following amino acids: 1, 2, 3, 4, 5, 6, or 7. They have one, two, or three characteristic powder X-ray diffraction peaks as listed. Table D [Table 19]

[0248] In one embodiment, provided herein is a representative example of a medicament for the treatment of dengue fever, as shown in FIG. of crystalline forms with thermogravimetric analysis (TGA) thermograms substantially corresponding to TGA thermograms. Compound 1. In certain embodiments, Form D exhibits a solubility of about 14.1° C. up to 140° C. The % TGA weight loss is shown.

[0249] In certain embodiments, Form D has a molecular weight of 100,000 as determined by gas chromatography. Contains approximately 14.3% by weight of DMSO.

[0250] In yet another embodiment, Form D of Compound 1 is substantially pure. In embodiments, the substantially pure Form D of Compound 1 may be present in other solid forms, such as amorphous forms. In certain embodiments, the purity of the substantially pure D form of Compound 1 is is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 9 8.5% or more pure, approximately 99% or more pure, approximately 99.5% or more pure, or approximately 99.8% or more pure It is pure.

[0251] In certain embodiments, Form D of Compound 1 is substantially pure. In this context, the D-form of Compound 1 is not limited to other solid forms of Compound 1, such as those provided herein. Forms A, B, C, E, and / or amorphous solids comprising Compound 1 as provided In certain embodiments, Form D is substantially free of the solid form that constitutes Compound 1. The mixture is a mixture of the above-mentioned type, and examples of the mixture include a mixture containing one or more of the following: Forms A, B, C, E, and amorphous solids that comprise Compound 1.

[0252] E-type 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3 -yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroaceto amide In certain embodiments, the formulations provided herein are prepared from Form E of Compound 1. In certain embodiments, Form E of Compound 1 is a DMSO solvate.

[0253] In certain embodiments, Form E can be prepared by dissolving Form C in DMSO / MIBK or DMSO at room temperature. It can be obtained by adding DMSO / IPA or DMSO / anisole.

[0254] In certain embodiments, Form E is, for example, as shown by powder X-ray diffraction measurements. In one embodiment, Form E of Compound 1 is substantially as shown in Figure 25. The powder X-ray diffraction pattern is as follows:

[0255] In one embodiment, Form E of Compound 1 has a molecular weight of about 10.5, 12. 5, 16.1, 17.0, 18.5, 21.2, 21.7, 22.6, 22.9, 23. Characteristic powder X at 2θ angles of 4, 23.8, 24.1, 25.1, or 26.7°2θ In another embodiment, Form E of Compound 1 has one or more X-ray diffraction peaks of about 1 One, two, three, or four 2θ angles of 6.1, 17.0, 21.2, or 22.9° 2θ In another embodiment, Form E of Compound A has four or more characteristic X-ray powder diffraction peaks. 1 has one, two, three, or four characteristic powder X-ray diffraction peaks as listed in Table E. In another embodiment, Form E of Compound 1 has one of the following structures: They have one, two, or three characteristic powder X-ray diffraction peaks as listed. Table E [Table 20]

[0256] In one embodiment, provided herein is a representative example of a medicament for the treatment of dengue fever, as shown in FIG. of crystalline forms with thermogravimetric analysis (TGA) thermograms substantially corresponding to TGA thermograms. Compound 1. In certain embodiments, Form E exhibits a viscosity of about 19.4° C. up to 120° C. In certain embodiments, Form E exhibits a TGA weight loss of 120-220°C. This represents a further weight loss of 24.9%.

[0257] In yet another embodiment, Form E of Compound 1 is substantially pure. In embodiments, substantially pure Form E of Compound 1 may be present in other solid forms, such as amorphous forms. In certain embodiments, the purity of substantially pure Form E of Compound 1 is is about 95% or more pure, about 96% or more pure, about 97% or more pure, about 98% or more pure, about 9 8.5% or more pure, approximately 99% or more pure, approximately 99.5% or more pure, or approximately 99.8% or more pure It is pure.

[0258] In certain embodiments, Form E of Compound 1 is substantially pure. In this embodiment, Form E of Compound 1 may be used in combination with other solid forms of Compound 1, such as Forms A, B, C, D, and / or 1, which comprise Compound 1 as provided herein Form E is substantially free of amorphous solids. In certain embodiments, Form E comprises Compound 1. The mixture is a solid mixture containing, for example, one or more of the following: Examples include: Forms A, B, C, and D of Compound 1, and amorphous solids.

[0259] Amorphous form of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Cetoamide In certain embodiments, the formulations provided herein contain amorphous Compound 1. nothing.

[0260] In certain embodiments, provided herein are methods for preparing compounds comprising dissolving Compound 1 in THF and water. This method involves heating the solution at room temperature and cooling it to form the amorphous form.

[0261] In one embodiment, provided herein is a modulated DS as shown in FIG. Compound 1 in amorphous solid form with a C thermogram.

[0262] In one embodiment, amorphous Compound 1 is prepared as powder X, substantially as shown in FIG. It has a linear diffraction pattern.

[0263] In one embodiment, amorphous Compound 1 has a structure substantially as shown in FIG. 1 H It has an NMR spectrum.

[0264] In yet another embodiment, amorphous Compound 1 is substantially pure. In embodiments, substantially pure amorphous Compound 1 may be present in other solid forms, e.g., , substantially free of Form A, Form B, Form C, Form D, or Form E. In certain embodiments, The purity of the substantially pure amorphous Compound 1 is about 95% or more pure, about 96% or more pure, Approximately 97% or more pure, approximately 98% or more pure, approximately 98.5% or more pure, approximately 99% or more pure, approximately 9 It is at least 9.5% pure, or at least about 99.8% pure.

[0265] Compound 1 Formulation In one embodiment, provided herein is a stable formulation of Compound 1. In some embodiments, the formulation of Compound 1 is a solid 2-(4-chlorophenyl)-N-{ [2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl] In one embodiment, the compound The compound 1 is an amorphous form of 2-(4-chlorophenyl)-N-{[2-(2,6-dichlorophenyl)-N-(4-chlorophenyl)-N ... 2,2-Dihydroxypiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl -Contains difluoroacetamide.

[0266] In certain embodiments, the formulation contains dimethyl sulfonate as a cosolvent or processing aid. In certain embodiments, the formulation is prepared using a co-solvent or processing oxide. In certain embodiments, the formulation is prepared using formic acid as an auxiliary agent. It is prepared without the use of any co-solvents or processing aids.

[0267] In certain embodiments, the formulation contains dimethyl sulfonate as a cosolvent or processing aid. In certain embodiments, the formulation contains a gypsum oxide as a co-solvent or processing aid. In certain embodiments, the formulation does not include any co-solvents or processing aids. do not have.

[0268] In certain embodiments, the formulations provided herein are lyophilized formulations. In certain embodiments, the formulations provided herein contain a pharmaceutically acceptable solvent. and adding the above to form a pharmaceutically acceptable solution.

[0269] Formulation Ia In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was used in an amount of about 0.05 to 0.2%, citrate buffer in an amount of about 3% to 6%, and Contains approximately 92-98% hydroxypropyl β-cyclodextrin (HPBCD), It is a compound.

[0270] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was used in an amount of about 0.05 to 0.2%, citrate buffer in an amount of about 3% to 6%, and A formulation containing methyl methyl ether-β-cyclodextrin in an amount of about 92 to 98%. do.

[0271] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added in an amount of about 0.05 to 0.2%, citrate buffer was added in an amount of about 3% to 6%, and HPB A formulation containing CD in an amount of about 92-98% and dimethyl sulfoxide in an amount of about 1% or less. be.

[0272] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added in an amount of about 0.05 to 0.2%, and citrate buffer was added in an amount of about 3% to 6%. butyl ether-β-cyclodextrin in an amount of about 92-98%, and dimethyl sulfoxide. The formulation contains about 1% or less of oxide.

[0273] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.08 to 0.15%, citrate buffer in an amount of about 3% to 6%, and The formulation contains HPBCD in an amount of approximately 94-96%.

[0274] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.08 to 0.15%, citrate buffer in an amount of about 3% to 6%, and A formulation containing sulfobutylether-β-cyclodextrin in an amount of approximately 94-96%. be.

[0275] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added at a concentration of about 0.08-0.15%, citrate buffer was added at a concentration of about 3%-6%, and HP A formulation comprising BCD in an amount of about 94-96% and dimethyl sulfoxide in an amount of about 1% or less. is.

[0276] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added in an amount of about 0.08 to 0.15%, and citrate buffer was added in an amount of about 3% to 6%. butyl ether-β-cyclodextrin in an amount of about 94-96%, and dimethyl sulfoxide. The formulation contains about 1% or less of phenoxide.

[0277] In one embodiment, the formulations provided herein comprise, based on the total weight of the formulation: Compound 1 is present in an amount of about 0.08 to about 0.15%. The amount of 1 is about 0.09% to about 0.15%, about 0.1% to about 1.0% based on the total weight of the formulation. 0.13%, or about 0.11% to about 0.12%. The amount of Compound 1 was about 0.05%, 0.07%, 0.09%, based on the total weight of the formulation. , 0.11%, 0.12%, 0.13%, or 0.15%. In this case, the amount of Compound 1 in the formulation is about 0.12% based on the total weight of the formulation.

[0278] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising dissolving Compound 1 in a 20 cc vial at about 0.5°C. In yet another embodiment, a formulation containing 0.5 mg to about 2 mg of hydroxybenzoates in a 20 cc vial contains: Compound 1 is added in an amount of about 0.5 mg to about 1.5 mg, about 0.75 mg to about 1.25 mg, or about 0 In one embodiment, Compound 1 is present in an amount of 2.8 mg to about 1.1 mg. Approximately 0.7, 0.75, 0.76, 0.8, 0.9, 1.0, 1.05 in a 0cc vial In one embodiment, Compound 1 is present in an amount of 1.2 mg or 2.0 mg. It is present in an amount of about 1.05 mg per tablet.

[0279] In one embodiment, the formulations provided herein contain a citrate buffer. In one embodiment, the amount of citrate buffer in the formulations provided herein is 0.01g / ml of citrate buffer in the total formulation. Based on the total weight, it is about 3% to about 6%. The amount of citrate buffer in the formulation is about 3%, 3.5%, 4%, or 5% by weight based on the total weight of the formulation. %, 4.2%, 4.5%, or 5%. The amount of citrate buffer in the formulation is about 4.2%, based on the total weight of the formulation. In one embodiment, the amount of citrate buffer in the formulations provided herein is 20 cc There is approximately 37 mg in the vial.

[0280] In one embodiment, the citrate buffer is a mixture of anhydrous citric acid and anhydrous sodium citrate. In certain embodiments, the amount of anhydrous citric acid is based on the total weight of the formulation. Approximately 1.5% to approximately 3%, approximately 1.75% to approximately 2.75%, or approximately 2% to approximately 2.5% In certain embodiments, the amount of anhydrous citric acid in the formulation is about 1 / 2 of the total weight of the formulation. Based on the above, the average annual income is approximately 1.5%, 1.75%, 2%, 2.1%, or 2.5%. In embodiments, the amount of anhydrous citric acid in the formulation is about 2% by weight based on the total weight of the formulation. %, 2.1%, 2.22%, or 2.3%. In one embodiment, the formulation The amount of anhydrous citric acid is about 2.10% based on the total weight of the formulation.

[0281] In yet another embodiment, anhydrous citric acid is added in an amount of about 16 mg to about 20 mg in a 20 cc vial. In one embodiment, the amount of anhydrous citric acid is 20 cc vial Medium, approximately 16, 17, 18, 18.2, 18.4, 18.6, 18.8, 19, or 20 In one embodiment, the amount of anhydrous citric acid is about 1 mg in a 20 cc vial. It is 8.6mg.

[0282] In certain embodiments, the amount of anhydrous sodium citrate is based on the total weight of the formulation. Based on the above, approximately 1.5% to approximately 3%, approximately 1.75% to approximately 2.75%, or approximately 2% to approximately 2.5% In certain embodiments, the amount of anhydrous sodium citrate in the formulation is Approximately 1.5%, 1.75%, 2%, 2.1%, or 2.5% based on the total weight of the item In one embodiment, the amount of anhydrous sodium citrate in the formulation is Approximately 2%, 2.05%, 2.08%, or 2.1% based on the weighed weight. In embodiments, the amount of anhydrous sodium citrate in the formulation is based on the total weight of the formulation. This is approximately 2.08%.

[0283] Yet another embodiment is a 20 cc vial containing about 16 mg to about 2 mg of anhydrous sodium citrate. In one embodiment, the amount of anhydrous sodium citrate is 0 mg. In a 20cc vial, the contents are approximately 16, 17, 18, 18.2, 18.4, 18.6, and 18. In one embodiment, the amount of anhydrous sodium citrate is 8, 19, or 20 mg. The amount is approximately 18.4 mg in a 20 cc vial.

[0284] In certain embodiments, the amount of HPBCD in the formulations provided herein is In one embodiment, the amount of the hydroxybenzoates is about 94 to about 97% based on the total weight of the mixture. The amount of HPBCD in the formulation provided herein is approximately 94.5g based on the total weight of the formulation. %, 95%, 95.5%, or 96%. The amount of HPBCD in the formulation provided is about 95% based on the total weight of the formulation.

[0285] In certain embodiments, the sulfobutyl ether in the formulations provided herein The amount of -β-cyclodextrin is about 94 to about 97% based on the total weight of the formulation. In one embodiment, the sulfobutyl ether- The amount of β-cyclodextrin was about 94.5%, 95%, 95.5%, or 96%. In one embodiment, the formulations provided herein The amount of sulfobutylether-β-cyclodextrin in the formulation is based on the total weight of the formulation. The figure is approximately 95%.

[0286] Another embodiment is a formulation containing HPBCD in an amount of about 800-900 mg in a 20 cc vial. In another embodiment, about 810 to 880 mg of HPBCD and 82 mg of HPBCD are contained in a 20 cc vial. In another embodiment, the formulation contains 20 to 860 mg, or 830 to 850 mg. The formulation contains approximately 840 mg of HPBCD in a cc vial.

[0287] Another embodiment is a 20 cc vial containing sulfobutylether-β-cyclodextrin. In another embodiment, the formulation contains about 800 to 900 mg of the active ingredient in a 20 cc vial. About 810-880mg, 820-860mg of butyl ether-β-cyclodextrin g, or 830-850 mg. In another embodiment, a 20 cc vial A formulation containing sulfobutyl ether-β-cyclodextrin in an amount of approximately 840 mg. be.

[0288] Another embodiment is a 20 cc vial containing approximately 840 mg of Kleptose® HPB. It is a formulation containing the following amounts:

[0289] In one embodiment, the formulation comprises dimethyl sulfoxide, based on the total weight of the formulation. In one embodiment, the formulation comprises about 1.5% or less of a hydroxybenzoate by weight of the total formulation. Dimethyl sulfoxide up to 0.1%, 0.2%, 0.3%, 0.4%, based on volume In one embodiment, the amount is 0.6%, 0.7%, 0.8%, 0.9%, or 1%. The formulation may contain approximately 0.1%, 0.2%, 0.3%, 0. 4%, 0.6%, 0.7%, 0.8%, 0.9%, or 1% or less of dimethyl sulfoxide In one embodiment, the formulation comprises, based on the total weight of the formulation, dimethyl ether. In one embodiment, the present invention includes a sulfoxide in an amount of up to about 0.1 to about 1.5%. The amount of dimethyl sulfoxide in the formulations provided herein is based on the total weight of the formulation. In one embodiment, the formulations provided herein contain from about 0.1 to about 1.3%. The amount of dimethyl sulfoxide is about 0.1%, 0.2%, or 0.3%, 0.4%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%. 1 In one embodiment, the formulations provided herein contain only dimethyl sulfoxide. In one embodiment, the dimethyl sulfoxide in the formulations provided herein is The amount of hydroxyl is about 0.4% to 0.8% based on the total weight of the formulation.

[0290] Another embodiment is a formulation containing dimethyl sulfoxide in an amount of about 4 to 7 mg in a 20 cc vial. Another embodiment is a mixture of about 4.5 to 6.0 ml of dimethyl sulfoxide in a 20 cc vial. The formulation contains 5 mg or 5-6 mg.

[0291] In certain embodiments, the formulations provided herein are lyophilized and can be frozen. The lyophilized formulation, upon reconstitution, has a pH of about 4-5. In certain embodiments, The formulation, upon reconstitution, has a pH of about 4.2 to 4.4. The dried formulations, when reconstituted, had pH values ​​of approximately 4, 4.1, 4.2, 4.3, 4.4, and 4.5. , 4.6, 4.7, 4.8, 4.9, or 5.

[0292] In certain embodiments, the lyophilized formulation, upon reconstitution, has an osmolality of In certain embodiments, the lyophilized formulation The product, when reconstituted, has an osmolality of approximately 260-280 mOsm / kg.

[0293] In certain embodiments, provided herein are compositions comprising the compositions provided herein. In one embodiment, the container is a glass vial. In the above, the container is a 20 cc glass vial.

[0294] In one embodiment, provided herein is a composition in a 20 cc vial comprising: Compound: 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Compound 1 in an amount to provide 1.05 mg of cetoamide, and In one embodiment, the formulation comprises a pharmaceutically acceptable carrier or excipient. and further containing about 7 mg or less of dimethyl sulfoxide as a residual solvent. In the formulation, the residual solvent is about 6 mg or less of dimethyl sulfoxide. In this embodiment, the formulation contains no more than about 5 mg of dimethyl sulfoxide as a residual solvent. In one embodiment, the formulation contains no more than about 4 mg of dimethyl sulfoxide as residual solvent. In one embodiment, the formulation contains about 3 mg to about 7 mg of residual solvent. g, about 4 mg to about 6 mg, about 4 mg to about 5 mg, or about 5 mg to about 6 mg of dimethylsulfate In one embodiment, the formulation contains about 4, 4.5, or 5,000 sulphoxide as residual solvent. Contains 5, 5.3, 5.5, 5.7, 6, or 6.5 mg of dimethyl sulfoxide.

[0295] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.2%, citrate buffer in an amount of about 3% to 6%, and The formulation consists essentially of HPBCD in an amount of ∼98%.

[0296] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.2%, citrate buffer in an amount of about 3% to 6%, and A formulation consisting essentially of sulfobutylether-β-cyclodextrin in an amount of ∼98% is.

[0297] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05-0.2%, citrate buffer in an amount of about 3%-6%, A formulation consisting essentially of 8% HPBCD and about 1% or less dimethyl sulfoxide. be.

[0298] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05-0.2%, citrate buffer in an amount of about 3%-6%, Sulfobutylether-β-cyclodextrin in an amount of 8%, and not more than about 1% dimethyl A formulation consisting essentially of sulfoxides.

[0299] In one embodiment, provided herein is a composition in a 20 cc vial comprising: Compound: 1.05 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dichlorophenyl)-N-(4-chlorophenyl)-N ... 2,2-Dihydroxypiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl - Compound 1 in an amount that provides difluoroacetamide, buffer as described herein and a pharmaceutically acceptable carrier or excipient, including a bulking agent and a filler, and about 5 mg to about 6 mg of dimethyl sulfoxide. Buffering and bulking agents are described herein. It can be present in the amount

[0300] In one embodiment, provided herein is a composition in a 20 cc vial comprising: Compound: 1.05 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dichlorophenyl)-N-(4-chlorophenyl)-N ... 2,2-Dihydroxypiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl - Compound 1 in an amount that results in difluoroacetamide, 18.6 mg of anhydrous citric acid, 18 0.4 mg anhydrous sodium citrate, 840 mg HPBCD, and About 5 mg to about 6 mg of dimethyl sulfoxide as residual solvent as shown in one embodiment. In the formulation in a 20 cc vial, the formulation is reconstituted with 3.8 mL of sterile water for injection.

[0301] In one embodiment, provided herein is a 20 cc vial containing essentially the following: The formulation consists of: 1.05 mg of 2-(4-chlorophenyl)-N-{[2-(2 ,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl Compound 1 in an amount to yield 2,2-difluoroacetamide, 18.6 mg of anhydrous acetamide, phosphate, 18.4 mg of anhydrous sodium citrate, 840 mg of HPBCD, and Approximately 5 mg to 6 mg of dimethyl sulfoxide as the residual solvent as described in the table. In one embodiment, the formulation in a 20 cc vial is reconstituted with 3.8 mL of sterile water for injection. will be done.

[0302] In one embodiment, provided herein is a 20 cc vial containing: The formulation is: 1.05 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dichlorophenyl)-N-(4- ... Oxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2, Compound 1 in an amount that results in 2-difluoroacetamide, 18.6 mg of anhydrous citric acid, 1 8.4 mg of anhydrous sodium citrate, 840 mg of HPBCD, and About 5 mg to about 6 mg of dimethyl sulfoxide as residual solvent as described in one embodiment. In this embodiment, the formulation in a 20 cc vial is reconstituted with 3.8 mL of sterile water for injection.

[0303] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.05 to 0.2%, and C1 in an amount of about 3% to 6% based on the total weight of the solids. acetic acid buffer, HPBCD in an amount of approximately 92-98% based on the total weight of solids, and dilution It is an aqueous formulation containing the agent.

[0304] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.05 to 0.2%, and C1 in an amount of about 3% to 6% based on the total weight of the solids. acetic acid buffer, HPBCD in an amount of approximately 92-98% based on the total weight of solids, and dilution It is an aqueous formulation consisting essentially of the agent.

[0305] In one embodiment, provided herein is an aqueous formulation comprising: 1. 0.5mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine- 3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroacetate Compound 1 in an amount to yield methyl methyl ester amide, 18.6 mg of anhydrous citric acid, 18.4 mg of anhydrous citric acid Sodium enoate, 840 mg of HPBCD, and about 5 mg to about 6 mg of residual solvent. Dimethyl sulfoxide, as well as approximately 3.8 mL of diluent.

[0306] In one embodiment, provided herein is an aqueous formulation consisting essentially of: Contains: 1.05 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopyrrolidone] 2,2-difluoromethanesulfonyl)-1-oxoisoindolin-5-yl]methyl Compound 1 in an amount to yield fluoroacetamide, 18.6 mg of anhydrous citric acid, 18.4 mg of g of anhydrous sodium citrate, 840 mg of HPBCD, and approximately 5 mg of residual solvent. Approximately 6 mg of dimethyl sulfoxide and approximately 3.8 mL of diluent.

[0307] In one embodiment, provided herein is an aqueous formulation consisting of: 0.05 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine -3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Compound 1 in an amount that yields cetoamide, 18.6 mg of anhydrous citric acid, 18.4 mg of anhydrous Sodium citrate, 840 mg of HPBCD, and approximately 5 mg to 6 mg of residual solvent of dimethyl sulfoxide, as well as approximately 3.8 mL of diluent.

[0308] In certain embodiments, the formulation has a composition as set forth in Table 43.

[0309] Formulation Ib In one embodiment, provided herein is a method for treating a patient with Compound 1 in an amount of about 0.01 to 0.1 At 5% level, hydroxypropyl β-cyclodextrin is added to approximately 99.1-99.99% In one embodiment, provided herein is a formulation comprising: Compound 1 was added in an amount of about 0.01 to 0.15% based on the total weight of the compound, and hydroxypropyl beta - cyclodextrin in an amount of about 99.1 to 99.99% and formic acid in an amount of about 0.5% or less It is a formulation comprising:

[0310] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and HPBCD in an amount of about 99.1 to 99.9% It is a formulation comprising:

[0311] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05-0.25% and HPBCD in an amount of about 99.1-99.9% and formic acid at about 0.5% or less.

[0312] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and HPBCD in an amount of about 99.75 to 99.9% The composition contains the compound in an amount of

[0313] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and HPBCD in an amount of about 99.75 to 99.9% and formic acid at about 0.5% or less.

[0314] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and HPBCD in an amount of about 99.75 to 99.9% and a formulation containing formic acid at about 0.2% or less.

[0315] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.08 to 0.15% and HPBCD in an amount of about 99.8 to 99.9% It is a formulation containing the following amounts:

[0316] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of approximately 0.08-0.15% and HPBCD in an amount of approximately 99.8-99.9% and formic acid at about 0.5% or less.

[0317] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of approximately 0.08-0.15% and HPBCD in an amount of approximately 99.8-99.9% and a formulation containing formic acid at about 0.12%.

[0318] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: A formulation comprising Compound 1 in an amount of about 0.12% and HPBCD in an amount of about 99.88%. do.

[0319] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and sulfobutylether-β-cyclodextrin The formulation contains about 99.1 to 99.9% of string.

[0320] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added in an amount of about 0.05 to 0.25% to sulfobutylether-β-cyclodextrin. The formulation includes phosphorus in an amount of about 99.1 to 99.9% and formic acid in an amount of about 0.5% or less.

[0321] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25% and sulfobutylether-β-cyclodextrin The formulation contains approximately 99.75 to 99.9% of stringins.

[0322] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.08 to 0.15% and sulfobutylether-β-cyclodextrin The formulation contains approximately 99.8 to 99.9% of stringins.

[0323] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added in an amount of about 0.08-0.15% to sulfobutylether-β-cyclodextrin. The formulation includes phosphorus in an amount of about 99.8 to 99.9% and formic acid in an amount of about 0.5% or less.

[0324] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.12% and sulfobutylether-β-cyclodextrin The formulation contains approximately 99.88% of

[0325] In one embodiment, the formulations provided herein comprise, based on the total weight of the formulation: Compound 1 is present in an amount of about 0.08 to about 0.15%. The amount of 1 is about 0.09% to about 0.15%, about 0.1% to about 1.0% based on the total weight of the formulation. 0.13%, or about 0.11% to about 0.12%. The amount of Compound 1 was about 0.05%, 0.07%, 0.09%, based on the total weight of the formulation. , 0.11%, 0.12%, 0.13%, or 0.15%. In this case, the amount of Compound 1 in the formulation is about 0.12% based on the total weight of the formulation.

[0326] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising dissolving Compound 1 in a 20 cc vial at about 0.5°C. In yet another embodiment, a formulation containing 0.5 mg to about 2 mg of hydroxybenzoates in a 20 cc vial contains: Compound 1 is added in an amount of about 0.5 mg to about 1.5 mg, about 0.75 mg to about 1.25 mg, or about 0 In one embodiment, Compound 1 is present in an amount of 2.8 mg to about 1.1 mg. Approximately 0.7, 0.75, 0.76, 0.8, 0.9, 1.0, 1.05 in a 0cc vial In one embodiment, Compound 1 is present in an amount of 1.2 mg or 2.0 mg. It is present in an amount of approximately 1 mg per tablet.

[0327] In one embodiment, the amount of HPBCD in the formulations provided herein is In one embodiment, the content of the cellulose acetate ester compound is about 97 to about 99.9% based on the total weight of the cellulose acetate ester compound. The amount of HPBCD in the formulations provided herein ranges from about 98 to about 100% by weight, based on the total weight of the formulation. 99.9%. In one embodiment, the HPBC in the formulations provided herein The amount of D may be about 99.1%, 99.3%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.1%, 99.3%, 99.5 ...9%, 99.5%, 99.9%, 99.9%, 99.1%, In one embodiment, the formulations provided herein are The amount of HPBCD in the formulation is about 99.5%, based on the total weight of the formulation. is a formulation containing approximately 750-850 mg of HPBCD in a 20 cc vial. Another embodiment is a 20 cc vial containing about 790 to 840 mg of HPBCD, 780 to 830 mg of HPBCD, or mg, or 790-810 mg. The formulation contains approximately 800 mg of HPBCD per tablet.

[0328] Another embodiment is a 20 cc vial containing approximately 800 mg of Kleptose® HPB. It is a formulation containing the following amounts:

[0329] In one embodiment, the sulfobutyl ether-β The amount of cyclodextrin is about 97 to about 99.9% based on the total weight of the formulation. In one embodiment, the sulfobutyl ether- The amount of β-cyclodextrin is about 98 to about 99.9% based on the total weight of the formulation. In one embodiment, the sulfobutyl ether in the formulations provided herein The amount of -β-cyclodextrin is approximately 99.1%, 99. 3%, 99.5%, 99.7%, or 99.9%. The amount of sulfobutylether-β-cyclodextrin in the formulations provided herein is Approximately 99.5% based on the total weight of the formulation.

[0330] Another embodiment is a 20 cc vial containing sulfobutylether-β-cyclodextrin. In another embodiment, the formulation contains about 750 to 850 mg of the active ingredient in a 20 cc vial. About 790-840mg, 780-830mg of butyl ether-β-cyclodextrin g, or 790-810 mg. In another embodiment, a 20 cc vial A formulation containing sulfobutylether-β-cyclodextrin in an amount of approximately 800 mg. be.

[0331] Another embodiment is a 20 cc vial containing approximately 800 mg of Kleptose® HPB. It is a formulation containing the following amounts:

[0332] In one embodiment, the formulation contains about 0.5% formic acid based on the total weight of the formulation. In one embodiment, the formulation comprises formic acid, based on the total weight of the formulation. Maximum approximately 0.05%, 0.07%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4% In one embodiment, the formulation contains 0.5% or 0.5% of the total weight of the formulation. Based on the results, formic acid was added at approximately 0.05%, 0.07%, 0.09%, 0.1%, 0.2%, and 0.3% concentrations. %, 0.4%, or 0.5% or less. The amount of formic acid in the formulation is about 0.05 to about 0.5% based on the total weight of the formulation. In one embodiment, the amount of formic acid in the formulations provided herein is In one embodiment, the amount is about 0.05 to about 0.1% based on the total weight. The amount of formic acid in the formulation provided is approximately 0.05%, 0. 0.07%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, or 0.5% In one embodiment, the formulations provided herein do not contain any formic acid. In one embodiment, the amount of formic acid in the formulations provided herein is Approximately 0.05% to 0.09% by weight.

[0333] Another embodiment is a formulation containing formic acid in an amount of about 1 mg or less in a 20 cc vial. In some embodiments, formic acid is added in a 20 cc vial at a concentration of up to about 0.2, 0.5, 0.7, 0.9 mg, or In another embodiment, the formulation contains about 0.3 to 0.1 mg of formic acid in a 20 cc vial. It is a formulation containing 0.9mg, or 0.4-0.8mg.

[0334] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising administering Compound 1 in a 20 cc vial at about 1000 rpm. mg and HPBCD in an amount of about 800 mg.

[0335] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising administering Compound 1 in a 20 cc vial at about 1000 rpm. mg of HPBCD and formic acid in an amount of approximately 0.9 mg. It is a thing.

[0336] In certain embodiments, the formulation has a composition as set forth in Table 43.

[0337] Formulation Ic In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.01 to 0.08% and HPBCD in an amount of about 99.40 to 99.99 % of the formulation.

[0338] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was used in an amount of approximately 0.01 to 0.08%, and HPBCD was used in an amount of approximately 99.40 to 99.99%. and formulations containing about 0.5% or less of formic acid.

[0339] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.03 to 0.06% and HPBCD in an amount of about 99.60 to 99.99 % of the formulation.

[0340] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 was added at about 0.01 to about 0.08%, and hydroxypropyl β-cyclodextrin was added at about The formulation contains 99.40% to about 99.99% of cellulose acetate and about 0.1 to about 0.3% of formic acid.

[0341] In one embodiment, the formulations provided herein comprise, based on the total weight of the formulation: In certain embodiments, Compound 1 is present in an amount of about 0.02 to about 0.06%. The amount of 1 is about 0.03% to about 0.06%, or about 0.0 In certain embodiments, the amount of Compound 1 is from about 4% to about 0.06% of the total formulation. Based on the weight of the sample, the concentration is about 0.03%, 0.04%, 0.05%, or 0.06%. In one embodiment, the amount of Compound 1 is about 0.05% based on the total weight of the formulation. is.

[0342] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising dissolving Compound 1 in a 20 cc vial at about 0.5°C. In yet another embodiment, a 20 cc vial contains 0.75 mg to about 1.5 mg of glycerin. The formulation contains Compound 1 in an amount of about 0.75 mg to about 1.25 mg per tablet. In the above, Compound 1 was diluted to about 0.75, 0.8, 0.9, 1.0, 1 In one embodiment, Compound 1 is present in an amount of 20 cc Present in a vial in an amount of about 1 mg.

[0343] In one embodiment, the amount of HPBCD in the formulations provided herein is In one embodiment, the content of the hydroxybenzoates is about 99.40 to about 99.99% based on the total weight of the hydroxybenzoates. The amount of HPBCD in the formulations provided herein is about 100% by weight, based on the total weight of the formulation. 99.5, 99.6, 99.7, 99.8, 99.9, 99.95, or 99.99% In another embodiment, HPBCD is added in an amount of about 1800 to 1900 mg in a 20 cc vial. Another embodiment is a formulation containing HPBCD at about 1850-1900 cc in a 20 cc vial. Another embodiment is a formulation containing about 100 mg of HPBCD in a 20 cc vial. The formulation contains 875 mg of

[0344] In one embodiment, the formulation contains about 0.5% formic acid based on the total weight of the formulation. In one embodiment, the formulation comprises formic acid, based on the total weight of the formulation. Maximum approximately 0.05%, 0.07%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4% In one embodiment, the formulation contains 0.5% or 0.5% of the total weight of the formulation. Based on the results, formic acid was added at approximately 0.05%, 0.07%, 0.09%, 0.1%, 0.2%, and 0.3% concentrations. %, 0.4%, or 0.5% or less. The amount of formic acid in the formulation is about 0.05 to about 0.3% based on the total weight of the formulation. In one embodiment, the amount of formic acid in the formulations provided herein is In one embodiment, the amount of the compound of the present invention is about 0.05 to about 0.25% by weight. The amount of formic acid in the formulations provided herein is about 0.05%, 0.05%, based on the total weight of the formulation. In one embodiment, the concentration is 0.07%, 0.09%, 0.1%, 0.2%, or 0.3%. In one embodiment, the formulations provided herein are completely free of formic acid. In the formulations provided herein, the amount of formic acid is about 100% by weight, based on the total weight of the formulation. It is 0.11% to 0.3%.

[0345] Yet another embodiment is a formulation containing formic acid in an amount of about 4 mg or less in a 20 cc vial. Another embodiment is a 20 cc vial containing formic acid in a concentration of up to about 1, 1.8, 2, 2.1, 2.5, 3 , 3.5, 3.8, 3.9, 4, 4.5, 4.9 mg, or 5 mg of In another embodiment, in a 20 cc vial, about 1 to 1.8 mg, 2.1 to 3.8 mg of formic acid is or a formulation containing 3.9 to 4.9 mg.

[0346] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising administering Compound 1 in a 20 cc vial at about 1000 rpm. mg and HPBCD in an amount of about 1875 mg.

[0347] In another embodiment, provided herein is a method for preparing a pharmaceutical composition comprising administering Compound 1 in a 20 cc vial at about 1000 rpm. mg of HPBCD, about 1875 mg of formic acid, and about 2.1 to 3.8 mg of formic acid. It is a formulation comprising:

[0348] In certain embodiments, the formulation has a composition as set forth in Table 64.

[0349] Co-solvent-free formulation In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.15 to 0.5%, citrate buffer in an amount of about 15% to about 35%, and HPBCD in an amount of about 92% to about 98%. Citrate buffers include anhydrous citric acid and anhydrous sodium citrate.

[0350] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.25 to 0.30%, citrate buffer in an amount of about 30 to 32%, and and HPBCD in an amount of approximately 67-69%.

[0351] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.30 to 0.33%, citrate buffer in an amount of about 17 to 18%, and and HPBCD in an amount of approximately 80-85%.

[0352] Combination example In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25%, and HPB in an amount of about 99.75 to 99.95%. A formulation consisting essentially of CD.

[0353] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25%, and HPB in an amount of about 99.75 to 99.99%. A formulation consisting essentially of CD.

[0354] In one embodiment, provided herein is a formulation comprising, based on the total weight of the formulation: Compound 1 in an amount of about 0.05 to 0.25%, and sulfo in an amount of about 99.75 to 99.95%. butyl ether-β-cyclodextrin.

[0355] In one embodiment, provided herein is a composition in a 20 cc vial comprising: The compound is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopyrrolidone] 2,2-difluoromethanesulfonyl)-1-oxoisoindolin-5-yl]methyl Compound 1 in an amount to provide fluoroacetamide, 800 mg of HPBCD, and about 0.6 ml g of formic acid as described herein. In one embodiment, in a 20 cc vial The formulation is reconstituted with 4.5 mL of sterile water for injection.

[0356] In one embodiment, provided herein is a 20 cc vial containing essentially the following: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dichlorophenyl)-N-(4-chlorophenyl)-N ... Oxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2, Compound 1 in an amount to provide 2-difluoroacetamide, 800 mg of HPBCD, and about 0.6 mg of formic acid as described herein. In one embodiment, a 20 cc bath The formulation in the vial is reconstituted with 4.5 mL of sterile water for injection.

[0357] In one embodiment, provided herein is a 20 cc vial containing: The formulation is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxo Piperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-di Compound 1 in an amount to provide fluoroacetamide, 800 mg of HPBCD, and about 0.6 mg of formic acid as described herein. In one embodiment, a 20 cc vial The formulation in is reconstituted with 4.5 mL of sterile water for injection.

[0358] In one embodiment, provided herein is a composition in a 20 cc vial comprising: The compound is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopyrrolidone] 2,2-difluoromethanesulfonyl)-1-oxoisoindolin-5-yl]methyl Compound 1, 800 mg of sulfobutyl ether-β- cyclodextrin, and about 0.6 mg of formic acid as described herein. In an embodiment, the formulation in a 20 cc vial is reconstituted with 4.5 mL of sterile water for injection. do.

[0359] In one embodiment, provided herein is a 20 cc vial containing essentially the following: A formulation consisting of: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6- Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2 2-difluoroacetamide, 800 mg of compound 1, ter-β-cyclodextrin, and about 0.6 mg of formic acid as described herein In one embodiment, the formulation in a 20 cc vial is diluted with 4.5 mL of sterile water for injection. It will be reconstructed.

[0360] In one embodiment, provided herein is a 20 cc vial containing: The formulation is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxo Piperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-di Compound 1, 800 mg of sulfobutyl ether-β in an amount that results in fluoroacetamide - cyclodextrin, and about 0.6 mg of formic acid as described herein. In an embodiment, the formulation in a 20 cc vial is reconstituted with 4.5 mL of sterile water for injection. can be.

[0361] In one embodiment, provided herein is a formulation in a 20 cc vial comprising: The substance is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine] Lysin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Compound 1 in an amount to provide oroacetamide, 1875 mg of HPBCD, and approximately 2.1 3.8 mg of formic acid as described herein. In one embodiment, a 20 cc bath The formulation in the vial is reconstituted with 12.5 mL of normal saline for injection.

[0362] In one embodiment, provided herein is a 20 cc vial containing essentially the following: A formulation consisting of: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6- Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2 Compound 1 in an amount to provide 2-difluoroacetamide, 1875 mg of HPBCD, and and about 2.1 to 3.8 mg of formic acid as described herein. The formulation in a 20 cc vial is reconstituted with 12.5 mL of normal saline for injection.

[0363] In one embodiment, provided herein is a 20 cc vial containing: The formulation is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxo Piperidin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-di Compound 1 in an amount that results in fluoroacetamide, 1875 mg of HPBCD, and ca. 1 to 3.8 mg of formic acid as described herein. In one embodiment, 20c cThe formulation in the vial is reconstituted with 12.5 mL of normal saline for injection.

[0364] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.05-0.25%, approximately 99.1-99% based on the total weight of the solids. It is an aqueous formulation containing HPBCD in an amount of 9% and a diluent.

[0365] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.05 to 0.25%, and about 99.75 to 100% based on the total weight of the solids. It is an aqueous formulation containing HPBCD in an amount of 99.95% and a diluent.

[0366] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.05 to 0.25%, and about 99.75 to 100% based on the total weight of the solids. It is an aqueous formulation consisting essentially of HPBCD in an amount of 99.95% and a diluent.

[0367] In one embodiment, provided herein is an aqueous formulation comprising: 1 ml g of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3-yl] (I)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroacetamid Compound 1 in an amount that yields 800 mg of HPBCD, about 0.6 mg of formic acid, and about 4. 5mL of diluent.

[0368] In one embodiment, provided herein is an aqueous formulation consisting of: mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3- (yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroacetate Compound 1 in an amount to provide a medicament, 800 mg of HPBCD, about 0.6 mg of formic acid, and about 4 0.5mL of diluent.

[0369] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.01 to 0.08%, and about 99.50 to 100% based on the total weight of the solids. It is an aqueous formulation containing HPBCD in an amount of 99.99% and a diluent.

[0370] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.01 to 0.08%, and about 99.50 to 100% based on the total weight of the solids. It is an aqueous formulation containing HPBCD in an amount of 99.99% and a diluent.

[0371] In one embodiment, provided herein is a granulated sugar solution containing about 100% cereals per 1000g, based on the total weight of the solids. Compound 1 in an amount of 0.01 to 0.08%, and about 99.50 to 100% based on the total weight of the solids. It is an aqueous formulation consisting essentially of HPBCD in an amount of 99.99% and a diluent.

[0372] In one embodiment, provided herein is an aqueous formulation comprising: 1 ml g of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3-yl] (I)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroacetamid Compound 1 in an amount that yields 800 mg of HPBCD, about 0.6 mg of formic acid, and about 4. 5mL of diluent.

[0373] In one embodiment, provided herein is an aqueous formulation consisting of: mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine-3- (yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoroacetate Compound 1 in an amount to provide a medicament, 800 mg of HPBCD, about 0.6 mg of formic acid, and about 4 0.5mL of diluent.

[0374] In certain embodiments, the formulation has a composition as set forth in Table 43. In certain embodiments, the formulation has a composition as set forth in Table 64.

[0375] In certain embodiments, the formulations provided herein are lyophilized and can be frozen. The syrup dried formulation, upon reconstitution, has a pH of about 2.5 to 4. In certain embodiments, Thus, the lyophilized formulation, upon reconstitution, has a pH of about 2.5 to 3.5. In this form, the lyophilized formulation, upon reconstitution, has a pH of about 3.0 to 3.6. In some embodiments, the lyophilized formulation, upon reconstitution, has a pH of about 2.5, 3, 3.2, 3.4, 3.6, 3.8, or 4. In one embodiment, the lyophilized formulation When reconstituted, the pH was approximately 2.5, 2.8, 3, 3.2, 3.4, 3.6, 3.8, and is 4.

[0376] In certain embodiments, the lyophilized formulation, upon reconstitution, has an osmolality of In certain embodiments, the lyophilized formulation When reconstituted, the product has an osmolality of approximately 280 mOsm / kg. In embodiments, the lyophilized formulation, upon reconstitution, has an osmolality of about 260 to 300 mg / kg. 370 mOsm / kg. In certain embodiments, the lyophilized formulation is reconstituted. In certain embodiments, the osmolality is about 360 mOsm / kg. The lyophilized formulation, upon reconstitution, has an osmolality of approximately 350-450 mOs In certain embodiments, the lyophilized formulation, upon reconstitution, is The osmolality is approximately 416 mOsm.

[0377] In certain embodiments, the lyophilized formulation is in semi-normal saline (0.45% saline for injection). The reconstituted solution has an osmolality of approximately 280- In certain embodiments, the lyophilized formulation is semi-physiologically Reconstituted with saline (0.45% sodium chloride sterile solution for injection), pH The pH is 3.0 to 3.2 and the osmolality is approximately 280 to 320 mOsm / kg. In certain embodiments, the lyophilized formulation is semi-normal saline (0.45% sodium chloride for injection). The pH of the solution was 3.0-3.2 and the pH of the solution was 4.5 mL. The osmolality is about 280 to 320 mOsm / kg. The required dose of reconstitution solution was prepared in an infusion bag using normal saline (0.9% sodium chloride for injection). It is diluted to 50 mL for 30-minute intravenous administration with thorium sterile solution.

[0378] In certain embodiments, the lyophilized formulation is reconstituted with normal saline, and the reconstituted The osmolality upon construction is about 440 mOsm / kg. The required dose of reconstitution solution is diluted to a volume of 50 mL with saline and expressed as a molar equivalent. An administration solution having an osmolality of about 310 to 380 mOsm / kg is obtained. The required dose of reconstitution solution is diluted to a volume of 50 mL with normal saline and The resulting solution has an osmolality of approximately 310 to 355 mOsm / kg. In this condition, the required dose of reconstitution solution is diluted to a volume of 50 mL with normal saline. This results in a solution with an osmolality of approximately 317 to 371 mOsm / kg. In an embodiment, the required dose of reconstitution solution is diluted to a volume of 50 mL with normal saline. The resulting solution has an osmolality of approximately 317 mOsm / kg. In one embodiment, the required dose of reconstitution solution is diluted to a volume of 50 mL with normal saline. This results in a dosing solution with an osmolality of approximately 371 mOsm / kg. In this form, the osmolality of the administration solution is 352 mOsm / kg or less. In this embodiment, the osmolality of the dosing solution resulting in a dose of 4.8 mg of Compound 1 is , 352mOsm / kg.

[0379] In certain embodiments, provided herein are compositions comprising the compositions provided herein. In one embodiment, the container is a glass vial. In the above, the container is a 20 cc glass vial.

[0380] In one embodiment, provided herein is a formulation in a 20 cc vial comprising: The substance is: 1 mg of 2-(4-chlorophenyl)-N-{[2-(2,6-dioxopiperidine] Lysin-3-yl)-1-oxoisoindolin-5-yl]methyl}-2,2-difluoro Compound 1 in an amount that provides oroacetamide, and a bulking agent as described herein. In one embodiment, the formulation further comprises about 5 mg or less of formic acid as a residual solvent. In one embodiment, the formulation further comprises about 4 mg or less of formic acid as a residual solvent. In one embodiment, the formulation further comprises about 3 mg or less of formic acid as a residual solvent. In one embodiment, the formulation further comprises about 2 mg or less of formic acid as a residual solvent. In one embodiment, the formulation further comprises about 1.5 mg or less of residual solvent. In one embodiment, the formulation further comprises about 1 mg or more of formic acid as residual solvent. In one embodiment, the formulation further comprises about 0.8% formic acid as residual solvent. In one embodiment, the formulation contains less than about 0.4 mg of formic acid as residual solvent. g to about 1.5 mg, about 0.5 mg to about 1 mg, or about 0.5 mg to about 0.9 mg of formic acid In one embodiment, the formulation comprises about 0.4 mg of residual solvent, about 0.6 mg of g, about 0.8 mg, about 1 mg, or about 1.5 mg of formic acid. The formulation contained about 1.0 mg / mg compound 1 to about 1.8 mg / mg formic acid as the residual solvent. Compound 1, about 2.1 mg / mg Compound 1 to about 3.8 mg / mg Compound 1, or about 3.9 The compound contains 1 mg / mg of compound 1 to about 4.9 mg / mg of compound 1.

[0381] The formulations of Compound 1 provided herein can be administered using standard therapeutic methods to deliver Compound 1. and can be administered to patients in need thereof and are considered standard of care as described herein. In one embodiment, the method includes, but is not limited to, the methods described herein. The formulations provided herein may be reconstituted with a pharmaceutically acceptable solvent to form a pharmaceutically acceptable carrier. A solution containing the compound is produced, which is then administered to the patient (such as by intravenous injection).

[0382] In one embodiment, the formulations provided herein are lyophilized, and the lyophilized formulations , suitable for reconstitution with an appropriate diluent to the appropriate concentration prior to administration. In one embodiment, the lyophilized formulation is stable at room temperature. The dried formulation is stable at room temperature for up to about 24 months. In one embodiment, the lyophilized The formulations may be stored at room temperature for up to about 24 months, up to about 18 months, up to about 12 months, or up to about 6 months. In one embodiment, the compound is stable for up to about 1 month, up to about 3 months, or up to about 1 month. The freeze-dried formulation can be stored for up to approximately 12 months under accelerated conditions of 40°C / 75%RH, and for up to approximately 6 months. It is stable on storage for 10 days, or up to about 3 months.

[0383] The lyophilized formulations provided herein can be administered to patients using any pharmaceutically acceptable diluent. It can be reconstituted for parenteral administration to patients. Such diluents include sterile water for injection. (SWFI), 5% dextrose in water (D5W), or co-solvent systems. It can be lyophilized with any amount of diluent to prepare a suitable injection solution. The amount of diluent used to reconstitute the lyophilized formulation is therefore determined by the amount of diluent required to reconstitute the lyophilized formulation. In one embodiment, 1 to 5 mL or 1 to 4 mL Reconstitute the lyophilized formulation with 0.5 mL of diluent to achieve a final concentration of Compound 1 of approximately 0.05-0. In certain embodiments, the concentration is about 0.3 mg / mL or about 0.15 to 0.25 mg / mL. In this case, the final concentration of Compound 1 in the reconstitution solution is about 0.25 mg / mL. In an embodiment, the final concentration of Compound 1 in the reconstitution solution is about 0.20 mg / mL. In certain embodiments, the volume of reconstitution diluent is adjusted to a final concentration of 0.15 to 0.3 ml. In certain embodiments, the amount varies from 3 ml to 5 ml to obtain a total of 100 mg / mL. Depending on the dose, multiple vials may be used for reconstitution.

[0384] The reconstitution solution for the lyophilized formulation can be used within about 24 hours, about 12 hours, or about 8 hours. In one embodiment, the reconstituted aqueous solution is When the solution is added, it is stable at room temperature for approximately 1 to 24, 2 to 20, 2 to 15, or 2 to 10 hours. In terms of morphology, the reconstituted aqueous solution, upon reconstitution, can be stored at room temperature for up to about 20, 15, 12 In some embodiments, the solution is stable for 10, 8, 6, 4, or 2 hours from the time of preparation. Use within 8 hours. In some embodiments, the solution is used within 5 hours of preparation. In some embodiments, the solution is used within one hour of preparation.

[0385] Compounding process The formulations provided herein can be prepared using any method known in the art and as described herein. The preparation may be carried out as described herein, but all methods require the active ingredient to be in a pharmaceutically acceptable form. The method includes associating the compound with an excipient that is suitable for the compound, the excipient comprising one or more necessary ingredients. (e.g., bulking agents and / or buffering agents).

[0386] In one embodiment, the formulations provided herein comprise Compound 1, a bulking agent, and citric acid. Dissolving the acid buffer in water and dimethyl sulfoxide (DMSO) to obtain a solution; and optionally freeze-drying the solution. 1 provides a flow chart illustrating an example process for preparing the formulations provided herein.

[0387] In one embodiment, the process for preparing the formulation comprises: adding HPBCD to citric acid. Compound 1 was dissolved in DMSO to obtain a premix. adding the premix to a buffer solution to obtain a solution; and optionally, Lyophilizing the solution to produce a lyophilized formulation.

[0388] In one embodiment, the process comprises dissolving Kleptose® HPB in 20 mM Compound 1 was dissolved in a citrate buffer solution of pH 4 to 4.5 to obtain a buffer solution. 0 to obtain an active premix, and the premix is ​​added to a buffer solution to form a mixture. adding water to the mixture to obtain a bulk solution; The solution was filtered through a 0.45 μm and a 0.22 μm filter to obtain a filtered solution. In one embodiment, the method includes filling the solution into vials and lyophilizing the solution. The solution is filtered through one 0.45 μm filter and two 0.22 μm filters. In one embodiment, the process comprises adding Kleptose® HPB to 20 mM Compound 1 was dissolved in DMSO to obtain a buffer solution. Dissolving to obtain an active premix, adding the premix to a buffer solution to obtain a mixture Add water to the mixture to obtain a bulk solution, and filter the bulk solution with one 0.45 μm filter. The solution was filtered through a filter and two 0.22 μm filters to obtain a filtered solution. Filling into 20 cc glass vials and optionally lyophilizing the solution. In one embodiment, the vials are sealed under nitrogen after lyophilization.

[0389] In one embodiment, the formulations provided herein comprise Compound 1 dissolved in formic acid and processed. to obtain a premix, dissolving HPBCD in water to obtain a solution, dissolving the premix adding the drug solution to the solution to obtain a drug solution; and optionally lyophilizing the drug solution to obtain a lyophilized drug solution. It is prepared by forming a compound.

[0390] In one embodiment, the formulations provided herein comprise Compound 1 dissolved in formic acid to activate To obtain a premix, Kleptose® HPB is dissolved in water to obtain Kleptose® HPB. adding the premix to the kleptose solution to obtain a mixture; adding water to the substance to obtain a bulk solution; The solution is filtered through a 0.22 μm filter to obtain a filtered solution, which is then filled into vials. and freeze-drying the solution. is filtered through one 0.45 μm filter and two 0.22 μm filters. In one embodiment, the process comprises dissolving Compound 1 in formic acid to obtain an active premix. and dissolving Kleptose® HPB in water to obtain a Kleptose solution. The premix is ​​added to the kleptose solution to obtain a mixture, and water is added to the mixture to obtain a ballast. To obtain the bulk solution, the bulk solution was filtered through one 0.45 μm filter and two 0.22 μm filters. Filter the solution through a filter to obtain a filtered solution, and fill the filtered solution into a 20cc glass vial. and lyophilizing the solution. In one embodiment, the vial contains: After lyophilization, the mixture is sealed under nitrogen.

[0391] In one embodiment, the freeze-drying process comprises three stages: freezing, primary drying, and The liquid formulation is completely solidified through the freezing step and then frozen through primary drying. The solvent is sublimated and the remaining water and solvent are removed through secondary drying. The shelf temperature and chamber pressure for primary and secondary drying are is controlled to obtain the desired quality of the final formulation. The appearance and structure of the cakes were characterized by visual inspection.

[0392] kit Also provided are pharmaceutical packs or kits containing the pharmaceutical compositions or dosage forms provided herein. Examples of kits include those prescribed by government agencies that have jurisdiction over the manufacture, use, or sale of pharmaceutical products. The instructions include instructions in a format that includes any policy for manufacture, use, or sale for human administration. It takes into account approval by prefectural agencies.

[0393] Methods of use and compounds 1 for use in such methods Compound 1 as provided herein can be used in all of the methods provided herein. In one embodiment, provided herein is a compound comprising Compound 1 as a JAK inhibitor. Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors Cancer, including solid tumors and blood cancers, or one or more of its symptoms or Provided herein are methods for treating, preventing, managing, and / or ameliorating the causes of solid tumors. Cancer, including pulmonary and hematological cancers, or one or more of its symptoms or causes Compound 1 for use in a method for the treatment, prevention, management, and / or amelioration of Compound 1 is a JAK inhibitor, FLT3 inhibitor, mTOR inhibitor, spliceosome inhibitor, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, Topoi In combination with one or more second agents selected from a somerase inhibitor and an RTK inhibitor It is administered as follows.

[0394] In one embodiment, provided herein are methods for treating and preventing cancer. The method includes administering to the patient a formulation of Compound 1 provided herein. Provided herein are compounds 1 and 2 for use in such methods of treating and preventing cancer. It is a combination of

[0395] In another embodiment, provided herein is a method for managing cancer, the method comprising: The method includes administering to the patient a formulation of Compound 1 provided herein. Provided is Compound 1 for use in such methods for the management of cancer.

[0396] In one embodiment, the methods provided herein involve administering a formulation of Compound 1 to a JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from an RTK inhibitor. Includes.

[0397] Also provided herein are patients who have previously been treated for cancer but are now unable to treat the disease. Treatment strategies for non-responsive and previously untreated patients Also included are methods of treating patients regardless of their age. Some diseases or disorders are more prevalent in certain age groups. The following are patients who have undergone surgery to treat the disease or disorder in question, and This is a treatment method for patients who have never received such treatment. Cancer patients have a variety of clinical symptoms. As such, the treatment a patient receives may vary depending on the patient's prognosis. Therefore, specific second-line drugs that can be effectively used to treat individual cancer patients without undue experimentation are identified. The types of medications, surgery, and non-drug based standard of care can be easily determined.

[0398] In one embodiment, provided herein is a method for treating cancer patients with the Eastern Cooperative Oncology 2. A method for improving Eastern Cooperative Oncology Group (ECOG) performance status, the method comprising: The patient is administered an effective amount of Compound 1 in combination with a JAK inhibitor, FLT3 inhibitor, mTOR inhibitor, or supramolecular inhibitor. Ezisomal inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, B one or more selected from H3 mimetics, topoisomerase inhibitors, and RTK inhibitors Provided herein are methods for administering a compound of formula I to a patient with cancer in combination with a second agent of formula I. How to improve Eastern Cooperative Oncology Group (ECOG) performance status and Compound 1 for use in a patient, the method comprising administering to the patient an effective amount of Compound 1 in combination with a JAK inhibitor. , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. .

[0399] In one embodiment, provided herein is a method for treating cancer patients with the Eastern Cooperative Oncology 2. A method for improving Eastern Cooperative Oncology Group (ECOG) performance status, the method comprising: The patient is administered an effective amount of a combination of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, , spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors one or more selected from the group consisting of antitumor agents, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors Provided herein are methods for treating cancer, including administering the method in combination with one or more second agents. Improve patients' Eastern Cooperative Oncology Group (ECOG) performance status and a formulation of Compound 1 for use in a method for treating a patient with atopic dermatitis, the method comprising administering to the patient an effective amount of Compound 1. The compound is a combination of a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, and a spliceosome inhibitor. , BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors in combination with one or more second agents selected from an isomerase inhibitor and an RTK inhibitor. This includes administering the drug using a

[0400] In one embodiment, provided herein is a method for treating cancer patients with the Eastern Cooperative Oncology 2. A method for improving Eastern Cooperative Oncology Group (ECOG) performance status, the method comprising: The method includes administering to the patient an effective amount of a formulation of Compound 1. Provided herein are Improving Eastern Cooperative Oncology Group (ECOG) performance status in cancer patients 1 is a formulation of Compound 1 for use in a method for improving

[0401] In one embodiment, provided herein is a method for preventing disease progression in cancer patients. inhibition, inhibition of tumor growth, reduction of primary tumor, reduction of tumor-related symptoms, inhibition of tumor-secreted factors, Delay in the appearance of primary or secondary tumors, slowing of the development of primary or secondary tumors, or a reduction in the occurrence of secondary tumors, a delay in the secondary effects of the disease or a reduction in their severity, a reduction in the incidence of tumors cessation of tumor growth and tumor regression, prolongation of tumor growth cessation period, prolongation of progression-free survival, prolongation of overall survival or one or more thereof, the method comprising administering to a patient an effective amount of Compound 1 was used as a JAK inhibitor, FLT3 inhibitor, mTOR inhibitor, and spliceosome inhibitor. agents, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, and one or more second agents selected from a polyisomeric enzyme inhibitor and an RTK inhibitor. Provided herein are methods for administering such a combination in cancer patients. and Compound 1 for use in all of the methods, which comprise administering to a patient an effective amount of Compound 1, AK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors , SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a rheumatoid arthritis inhibitor, a rheumatoid arthritis reversal inhibitor, and a RTK inhibitor. This includes:

[0402] In one embodiment, provided herein is a method for preventing disease progression in cancer patients. inhibition, inhibition of tumor growth, reduction of primary tumor, reduction of tumor-related symptoms, inhibition of tumor-secreted factors, Delay in the appearance of primary or secondary tumors, slowing of the development of primary or secondary tumors, or a reduction in the occurrence of secondary tumors, a delay in the secondary effects of the disease or a reduction in their severity, a reduction in the incidence of tumors cessation of tumor growth and tumor regression, prolongation of tumor growth cessation period, prolongation of progression-free survival, prolongation of overall survival or one or more thereof, the method comprising administering to a patient an effective amount of The compound 1 was administered in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a splice inhibitor, tumour inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics one or more second inhibitors selected from a nucleotide analogue, a topoisomerase inhibitor, and a RTK inhibitor; Provided herein are methods for administering the same in cancer patients in combination with an agent that inhibits or inhibits the growth of cancer cells. and a compound 1 for use in any one or more of the methods of The method includes administering to a patient an effective amount of a combination of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOF inhibitor, an IL-1 ... R inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, L an SD1 inhibitor, a BH3 mimetic, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering the compound in combination with one or more second agents that are

[0403] In one embodiment, provided herein is a method for preventing disease progression in cancer patients. inhibition, inhibition of tumor growth, reduction of primary tumor, reduction of tumor-related symptoms, inhibition of tumor-secreted factors, Delay in the appearance of primary or secondary tumors, slowing of the development of primary or secondary tumors, or a reduction in the occurrence of secondary tumors, a delay in the secondary effects of the disease or a reduction in their severity, a reduction in the incidence of tumors cessation of tumor growth and tumor regression, prolongation of tumor growth cessation period, prolongation of progression-free survival, prolongation of overall survival or one or more thereof, the method comprising administering to a patient an effective amount of Provided herein are methods for treating cancer patients comprising administering a compound of Compound 1 to a patient. and Compound 1 for use in all or one or more of such methods. The method includes administering to the patient an effective amount of a formulation of Compound 1.

[0404] In certain embodiments, the cancer is a solid tumor or a hematological cancer. In some forms, the cancer is interleukin-3 (IL-3) independent. In embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is In certain embodiments, the solid tumor is drug-resistant.

[0405] In certain embodiments, cancer refers to diseases of skin tissue, organs, blood, and blood vessels. In certain embodiments, the cancer is of the bladder, bone, blood, brain, breast, cervix, chest, Colon, endometrium, esophagus, eyes, head, kidneys, liver, lymph nodes, lungs, mouth, neck, ovaries, pancreas, prostate solid tumors, including, but not limited to, cancers of the gland, rectum, stomach, testicle, pharynx, and uterus Not specified. Specific cancers include advanced malignant tumors, amyloidosis, neuroblastoma, and meningioma. , hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis Benign and malignant brain tumors, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma tumors, neuroendocrine tumors, rectal adenocarcinoma, colorectal cancer (including stage 3 and stage 4), resection Intractable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotypic acute myeloblastic leukemia (karyo type acute myeloblastic leukemia), Hodgkin's lymphoma lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large cell Type B-cell lymphoma, low-grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural mesothelioma syndrome (malignant pleural effusion mesotheli oma syndrome), peritoneal cancer, serous adenocarcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma , cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, Endocrine therapy-resistant prostate cancer, post-resection high-grade soft tissue sarcoma, unresectable hepatocellular carcinoma, Walden Ström's macroglobulinemia, smoldering myeloma, asymptomatic myeloma, fallopian tube cancer, and androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-dependent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer chemotherapy-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, cellular carcinomas such as papillary thyroid carcinoma, follicular Thyroid cancer, medullary thyroid cancer, and leiomyoma. do not have.

[0406] In certain embodiments, the cancer is of the skin, central nervous system, soft tissue, salivary gland, ovary, Kidneys, lungs, bones, stomach, endometrium, pancreas, urinary tract, thyroid gland, upper aerodigestive tract, breasts, large intestine, esophagus solid tumors, including cancer of the prostate, liver, autonomic ganglia, and malignant pleural mesothelioma , but not limited to these.

[0407] In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or neuroendocrine carcinoma. It is a glioblastoma.

[0408] In certain embodiments, the solid tumor is breast cancer, renal cancer, pancreatic cancer, gastrointestinal cancer, lung cancer, neuronal cancer, or the like. Endocrine tumors (NETs) or renal cell carcinoma (RCC).

[0409] In certain embodiments, the cancer is a hematological cancer. The hematological cancer is metastatic. In certain embodiments, the hematological cancer is treated with at least one anti-cancer drug. In certain embodiments, the hematological cancer is at least Relapsed or refractory to one anticancer therapy.

[0410] In one embodiment, the hematological cancer is multiple myeloma (MM). In one embodiment, the hematological cancer is relapsed / refractory (R / R) MM. Patients with RMM have impaired renal function.

[0411] In one embodiment, provided herein are methods for achieving stringent complete response (SCR) in MM patients. The method comprises administering to a patient an effective amount of Compound 1 in combination with a JAK inhibitor, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors antitumor agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and R and administering the compound in combination with one or more second agents selected from TK inhibitors. Provided herein are methods for achieving stringent complete remission (sCR) in MM patients. The method comprises administering to a patient an effective amount of Compound 1 in combination with a JAK inhibitor, F LT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RT and administering the compound in combination with one or more second agents selected from K inhibitors.

[0412] In one embodiment, provided herein are methods for achieving stringent complete response (SCR) in MM patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 to treat a JAK1 protein-binding protein (JAK1 protein). inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from an RTK inhibitor. Provided herein are methods for achieving stringent complete remission (sCR) in MM patients. and a formulation of Compound 1 for use in a method of administering to a patient an effective amount of a formulation of Compound 1. The compound was used in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a spliceosome inhibitor, and B ET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a methylmerase inhibitor and a RTK inhibitor. This includes administering the drug.

[0413] In one embodiment, provided herein are methods for achieving stringent complete response (SCR) in MM patients. A method for achieving CR (combined remission), comprising administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving stringent complete remission (sCR) in MM patients. and a formulation of Compound 1 for use in a method for treating a patient with atopic dermatitis, the method comprising administering to the patient an effective amount of Compound 1. The method includes administering a combination of

[0414] In one embodiment, provided herein are methods for achieving complete remission (CR) in MM patients. The method includes administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, E RK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided are compounds for use in methods of achieving complete remission (CR) in patients with MM. 1, and the method comprises administering to a patient an effective amount of Compound 1 in combination with a JAK inhibitor, a FLT3 inhibitor, m TOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors , LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors. This includes administering the compound in combination with one or more second agents that are

[0415] In one embodiment, provided herein are methods for achieving complete remission (CR) in MM patients. The method includes administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors antitumor agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and R and administering the compound in combination with one or more second agents selected from TK inhibitors. Provided herein are compounds for use in methods of achieving complete remission (CR) in MM patients. and the method comprises administering to the patient an effective amount of a compound 1 formulation containing a JAK inhibitor. Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors. include.

[0416] In one embodiment, provided herein are methods for achieving complete remission (CR) in MM patients. The method includes administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete remission (CR) in MM patients. and a formulation of Compound 1 for the treatment of rheumatoid arthritis, the method comprising administering to a patient an effective amount of the formulation of Compound 1. This includes:

[0417] In one embodiment, provided herein are methods for achieving very good partial responses in MM patients. The method comprises administering to a patient an effective amount of Compound 1 in combination with a JAK inhibitor. Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors. Provided herein are methods for achieving very good partial responses (VGPR) in MM patients. The method comprises administering to a patient an effective amount of Compound 1, K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0418] In one embodiment, provided herein are methods for achieving very good partial responses in MM patients. A method for achieving VGPR, comprising administering to a patient an effective amount of a formulation of Compound 1: JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors agents, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase and one or more second agents selected from the group consisting of a rheumatoid arthritis inhibitor, a rheumatoid arthritis reversal inhibitor, and a rheumatoid arthritis reversal inhibitor. Provided herein are methods for achieving very good partial response (VGPR) in patients with MM. a formulation of Compound 1 for use in a method for achieving the above, the method comprising administering to a patient an effective amount of The compound 1 formulation was administered in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a spliceosome inhibitor, and rM inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics one or more second agents selected from a compound, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering it in combination with other drugs.

[0419] In one embodiment, provided herein are methods for achieving very good partial responses in MM patients. A method for achieving VGPR (Vascular-Gastrointestinal Proliferation), the method comprising administering to a patient an effective amount of a formulation of Compound 1. Provided herein are studies that have demonstrated very good partial responses (VGP) in patients with MM. R) is a formulation of Compound 1 for use in a method for achieving

[0420] In one embodiment, provided herein are methods for treating MM patients who achieve a partial response (PR). The method includes administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, E RK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided are compounds for use in methods to achieve partial responses (PRs) in patients with MM. 1, the method comprising administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mT OR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, selected from LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents that are

[0421] In one embodiment, provided herein are methods for treating MM patients who achieve a partial response (PR). The method includes administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors antitumor agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and R and administering the compound in combination with one or more second agents selected from TK inhibitors. Provided herein are compounds for use in methods of achieving a partial response (PR) in MM patients. and the method comprises administering to the patient an effective amount of a compound 1 formulation containing a JAK inhibitor. Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors. include.

[0422] In one embodiment, provided herein are methods for treating MM patients who achieve a partial response (PR). The method includes administering to a patient an effective amount of a formulation of Compound 1. Provided herein are compounds for use in methods of achieving a partial response in MM patients. This is a compound of Compound 1.

[0423] In one embodiment, provided herein are methods for achieving stable disease (SD) in MM patients. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, agents, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors The present invention also includes administering the compound of formula (I) in combination with one or more second agents selected from the group consisting of: Provided is Compound 1 for use in a method of achieving stable disease (SD) in a patient with MM. The method includes administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, or Toxicants, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD 1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors. This includes administering the compound in combination with one or more second agents.

[0424] In one embodiment, provided herein are methods for achieving stable disease (SD) in MM patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 in combination with a JAK inhibitor, FL T3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors , ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK The present invention also includes administering the compound in combination with one or more second agents selected from the group consisting of steroid hormone inhibitors. Provided herein are compounds for use in methods of achieving stable disease (SD) in patients with MM. 1, and the method comprises administering to a patient an effective amount of a formulation of Compound 1 in combination with a JAK inhibitor, F LT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RT and administering the compound in combination with one or more second agents selected from K inhibitors.

[0425] In one embodiment, provided herein are methods for achieving stable disease (SD) in MM patients. The method comprises administering to the patient an effective amount of a formulation of Compound 1. Provided herein is a method for achieving stabilization in a patient with MM, comprising administering to a patient a therapeutically effective amount of Compound 1. It is a compound.

[0426] In one embodiment, the hematological cancer is acute myeloid leukemia (AML). In one embodiment, the blood cancer is acute lymphocytic leukemia (ALL). In one embodiment, the hematological cancer is adult T-cell leukemia. In one embodiment, the hematological cancer is chronic lymphocytic leukemia. In one embodiment, the hematological cancer is hairy cell leukemia (CLL). In one embodiment, the hematological cancer is myelodysplastic syndrome. In one embodiment, the hematological cancer is a myeloproliferative disease or myeloproliferative neoplasm (MPN). In one embodiment, the hematological cancer is chronic myeloid leukemia (CML). The hematological cancer is myelodysplastic syndrome (MDS). In one embodiment, the hematological cancer is a human In one embodiment, the leukemia is HTLV-1 leukemia. The liquid cancer is mastocytosis. In one embodiment, the blood cancer is B-cell acute lymphoblastic leukemia. In one embodiment, the hematological cancer is CLL.

[0427] In one embodiment, provided herein is a method for detecting diffuse large cell carcinoma (DLC) in a subject. DLBCL, B-cell immunoblastic lymphoma, small non-dividing cell lymphoma , Human lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, Adult T-cell lymphoma lymphoma, mantle cell lymphoma (MCL), Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / Histiocytic large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) B-cell large Cellular lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, and A For the treatment, prevention, or management of cancer selected from LK-positive large B-cell lymphoma, and / or The method includes administering to a subject a formulation of Compound 1 provided herein to treat a cancer. The present invention includes administering an amount effective for treating, preventing, and / or managing the disease. Provided herein are all of these methods of treating, preventing, managing, and / or ameliorating cancer. and a formulation of Compound 1 for use in treating a patient with diffuse large B-cell myopathy in a subject. DLBCL, B-cell immunoblastic lymphoma, small non-dividing cell lymphoma, human Human T-cell lymphotropic virus type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, myeloma MCL, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NH) L), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocytic lymphoma Rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma Lymphoma, splenic marginal zone lymphoma, Richter transformation, nodal marginal zone lymphoma, and ALK positive In some embodiments, the method comprises administering to the subject a tumor comprising the tumor necrosis factor (TNF-α) or a ... The formulations of Compound 1 provided herein can be used to treat, prevent, and / or manage cancer. In one embodiment, the method comprises administering an effective amount of the compound in combination with a second active agent. The hematological cancer is HL. In one embodiment, the hematological cancer is NHL. In form, blood cancer is an asymptomatic lymphoma, such as DLBCL, follicular lymphoma, These include leukocyte tumors, leukocyte lymphomas, and marginal zone lymphomas.

[0428] In one embodiment, provided herein is a method for treating NHL patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are compounds for use in achieving complete remission (CR) in patients with NHL. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0429] In one embodiment, provided herein is a method for treating NHL patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving complete remission (CR) in NHL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0430] In one embodiment, provided herein is a method for treating NHL patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete remission (CR) in NHL patients. Compound 1 is a formulation for

[0431] In one embodiment, provided herein is a method for treating NHL patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are chemicals for use in achieving partial remission (PR) in patients with NHL. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0432] In one embodiment, provided herein is a method for treating NHL patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving partial remission (PR) in NHL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0433] In one embodiment, provided herein is a method for treating NHL patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving partial remission (PR) in NHL patients. Compound 1 is a formulation for

[0434] In one embodiment, provided herein are methods for achieving stable disease (SD) in NHL patients. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, a FLT3 inhibitor, Toxicants, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ER inhibitors K inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors and administering the compound in combination with one or more second agents selected from the group consisting of: Provided is Compound 1 for use in a method of achieving stable disease (SD) in patients with NHL. The method includes administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOF inhibitor, or a combination thereof. R inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, L an SD1 inhibitor, a BH3 mimetic, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering the compound in combination with one or more second agents that are

[0435] In one embodiment, provided herein are methods for achieving stable disease (SD) in NHL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 in combination with a JAK inhibitor, F LT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RT This includes administering the compound in combination with one or more second agents selected from the group consisting of ATP-1, ATP-2, ATP-3, ATP-4, ATP-5, ATP-6, ATP-7, ATP-8, ATP-9, ATP-10, ATP-11, ATP-12, ATP-13, ATP-14, ATP-15, ATP-16, ATP-17, ATP-18, ATP-19, ATP Provided herein are compounds for use in methods to achieve stable disease (SD) in patients with NHL. and a compound of formula 1, wherein the method comprises administering to the patient an effective amount of a compound of formula 1 in combination with a JAK inhibitor. , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. .

[0436] In one embodiment, provided herein are methods for achieving stable disease (SD) in NHL patients. a method for producing a therapeutically effective amount of a compound of formula 1, the method comprising administering to the patient an effective amount of a compound of formula 1 Provided herein are methods for achieving stable disease (SD) in patients with NHL. This is a formulation of Compound 1.

[0437] In one embodiment, provided herein is a method for administering to a subject a therapeutically active amount of Compound 1. The present invention relates to a method for treating, preventing, managing, and / or alleviating leukemia by administering That is, provided herein are methods for treating, preventing, managing, and / or remission of leukemia. For use in such a method, Compound 1 is provided. In one embodiment, the leukemia is acute In one embodiment, the AML is relapsed or refractory. In one embodiment, the AML is newly diagnosed AML. In another embodiment, the AML is classified as M0 / 1 by FAB classification. In another embodiment, the AML has a FAB classification of M2. In another embodiment, the AML is FAB classified as M4. In one embodiment, the AML is classified as M5 by the FAB classification. AML with at least one recurrent genetic abnormality (e.g., between chromosomes 8 and 21) AML with translocations; AML with translocations or inversions on chromosome 16; AML with translocations on chromosomes 9 and 11 AML with translocation between chromosomes; APL with translocation between chromosomes 15 and 17 (M 3); AML with a translocation between chromosomes 6 and 9; AML with a translocation or inversion on chromosome 3 AML with translocation between chromosomes 1 and 22 (megakaryoblastic); myeloblastic AML AML with dysplasia-related changes; AML associated with previous chemotherapy or radiation ( For example, alkylating agent-associated AML; or topoisomerase II inhibitor-associated AML); others AML that does not fall into the above categories (e.g., AML that does not fall into the above categories, i.e., Minimally differentiated AML (M0); Minimally differentiated AML (M1); Minimally differentiated AML (M2); Acute myelomonocytic AML acute leukemia (M4); acute monocytic leukemia (M5); acute erythroleukemia (M6); acute megakaryoblastic Leukemia (M7); acute basophilic leukemia; or acute panmyelosis with fibrosis); myeloid sarcoma (also known as granulocytic sarcoma, chloroma, or extramedullary myeloblastoma); or anaplastic and and biphenotypic acute leukemia (also known as mixed phenotypic acute leukemia). In one embodiment, the AML is characterized by a mutant allele of IDH2. In this embodiment, the mutant allele of IDH2 has an R140X mutation. In another aspect of this embodiment, the R140X mutation is a R140Q mutation. In another aspect of this embodiment, the R140X mutation is a R140W mutation. and the R140X mutation is a R140L mutation. The mutant allele of H2 has a R172X mutation. The R172X mutation is a R172K mutation. The X mutation is an R172G mutation.

[0438] In one embodiment, the AML is relapsed AML after allogeneic HSCT. In one embodiment, the AML is a second or subsequent relapse of the AML. ML is refractory to initial induction or reinduction therapy. In certain embodiments, In this setting, AML is refractory to at least one induction / reinduction or consolidation therapy. In one embodiment, the AML is refractory to hypomethylating agents (HMA). As used herein, HMA failure is defined as a failure of the initial HM due to progression or lack of clinical benefit after at least 6 cycles or toxicity In one embodiment, AML is defined as an inability to tolerate A. Relapse within one year of treatment (excluding AML with a good prognosis).

[0439] In certain embodiments, the present invention relates to the treatment, prevention, and / or management of acute myeloid leukemia in a subject. The method of administration includes administering to a subject a formulation of Compound 1 provided herein for treatment of acute myeloid leukemia. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound or compound that is effective to treat, prevent, and / or manage the disease. The method includes administering to a subject a formulation of Compound 1 provided herein to treat acute myeloid leukemia. in combination with an amount of a second active agent effective to treat, prevent, and / or manage the disease. The method includes the step of:

[0440] In one embodiment, provided herein is a method for detecting leukemia-associated leukemia in an AML patient. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, Antineoplastic agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SM G1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and one or more second agents selected from the group consisting of RTK inhibitors. Provided herein are methods for achieving a morphologically leukemia-free state in AML patients. The method comprises administering to a patient an effective amount of Compound 1, K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0441] In one embodiment, provided herein is a method for detecting leukemia-associated leukemia in an AML patient. The method comprises administering to a patient an effective amount of a formulation of Compound 1, JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors agents, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase and one or more second agents selected from the group consisting of a rheumatoid arthritis inhibitor, a rheumatoid arthritis reversal inhibitor, and a rheumatoid arthritis reversal inhibitor. Provided herein are methods for treating AML patients with a morphologically non-leukemic state. a formulation of Compound 1 for use in a method for achieving the above, the method comprising administering to a patient an effective amount of The compound 1 formulation was administered in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a spliceosome inhibitor, and rM inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics one or more second agents selected from a compound, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering it in combination with other drugs.

[0442] In one embodiment, provided herein is a method for detecting leukemia-associated leukemia in an AML patient. The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for administering to patients with AML who are not morphologically leukemia. A formulation of Compound 1 for use in a method for achieving the condition.

[0443] In one embodiment, provided herein is a method for treating AML patients with morphologic complete response. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are chemical compounds for use in methods to achieve morphologic complete response in patients with AML. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0444] In one embodiment, provided herein is a method for treating AML patients with morphologic complete response. The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving morphologic complete response in AML patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0445] In one embodiment, provided herein is a method for treating AML patients with morphologic complete response. The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete morphologic response in patients with AML. Compound 1 is a formulation for

[0446] In one embodiment, provided herein is a method for determining complete cytogenetics in patients with AML. The method includes administering to a patient an effective amount of Compound 1 to induce remission (CRc) of a JAK1 gene. inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from an RTK inhibitor. Includes.

[0447] In one embodiment, provided herein is a method for determining complete cytogenetics in patients with AML. A method for achieving complete remission (CRc) in a patient, the method comprising administering to the patient an effective amount of a formulation of Compound 1. , JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors Toxicants, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomers and one or more second agents selected from the group consisting of enzyme inhibitors and RTK inhibitors. Provided herein are methods for achieving complete cytogenetic response (CR) in patients with AML. c) a formulation of Compound 1 for use in a method for achieving the above-mentioned objectives, the method comprising administering to a patient an effective A combination of a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a splice inhibitor, and a 200 mg dose of Compound 1 was administered. thrombus inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 one or more inhibitors selected from the group consisting of a mimetic, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering in combination with a dual agent.

[0448] In one embodiment, provided herein is a method for determining complete cytogenetics in patients with AML. A method for achieving complete remission (CRc) in a patient, the method comprising administering to the patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete cytogenetic response (CR) in patients with AML. and a formulation of Compound 1 for use in a method for achieving CRc).

[0449] In one embodiment, provided herein is a method for the detection of complete molecular genetic mutations in AML patients. The method includes administering to a patient an effective amount of Compound 1 to induce remission (CRm) of a JAK1 gene. inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from an RTK inhibitor. Provided herein are methods for achieving complete molecular response (CRm) in patients with AML. and Compound 1 for use in a method for producing a medicament for treating a medicament for the treatment of ... JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors agents, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase and one or more second agents selected from the group consisting of a rheumatoid arthritis inhibitor, a rheumatoid arthritis reversal inhibitor, and a rheumatoid arthritis reversal inhibitor. This includes:

[0450] In one embodiment, provided herein is a method for the detection of complete molecular genetic mutations in AML patients. A method for achieving complete remission (CRm), the method comprising administering to a patient an effective amount of a formulation of Compound 1. , JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors Toxicants, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomers and one or more second agents selected from the group consisting of enzyme inhibitors and RTK inhibitors. Provided herein are methods for achieving complete molecular response (CR) in patients with AML. m), the method comprising administering to a patient an effective A combination of a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a splice inhibitor, and a 200 mg dose of Compound 1 was administered. thrombus inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 one or more inhibitors selected from the group consisting of a mimetic, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering in combination with a dual agent.

[0451] In one embodiment, provided herein is a method for the detection of complete molecular genetic mutations in AML patients. A method for achieving complete remission (CRm), the method comprising administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete molecular remission (CR) in AML patients. A formulation of Compound 1 for use in a method for achieving CRm.

[0452] In one embodiment, provided herein is a method for treating AML patients with incomplete hematologic recovery. The method involves administering to a patient an effective amount of a compound that achieves a complete morphological response (CRi). Compound 1 was used in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a spliceosome inhibitor, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, Topoi In combination with one or more second agents selected from a somerase inhibitor and an RTK inhibitor Provided herein are methods for treating AML patients with incomplete hematologic recovery. Compound 1 for use in a method for achieving a morphological complete response (CRi), The present invention relates to administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a steroid inhibitor, or a steroid inhibitor. Plyosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors , a BH3 mimetic, a topoisomerase inhibitor, and an RTK inhibitor; or This includes administering multiple second agents in combination.

[0453] In one embodiment, provided herein is a method for treating AML patients with incomplete hematologic recovery. The method involves administering to a patient an effective amount of a compound that achieves a complete morphological response (CRi). The compound 1 was administered as a combination of a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, and a spliceosome inhibitor. inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics , a topoisomerase inhibitor, and a RTK inhibitor. Provided herein are methods for improving hematologic recovery in AML patients, including administering the method in combination with an agent. Formulation of Compound 1 for use in methods to achieve incomplete morphologic complete response (CRi) The method comprises administering to a patient an effective amount of a combination of Compound 1, a JAK inhibitor, an FLT3 inhibitor, and a combination of Compound 1 ... Toxicants, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ER inhibitors K inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors and administering the compound in combination with one or more second agents selected from the group consisting of:

[0454] In one embodiment, provided herein is a method for treating AML patients with incomplete hematologic recovery. The method involves administering to a patient an effective amount of a compound that achieves a complete morphological response (CRi). Provided herein are methods for administering a combination of Compound 1 to patients with AML. Compound 1 for use in methods to achieve incomplete morphologic complete response (CRi) It is a compound.

[0455] In one embodiment, provided herein are methods for achieving partial remission in AML patients. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors and administering the compound in combination with one or more selected second agents. The present disclosure relates to Compound 1 for use in a method of achieving partial remission in patients with AML. The method comprises administering to the patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, or , spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors one or more selected from the group consisting of antitumor agents, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents.

[0456] In one embodiment, provided herein is a method for treating AML patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving partial remission (PR) in AML patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0457] In one embodiment, provided herein is a method for treating AML patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving partial remission (PR) in AML patients. Compound 1 is a formulation for

[0458] In one embodiment, provided herein is a method for treating AML patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are compounds for use in methods to achieve complete remission (CR) in patients with AML. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0459] In one embodiment, provided herein is a method for treating AML patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving complete remission (CR) in AML patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0460] In one embodiment, provided herein is a method for treating AML patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete remission (CR) in AML patients. Compound 1 is a formulation for

[0461] In some embodiments, the methods provided herein include treating acute lymphoblastic leukemia in a subject. In some embodiments, the present invention encompasses methods for the treatment, prevention, and / or management of ALL. L includes leukemias originating from blast cells in the bone marrow (B cells), thymus (T cells), and lymph nodes ALL is classified according to the French-American-British (FAB) morphological classification scheme: L1 - mature-appearing lymphoblasts (T cells or precursor B cells), L2 - immature and pleomorphic (like lymphoblasts (T cells or precursor B cells of various forms), and L3-lymphoblasts (B cells; In one embodiment, ALL can be classified as a blast cell type in the bone marrow. (B cells). In one embodiment, ALL originates from the thymus (T cells). In one embodiment, the ALL originates from a lymph node. ALL is an L1 subtype characterized by mature-appearing lymphoblasts (T cells or precursor B cells). In one embodiment, ALL is characterized by immature and pleomorphic (variously shaped) lymphoblasts ( In one embodiment, ALL is characterized by the L2 type (T cells or precursor B cells). The L3 type is characterized by lymphoblasts (B cells; Burkitt cells). In one embodiment, the ALL is a T-cell leukemia. In another embodiment, the T-cell leukemia is a peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. In some embodiments, the methods for treating, preventing, and / or managing ALL in a subject include administering to the subject a therapeutically effective amount of a compound according to the present invention. The formulations of Compound 1 provided herein can be used to treat, prevent, and / or manage ALL. In some embodiments, the method comprises administering to the subject an effective amount of any of the compounds provided herein. The compound 1 formulation is provided in an amount effective to treat, prevent, and / or manage ALL. in combination with a second active agent of

[0462] In some embodiments, the methods provided herein include treating chronic myeloid leukemia (CML) in a subject. The methods encompass methods for treating, preventing, and / or managing CML (chronic myeloma), including administering to a subject a therapeutically effective amount of the compound described herein. The provided formulations of Compound 1 are effective in treating, preventing, and / or managing CML. In some embodiments, the method includes administering to the subject a therapeutically effective amount of any of the therapeutically effective amounts provided herein. and administering to a subject a formulation of Compound 1 in an amount effective to treat, prevent, and / or manage CML. This includes administering the compound in combination with a second active agent.

[0463] In some embodiments, the methods provided herein include treating chronic lymphocytic leukemia in a subject. The methods include methods for treating, preventing, and / or managing chronic lymphocytic leukemia (CLL), which comprise administering to a subject a therapeutically effective amount of the compounds described herein. The formulations of Compound 1 provided herein may be used to treat, prevent, and / or manage chronic lymphocytic leukemia. In some embodiments, the method includes administering to the subject an amount of the compound effective to treat the disease. Formulations of Compound 1 provided herein can be used to treat, prevent, and / or manage CLL. The method includes administering the compound in combination with an effective amount of a second active agent.

[0464] In one embodiment, provided herein are methods for treating CLL patients who achieve complete remission (CR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are compounds for use in methods to achieve complete remission (CR) in patients with CLL. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0465] In one embodiment, provided herein are methods for treating CLL patients who achieve complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving complete remission (CR) in CLL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0466] In one embodiment, provided herein are methods for treating CLL patients who achieve complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete remission (CR) in CLL patients. Compound 1 is a formulation for

[0467] In one embodiment, provided herein is a method for treating CLL patients who have achieved partial remission (PR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are chemicals for use in methods to achieve partial remission (PR) in patients with CLL. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0468] In one embodiment, provided herein is a method for treating CLL patients who have achieved partial remission (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving partial remission (PR) in CLL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0469] In one embodiment, provided herein is a method for treating CLL patients who have achieved partial remission (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving partial remission (PR) in CLL patients. Compound 1 is a formulation for

[0470] In one embodiment, provided herein are methods for achieving stable disease (SD) in CLL patients. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, a FLT3 inhibitor, Toxicants, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ER inhibitors K inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors and administering the compound in combination with one or more second agents selected from the group consisting of: Provided is Compound 1 for use in a method of achieving stable disease (SD) in a patient with CLL. The method includes administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOF inhibitor, or a combination thereof. R inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, L an SD1 inhibitor, a BH3 mimetic, a topoisomerase inhibitor, and an RTK inhibitor; This includes administering the compound in combination with one or more second agents that are

[0471] In one embodiment, provided herein are methods for achieving stable disease (SD) in CLL patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 in combination with a JAK inhibitor, F LT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors agents, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RT This includes administering the compound in combination with one or more second agents selected from the group consisting of ATP-1, ATP-2, ATP-3, ATP-4, ATP-5, ATP-6, ATP-7, ATP-8, ATP-9, ATP-10, ATP-11, ATP-12, ATP-13, ATP-14, ATP-15, ATP-16, ATP-17, ATP-18, ATP-19, ATP Provided herein are compounds for use in methods to achieve stable disease (SD) in patients with CLL. and a compound of formula 1, wherein the method comprises administering to the patient an effective amount of a compound of formula 1 in combination with a JAK inhibitor. , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. .

[0472] In one embodiment, provided herein are methods for achieving stable disease (SD) in CLL patients. a method for producing a therapeutically effective amount of a compound of formula 1, the method comprising administering to the patient an effective amount of a compound of formula 1 Provided herein are methods for achieving stable disease (SD) in CLL patients. Compound 1 of the formula:

[0473] In one embodiment, provided herein is a method for administering to a subject a therapeutically active amount of Compound 1. the treatment, prevention, management, and / or administration of myelodysplastic syndromes (MDS) In one embodiment, provided herein is a method for treating MDS. That is, provided herein are methods for treating, preventing, managing, and / or treating MDS. For use in such methods of treatment or amelioration, Compound 1 is provided. The MDS is relapsed, resistant, or refractory MDS. In one embodiment, MDS refractory anemia (RA); RA with ringed sideroblasts (RARS); RA with excess blasts (RARS) AEB); refractory cytopenia with multilineage dysplasia (RCMD), single blood lineage dysplasia refractory cytopenia with unclassifiable myelodysplastic syndrome (RCUD); myelodysplastic syndrome, unclassifiable (MDS-U); Myelodysplastic syndromes associated with del(5q) chromosomal abnormalities, therapy-related myeloid neoplasms, or chronic myeloid neoplasms In some embodiments, MDS is a very low-risk form of myelomonocytic leukemia (CMML). The patients are classified as high-risk, low-risk, intermediate-risk, high-risk, or very high-risk MDS. In one embodiment, the MDS is very low-risk MDS. S is low-risk MDS. In another embodiment, the MDS is intermediate-risk MDS. In another embodiment, the MDS is high-risk MDS. DS is very high-risk MDS. In one embodiment, MDS is recurrent or In one embodiment, the MDS is refractory high-risk MDS. have a score of >3.5 points on the Interventional Therapy Scoring System (IPSS-R) (e.g., IPSS-R intermediate risk (>10% myeloblasts or poor or very poor IPSS) SR cytogenetic risk), IPSS-R high risk, and IPSS-R very high risk In one embodiment, MDS is a disease that is not treatable with other established therapies (e.g., transplantation). In some embodiments, the MDS is a primary or In another embodiment, the MDS is secondary MDS. In one embodiment, the MDS is refractory to initial induction or reinduction therapy. In certain embodiments, the MDS is characterized by at least one of introduction / reintroduction or In certain embodiments, the MDS in a subject is refractory to consolidation therapy. The methods of treatment, prevention, and / or management include administering to a subject a formulation of Compound 1 provided herein. in an amount effective to treat, prevent, and / or manage MDS. In some embodiments, the method includes administering to the subject a formulation of Compound 1 provided herein, in a MD in combination with an amount of a second active agent effective to treat, prevent, and / or manage S. The method includes the step of:

[0474] In one embodiment, provided herein is a method for treating MDS patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors The present invention also includes administering the compound in combination with one or more second agents selected from the group consisting of steroid inhibitors, anti-inflammatory drugs ...

[0475] In one embodiment, provided herein is a method for treating MDS patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving complete remission (CR) in MDS patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0476] In one embodiment, provided herein is a method for treating MDS patients who have achieved complete remission (CR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving complete remission (CR) in MDS patients. Compound 1 is a formulation for

[0477] In one embodiment, provided herein are methods for achieving myelocardial remission (mCR) in MDS patients. ), the method comprising administering to a patient an effective amount of Compound 1, a JAK inhibitor, FL T3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors , ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK The present invention also includes administering the compound in combination with one or more second agents selected from the group consisting of steroid hormone inhibitors. Provided herein is a method for achieving myelocardial remission (mCR) in patients with MDS. The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, Toxicants, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ER inhibitors K inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors and administering the compound in combination with one or more second agents selected from the group consisting of:

[0478] In one embodiment, provided herein are methods for achieving myelocardial remission (mCR) in MDS patients. ), the method comprising administering to a patient an effective amount of a formulation of Compound 1, agents, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG 1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and RTK inhibitors. Provided herein are methods for achieving myelocardial remission (mCR) in MDS patients. and a compound 1 formulation for treating a patient, the method comprising administering to the patient an effective amount of a compound 1 formulation, JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors agents, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase and one or more second agents selected from the group consisting of a rheumatoid arthritis inhibitor, a rheumatoid arthritis reversal inhibitor, and a rheumatoid arthritis reversal inhibitor. This includes:

[0479] In one embodiment, provided herein are methods for achieving myelocardial remission (mCR) in MDS patients. ), which method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving myelocardial remission (mCR) in MDS patients. Formulation of Compound 1 for use.

[0480] In one embodiment, provided herein is a method for treating MDS patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, FLT 3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with one or more second agents selected from the group consisting of: Provided herein are chemicals for use in methods to achieve partial response (PR) in patients with MDS. Compound 1, and the method comprises administering to a patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, , mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors from antitumor agents, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering it in combination with one or more selected second agents.

[0481] In one embodiment, provided herein is a method for treating MDS patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1, a JAK inhibitor, , FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and and administering the compound in combination with one or more second agents selected from RTK inhibitors. Provided herein are methods for achieving partial remission (PR) in MDS patients. The method comprises administering to a patient an effective amount of a formulation of Compound 1 for administering to a patient a JA K inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and one or more second agents selected from the group consisting of a steroid hormone receptor agonist (SHR) inhibitor and a RTK inhibitor. Includes:

[0482] In one embodiment, provided herein is a method for treating MDS patients who have achieved partial response (PR). The method comprises administering to a patient an effective amount of a formulation of Compound 1. Provided herein are methods for achieving partial response (PR) in MDS patients. Compound 1 is a formulation for

[0483] In one embodiment, provided herein are methods for determining overall survival in MDS patients. prolongation of recurrence-free survival, prolongation of progression-free survival, prolongation of event-free survival, remission period This is a method for extending the time to treatment, the duration of response, or the time to transformation to AML. The method comprises administering to the patient an effective amount of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, or , spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors one or more selected from the group consisting of antitumor agents, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors Provided herein are methods for administering MD Prolonged overall survival, prolonged recurrence-free survival, prolonged progression-free survival, and safe survival in S patients Longer survival, longer duration of remission, longer duration of response, or time to transformation to AML and Compound 1 for use in a method for extending the duration of a patient's life, the method comprising administering to a patient an effective amount of Compound 1. JAK inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomers and one or more second agents selected from the group consisting of a phosphodiesterase inhibitor, a phosphodiesterase inhibitor, and a RTK inhibitor. This includes giving.

[0484] In one embodiment, provided herein are methods for determining overall survival in MDS patients. prolongation of recurrence-free survival, prolongation of progression-free survival, prolongation of event-free survival, remission period This is a method for extending the time to treatment, the duration of response, or the time to transformation to AML. The method includes administering to a patient an effective amount of a combination of Compound 1, a JAK inhibitor, an FLT3 inhibitor, an mTOF inhibitor, an IL-1 ... R inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, L an SD1 inhibitor, a BH3 mimetic, a topoisomerase inhibitor, and an RTK inhibitor; The present invention also includes administering the compounds provided herein in combination with one or more second agents. has been shown to improve overall survival, recurrence-free survival, and progression-free survival in MDS patients. prolonged event-free survival, prolonged duration of remission, prolonged duration of response, or conversion to AML a formulation of Compound 1 for use in a method for extending the time to An effective amount of Compound 1 is administered in combination with a JAK inhibitor, an FLT3 inhibitor, an mTOR inhibitor, a supramolecular inhibitor, a steroid ... Ezisomal inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors, LSD1 inhibitors, B one or more selected from H3 mimetics, topoisomerase inhibitors, and RTK inhibitors This includes administering the compound in combination with a second agent of the formula:

[0485] In one embodiment, provided herein are methods for determining overall survival in MDS patients. prolongation of recurrence-free survival, prolongation of progression-free survival, prolongation of event-free survival, remission period This is a method for extending the time to treatment, the duration of response, or the time to transformation to AML. The method includes administering to the patient an effective amount of a formulation of Compound 1. The benefits of this treatment include extending overall survival, recurrence-free survival, and progression-free survival in MDS patients. prolonged survival, event-free survival, duration of remission, duration of response, or conversion to AML 2. A formulation of Compound 1 for use in a method of extending the time to

[0486] In some embodiments, the methods provided herein are useful for treating, preventing, and / or treating myeloproliferative neoplasms. In one embodiment, the myeloproliferative neoplasm is a definitive myeloproliferative neoplasm. Polycythemia, primary or essential thrombocythemia, myelofibrosis, chronic myeloid leukemia, chronic erythrocytosis, eosinophilic leukemia, juvenile myelomonocytic leukemia, chronic eosinophilic leukemia, or hypereosinophilic syndrome. In one embodiment, the myeloproliferative neoplasm is polycythemia vera, primary or essential. Thrombocythemia, primary or idiopathic myelofibrosis, secondary myelofibrosis, post-polycythemia vera Myelofibrosis, post-essential thrombocythemia myelofibrosis, chronic myeloid leukemia, chronic neutrophilic leukemia, young adult Patients with chronic myelomonocytic leukemia, chronic eosinophilic leukemia, or hypereosinophilic syndrome. In one embodiment, the myeloproliferative neoplasm is polycythemia vera. The myeloproliferative neoplasm is primary or essential thrombocythemia. The myeloproliferative neoplasm is myelofibrosis. In one embodiment, the myeloproliferative neoplasm is a primary In one embodiment, the myeloproliferative neoplasm is a secondary or idiopathic myelofibrosis. In one embodiment, the myeloproliferative neoplasm is polycythemia vera. In one embodiment, the myeloproliferative neoplasm is post-essential thrombocythemia myelofibrosis. fibrosis. In one embodiment, the myeloproliferative neoplasm is chronic myeloid leukemia. In one embodiment, the myeloproliferative neoplasm is chronic neutrophilic leukemia. In one embodiment, the myeloproliferative neoplasm is juvenile myelomonocytic leukemia. In one embodiment, the myeloproliferative neoplasm is chronic eosinophilic leukemia. In certain embodiments, the myeloproliferative neoplasm is an eosinophilic syndrome. In some embodiments, the myeloproliferative neoplasm is interleukin-3 (IL-3) independent. , characterized by a JAK mutation, e.g., a V617 mutation such as V617F.

[0487] In certain embodiments, the present invention relates to the treatment, prevention, and / or treatment of myeloproliferative neoplasms in a subject. The administration method includes administering to a subject a formulation of Compound 1 provided herein to treat a myeloproliferative neoplasm. In some embodiments, the method comprises administering to a subject an amount effective to treat, prevent, and / or manage the disease. The method includes administering to a subject a formulation of Compound 1 provided herein to treat a myeloproliferative neoplasm. and administering the compound in combination with an amount of a second active agent effective to treat, prevent, and / or manage the compound. Includes the process.

[0488] In one embodiment, the methods for the treatment, prevention, and / or management of cancer provided herein The method includes intravenously administering a formulation of Compound 1. In one embodiment, The compound 1 formulation can be dissolved in water to provide the cancer treatment, prevention, and and / or administration in an aqueous solution for intravenous administration.

[0489] In some embodiments, the method includes administering to a subject a formulation of Compound 1 provided herein: administered in combination with an amount of a second active agent effective to treat, prevent, and / or manage cancer. The method includes a step of providing the

[0490] In certain embodiments, provided herein are methods for treating renal dysfunction in patients with impaired renal function. In certain embodiments, the present invention provides a method for the treatment, prevention, and / or management of cancer. Provided herein is a method for providing appropriately adjusted doses to patients with renal impairment. The causes of renal dysfunction include disease, age, or other patient factors. Not limited to:

[0491] In one embodiment, provided herein is a method for determining GSPT1 levels in a subject. The method comprises administering Compound 1 to a subject in combination with a second That is, provided herein are methods for administering to a subject in combination with an agent. Compound 1 for use in a method for reducing GSPT1 levels in a subject, the method comprising administering to a subject: This includes administering Compound 1 in combination with a second agent as described herein. In some embodiments, provided herein are compounds that can be used as a second agent in the treatment of cancer in a subject. a method for monitoring the efficacy of a treatment using Compound 1 in combination with a subject, the method comprising: (a) administering Compound 1 and a second agent to a subject; (b) obtaining a sample from the subject. (c) measuring the level of GSPT1 in the sample; (d) measuring the level of GSPT1 in the sample. comparing the level of GSPT1 in a reference sample; If PT1 levels are reduced, treatment with Compound 1 and a second agent is indicated for the target cancer. That is, provided herein are compounds that are effective in treating cancer in a subject. Such methods are used to monitor the efficacy of treatment with Compound 1 in combination with a second agent in In yet another embodiment, the compound provided herein is Compound 1 for use in the method. The present invention relates to a method for treating cancer using Compound 1 and a second agent in a subject with or suspected of having cancer. A method for predicting response to treatment, the method comprising: (a) Compound 1; and (b) administering a dual agent to a subject; (b) obtaining a sample from the subject; and (c) detecting GSP in the sample. (d) measuring the T1 level in the sample compared to the GSPT1 level in a reference sample; If PT1 levels are decreased, the subject is treated with Compound 1 and a second agent to treat the cancer. Diagnosing a patient as likely to respond to treatment. That is, provided herein is a method for diagnosing a patient as likely to respond to treatment. and a second agent for treatment of a subject having or suspected of having the disease. and Compound 1 for use in a method for predicting the reactivity of a compound.

[0492] In one embodiment, provided herein is a method for determining Mcl-1 levels in a subject. The method comprises administering Compound 1 to a subject in combination with a second That is, provided herein are methods for administering to a subject in combination with an agent. Compound 1 for use in such a method of reducing Mcl-1 levels in a subject, administers to a subject Compound 1 in combination with a second agent as described herein. In some embodiments, provided herein are methods for treating cancer in a subject. A method for monitoring the effectiveness of treatment using Compound 1 in combination with a second agent, The method includes: (a) administering Compound 1 and a second agent to the subject; (b) administering to the subject (c) measuring the level of Mcl-1 in the sample; (d) measuring the level of Mcl-1 in the sample; Comparing the Mcl-1 level to the Mcl-1 level in a reference sample, If Mcl-1 levels are decreased in the sample, treatment with Compound 1 and a second agent is effective in treating cancer in a subject. Monitoring the efficacy of treatment with Compound 1 in combination with a second agent in the treatment of cancer In yet another embodiment, the compound provided herein is Compound 1 for use in the method of The study involves the use of Compound 1 and a second agent in subjects with or suspected of having cancer. a method for predicting response to a treatment of a subject, the method comprising: (a) compound 1; and (b) administering a second agent to a subject; (b) obtaining a sample from the subject; (c) determining Mc in the sample. (d) measuring Mcl-1 levels in the sample compared to Mcl-1 levels in a reference sample; If cl-1 levels are decreased, the subject is treated with Compound 1 and a second agent. That is, provided herein is a method for diagnosing a patient as likely to respond to cancer treatment. for treatment of a subject having or suspected of having cancer with Compound 1 and a second agent; and Compound 1 for use in a method for predicting the reactivity of a compound to a target molecule.

[0493] In some embodiments of the methods provided herein, the reference sample comprises administering to the subject Compound 1 and The reference sample is of the same origin as the sample, as it is obtained from the subject prior to administration of the dual agent. In other embodiments of the methods provided herein, the reference sample is a sample from a second patient with cancer. The reference sample is obtained from the same source as the sample. In yet another embodiment, the reference sample is obtained from a group of patients with cancer, The sample is of the same origin as the sample.

[0494] In one embodiment, provided herein is a method for treating atopic dermatitis using Compound 1 and a second agent. a method for identifying a cancer subject suitable for a treatment, the method comprising: (a) determining whether the cancer is a (b) obtaining a sample from a subject; (b) measuring the level of GSPT1 in the sample; (c) (d) contacting the sample with Compound 1 and a second agent; and (d) detecting GSPT in the sample after the contacting step. (e) measuring the GSPT1 level of step (d) compared to the GSPT1 level of step (b); If SPT1 levels are decreased, the subject is selected for cancer treatment with Compound 1 and a second agent. That is, provided herein are compounds that identify a compound as likely to respond to a treatment. Compounds for use in methods for identifying cancer subjects suitable for treatment with compound 1 and a second agent Item 1.

[0495] In one embodiment, provided herein is a method for treating atopic dermatitis using Compound 1 and a second agent. a method for identifying a cancer subject suitable for a treatment, the method comprising: (a) determining whether the cancer is a (b) obtaining a sample from a subject; (b) measuring Mcl-1 levels in the sample; (c) (d) contacting the sample with Compound 1 and a second agent; and (d) detecting Mcl- in the sample after the contacting step. (e) measuring the Mcl-1 levels of step (d) compared to the Mcl-1 levels of step (b); If cl-1 levels are decreased, the subject is selected for cancer treatment with Compound 1 and a second agent. That is, provided herein are compounds that identify a compound as likely to respond to a treatment. Compounds for use in methods for identifying cancer subjects suitable for treatment with compound 1 and a second agent Item 1.

[0496] The term "sample" as used herein refers to a material or materials obtained from a subject. A mixture is obtained or reached in vivo or in situ as a sample. This includes samples of tissue or fluid origin collected from a patient, or samples of precancerous or includes samples from areas of a subject that contain cancer cells or tissue. The target organism may be, but is not limited to, organs, tissues, and cells isolated from mammals. Examples of samples include cell lysates, cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, These include, but are not limited to, cell organelles, biological fluids, blood samples, urine samples, skin samples, etc. In one embodiment, the sample may be whole blood, partially purified blood, PBMC, or bone marrow. Tissue biopsies include bone marrow core biopsies, bone marrow aspirates, isolated bone marrow mononuclear cells, and circulating tumor cells. Examples include, but are not limited to:

[0497] In some such embodiments, the second agent is a JAK inhibitor, as described herein. inhibitors, FLT3 inhibitors, mTOR inhibitors, spliceosome inhibitors, BET inhibitors, S MG1 inhibitors, ERK inhibitors, LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors and RTK inhibitors.

[0498] In certain embodiments, a therapeutically or prophylactically effective amount of Compound 1 ranges from about 0.005 to about 20mg / day, about 0.05~20mg / day, about 0.01~10mg / day, about 0.01~ Approximately 7mg / day, approximately 0.01 to approximately 5mg / day, approximately 0.01 to approximately 3mg / day, approximately 0.05 to approximately 10mg / day, about 0.05 to about 7mg / day, about 0.05 to about 5mg / day, about 0.05 to about 3mg / day, about 0.1 to about 15mg / day, about 0.1 to about 10mg / day, about 0.1 to about 7m g / day, about 0.1 to about 5 mg / day, about 0.1 to about 3 mg / day, about 0.5 to about 10 mg / day , about 0.05 to about 5 mg / day, about 0.5 to about 3 mg / day, about 0.5 to about 2 mg / day, about 0 .3 to about 10 mg / day, about 0.3 to about 8.5 mg / day, about 0.3 to about 8.1 mg / day, about In one embodiment, the dose is 0.6 to about 10 mg / day, or about 0.6 to about 5 mg / day. Therefore, the therapeutically or prophylactically effective amount of Compound 1 is about 0.005 to about 20 mg / day. In an embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.05 to 20 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.01 to about 10 In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is 0.01 to about 7 mg / day. In one embodiment, the therapeutic dose of Compound 1 is about 0.01 to about 5 mg / day. The prophylactically effective amount is about 0.01 to about 3 mg / day. The therapeutically or prophylactically effective amount is about 0.05 to about 10 mg / day. The therapeutically or prophylactically effective amount of Compound 1 is about 0.05 to about 7 mg / day. In this embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.05 to about 5 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.05 to about 3 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.1 to about 1 In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.5 mg / day. In one embodiment, the therapeutic or prophylactic efficacy of Compound 1 is 0.1 to about 10 mg / day. In one embodiment, the amount is about 0.1 to about 7 mg / day. The prophylactically effective amount is about 0.1 to about 5 mg / day. In one embodiment, the therapeutically or prophylactically effective amount is about 0.1 to about 3 mg / day. The therapeutically or prophylactically effective amount of compound 1 is about 0.5 to about 10 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.5 to about 5 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.5 to about 3 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.5 to about 2 mg / day. In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0.3 to about 10 In one embodiment, the therapeutically or prophylactically effective amount of Compound 1 is about 0. In one embodiment, the therapeutic or prophylactic efficacy of Compound 1 is 3 to about 8.5 mg / day. In one embodiment, the therapeutic amount of Compound 1 is about 0.3 to about 8.1 mg / day. The effective or prophylactic amount is about 0.6 to about 10 mg / day or about 0.6 to about 5 mg / day.

[0499] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0. 5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 mg / day In some such embodiments, the therapeutically or prophylactically effective amount is about 0.5, about 0.6, About 0.75, about 1, about 2, about 3, about 4, about 5, about 6, or about 7 mg / day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0.6, about 1.2, about 1.8, about 2.4, or about 3.6 mg / day. In certain embodiments, the therapeutic or prophylactic An effective amount is about 0.1 mg / day. In certain embodiments, a therapeutically or prophylactically effective In certain embodiments, the therapeutically or prophylactically effective amount is about 0.2 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about In certain embodiments, the therapeutically or prophylactically effective amount is about 2 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 3 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 4 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 5 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 6 mg / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 7 mg / day. A therapeutically or prophylactically effective amount is about 8 mg / day. A prophylactically effective amount is about 9 mg / day. In certain embodiments, a therapeutically or prophylactically effective amount is about 9 mg / day. The dose is approximately 10 mg / day.

[0500] In one embodiment, the recommended daily dose range for Compound 1 is as described herein. For symptoms, the range is from about 0.01 mg to about 20 mg per day, preferably as a single dose. It is administered as a single dose daily or as divided doses throughout the day. In certain embodiments, the recommended daily dose ranges for Compound 1 are as follows: The range is from about 0.01 mg to about 15 mg per day, preferably as a single, once-daily dose. In one embodiment, the compound is administered in a single dose or as divided doses throughout the day. The recommended daily dose range for Compound 1 is about 0.01 mg for the conditions described herein. to about 12 mg / day, preferably as a single, once-daily dose or In some embodiments, the dosage is administered in divided doses throughout the day. In other embodiments, dosages range from about 0.5 to about 5 mg / day. g / day. Specific daily doses are 0.1, 0.2, 0.5, and 0. 6, 1, 1.2, 1.5, 1.8, 2, 2.4, 2.5, 3, 3.5, 3.6, 4, 4. 5, 5, 5.5, 6, 6.5, 7, 7.2, 7.5, 8, 8.5, 9, 9.5, 10, 1 0.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.4, 14.5 In other embodiments, the dosage is from about 0.5 to about 5 mg / day. The specific daily doses are 0.1, 0.2, 0.5, 0 mg / day. .6, 1, 1.2, 1.5, 1.8, 2, 2.4, 2.5, 3, 3.5, 3.6, 4, 4 0.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg In one embodiment, the daily dose is 0.1 mg / day. In one embodiment, the daily dose is 0.2 mg / day. In one embodiment, the daily dose is 0.5 mg / day. The daily dose is 0.6 mg / day. In one embodiment, the daily dose is In one embodiment, the daily dose is 1.2 mg / day. In one embodiment, the daily dose is 1.5 mg / day. In one embodiment, the daily dose is 1.8 mg / day. In one embodiment, the daily dose is 2 mg / day. The dose is 2.4 mg / day. In one embodiment, the daily dose is 2.5 In one embodiment, the daily dose is 3 mg / day. In one embodiment, the daily dose is 3.5 mg / day. In one embodiment, the daily dose is 3.6 mg / day. The daily dose is 4 mg / day. In one embodiment, the daily dose is 4. 5 mg / day. In one embodiment, the daily dose is 5 mg / day. In one embodiment, the daily dose is 5.5 mg / day. In one embodiment, the daily dose is 6 mg / day. In one embodiment, the daily dose is 7 mg / day. mg / day. In one embodiment, the daily dose is 7.2 mg / day In one embodiment, the daily dose is 7.5 mg / day. In one embodiment, the daily dose is 8 mg / day. In one embodiment, the daily dose is 8.5 mg / day. In one embodiment, the daily dose is 9.5 mg / day. In one embodiment, the daily dose is 10 mg / day. In one embodiment, the daily dose is 12 mg / day. In one embodiment, the daily dose is 10 mg / day. In one embodiment, the daily dose is 14.4 mg / day. In one embodiment, the daily dose is 15 mg / day.

[0501] In certain embodiments, the recommended starting dosage is 0.1, 0.5, 0.6, 0.7 ,1, 1.2, 1.5, 1.8, 2, 2.4, 2.5, 3, 3.5, 3.6, 4, 4.5 In another embodiment, the recommended dose is 5, 5.5, 6, 6.5, or 7 mg / day. Recommended starting doses are 0.1, 0.5, 0.6, 1, 1.2, 1.8, 2, 2.4, and 3 In one embodiment, the dose is 7, 3.6, 4, or 5 mg / day. The dose may be increased to 8, 9, 10, 12, or 15 mg / day. In these cases, the dose can be increased to 7, 8, 9, or 10 mg / day.

[0502] In certain embodiments, Compound 1 is administered to patients with leukemia, including AML, at a dose of about 0.1 In certain embodiments, Compound 1 can be administered in an amount of 1 mg / day to treat AML. The compound can be administered in an amount of about 1 mg / day to patients with leukemia, including leukemia. In this study, Compound 1 was administered at a dose of approximately 3 mg / day to patients with leukemia, including AML. In certain embodiments, Compound 1 can be used to treat leukemia, including AML. The patient may be administered an amount of about 4 mg / day. The compound 1 provided herein is administered at a dose of approximately 5 mg / day to patients with leukemia, including AML. In certain embodiments, Compound 1 provided herein can be used to treat AML. The compound can be administered in an amount of about 6 mg / day to patients with leukemia, including leukemia. In this study, Compound 1 provided herein was shown to provide approximately 7% of the AML and other leukemia patients with In certain embodiments, the compounds provided herein can be administered in an amount of 100 mg / day. Compound 1 can be administered at a dose of approximately 10 mg / day to patients with leukemia, including AML. In certain embodiments, Compound 1 provided herein can be used to treat a variety of conditions, including AML. In certain embodiments, the compound may be administered in an amount of about 12 mg / day to patients with leukemia. Compound 1 provided herein provides approximately 15 mg of leukemia treatment to patients with AML and other leukemias. It can be administered in the amount of 100 mg / day.

[0503] In certain embodiments, Compound 1 is administered to patients with MDS in an amount of about 0.1 mg / day. In certain embodiments, Compound 1 is administered to patients with MDS at a dose of about 1 mg / day. In certain embodiments, Compound 1 can be administered to patients with MDS in an amount of about 3 In certain embodiments, Compound 1 can be administered in an amount of 1 mg / day to treat MDS. The patient may be administered an amount of about 4 mg / day. Provided Compound 1 can be administered to patients with MDS in an amount of about 5 mg / day. In one embodiment, Compound 1 provided herein is administered to a patient with MDS at a dose of about 6 mg / day. In certain embodiments, Compound 1 provided herein can be administered in an amount In certain embodiments, the compound may be administered to patients with MDS in an amount of about 7 mg / day. Compound 1 provided herein can be administered to patients with MDS in an amount of about 10 mg / day. In certain embodiments, Compound 1 provided herein can be administered to patients with MDS at a dose of about In certain embodiments, the compounds provided herein may be administered in an amount of 12 mg / day. Compound 1 can be administered to patients with MDS in an amount of about 15 mg / day.

[0504] In certain embodiments, a therapeutically or prophylactically effective amount is from about 0.001 to about 20 mg / kg / day, about 0.01 to about 15 mg / kg / day, about 0.01 to about 10 mg / kg / day, about 0.01 to approximately 9 mg / kg / day, 0.01 to approximately 8 mg / kg / day, approximately 0.01 to approximately 7 mg / kg / day, about 0.01 to about 6 mg / kg / day, about 0.01 to about 5 mg / kg / day, about 0 .01~about 4mg / kg / day, about 0.01~about 3mg / kg / day, about 0.01~about 2mg / kg / day, about 0.01 to about 1 mg / kg / day, or about 0.01 to about 0.05 mg / kg In certain embodiments, the therapeutically or prophylactically effective amount is about 0.001 to about 0.001 g / day. In certain embodiments, the therapeutically or prophylactically effective amount is about 20 mg / kg / day. In certain embodiments, the therapeutic or prophylactic dose is about 0.01 to about 15 mg / kg / day. The effective preventative amount is about 0.01 to about 10 mg / kg / day. A therapeutically or prophylactically effective amount is from about 0.01 to about 9 mg / kg / day. In this case, the therapeutically or prophylactically effective amount is 0.01 to about 8 mg / kg / day. In an embodiment, the therapeutically or prophylactically effective amount is from about 0.01 to about 7 mg / kg / day. In certain embodiments, a therapeutically or prophylactically effective amount is from about 0.01 to about 6 mg / kg / In certain embodiments, a therapeutically or prophylactically effective amount is from about 0.01 to about 5 mg / kg. In certain embodiments, the therapeutically or prophylactically effective amount is about 0.0 In certain embodiments, the therapeutically or prophylactically effective amount is 1 to about 4 mg / kg / day. In certain embodiments, the therapeutic or prophylactic dose is about 0.01 to about 3 mg / kg / day. In certain embodiments, the therapeutically effective amount is about 0.01 to about 2 mg / kg / day. A therapeutically or prophylactically effective amount is about 0.01 to about 1 mg / kg / day. In this case, the therapeutically or prophylactically effective amount is about 0.01 to about 0.05 mg / kg / day.

[0505] Dosages may be expressed in units other than mg / kg / day. For example, The dose is mg / m 2 / day. Those skilled in the art will appreciate that the If one or both are given, the dose should be increased from mg / kg / day to mg / m 2 Convert to / day It is easy to understand how to do this (www.fda.gov / cder / cancer For example, 1 mg / kg for a 65 kg human The dose of 38 mg / m 2 Approximately equal to / day.

[0506] In certain embodiments, the amount of Compound 1 administered is about 0.001 ~about 500μM, about 0.002 to about 200μM, about 0.005 to about 100μM, about 0.0 1 to about 50 μM, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM , about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM. In certain embodiments, the administered The amount of Compound 1 is about 0.001 to about 500 μM, about 0.002 to about 200 μM at steady state. M, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0. 02~about 25μM, about 0.05~about 20μM, about 0.1~about 20μM, about 0.5~about 20 sufficient to produce a plasma concentration of the compound in the range of about 1 to about 20 μM. .

[0507] In other embodiments, the amount of Compound 1 administered is about 5 to about 100 nM at steady state. , about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM, or about 50 to about 1 The dose is sufficient to produce a plasma concentration of the compound in the range of 1000 nM. The amount of Compound 1 administered is in the range of about 5 to about 100 nM of the compound in the blood at steady state. In other embodiments, the amount of Compound 1 administered is sufficient to produce a plasma concentration of , sufficient to produce a plasma concentration of the compound in the range of about 5 to about 50 nM at steady state. In another embodiment, the amount of Compound 1 administered is about 10 to about 100 mg / kg at steady state. In other embodiments, the amount of HCl is sufficient to produce a plasma concentration of the compound in the nM range. The amount of compound 1 formulation administered is in the range of about 10 to about 50 nM at steady state. In other embodiments, the amount of Compound 1 administered is sufficient to result in a plasma concentration of The amount of formulation is such that, at steady state, it provides a plasma concentration of the compound in the range of about 50 to about 100 nM. It is enough to

[0508] As used herein, the term "steady state plasma concentration" refers to the concentration of It is the concentration achieved after a certain period of time following administration of the formulation provided. When the solids are added, there is only a small increase or decrease in the time-dependent plasma concentration curve.

[0509] In certain embodiments, the amount of the formulation of Compound 1 administered is from about 0.001 to about 500μM, approximately 0.002~200μM, approximately 0.005~100μM, approximately 0.01~ Approximately 50μM, approximately 1 to approximately 50μM, approximately 0.02 to approximately 25μM, approximately 0.05 to approximately 20μM, approximately Compounds in the range of 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM In certain embodiments, the amount of hydroxybenzoates present in the blood is sufficient to provide a maximum plasma concentration (peak concentration) of 0.1 mg / kg or more. The amount of Compound 1 formulation administered ranges from about 0.001 to about 500 μM. In certain embodiments, the amount of hydroxybenzoates present in the blood is sufficient to provide a maximum plasma concentration (peak concentration) of 0.1 mg / kg or more. The amount of compound 1 administered ranges from about 0.002 to about 200 μM. In certain embodiments, the amount of hydroxybenzoates present in the blood is sufficient to provide a maximum plasma concentration (peak concentration) of 0.1 mg / kg or more. The amount of compound 1 administered ranges from about 0.005 to about 100 μM. In certain embodiments, the amount of hydroxybenzoates present in the blood is sufficient to provide a maximum plasma concentration (peak concentration) of 0.1 mg / kg or more. Therefore, the amount of the compound 1 formulation administered ranges from about 0.01 to about 50 μM, with the highest concentration of the compound. In certain embodiments, the amount of hydroxybenzoates present in the compound is sufficient to produce a high plasma concentration (peak concentration). The amount of Compound 1 formulation administered is in the range of about 1 to about 50 μM to achieve a maximum plasma concentration of the compound. In certain embodiments, the dose is sufficient to provide a peak concentration. The amount of Compound 1 in the formulation is adjusted to achieve a maximum plasma concentration ( In certain embodiments, the compound administered is sufficient to produce a peak concentration. The amount of compound 1 in the formulation is adjusted to achieve a maximum plasma concentration (Peak) of the compound in the range of about 0.05 to about 20 μM. In certain embodiments, the administered Compound 1 The amount of the compound in the formulation is in the range of about 0.1 to about 20 μM, which is the maximum plasma concentration (peak concentration) of the compound. In certain embodiments, the formulation of Compound 1 administered is sufficient to result in The amount of compound is in the range of about 0.5 to about 20 μM, and also provides a maximum plasma concentration (peak concentration) of the compound. In certain embodiments, the amount of Compound 1 formulation administered is sufficient to is required to produce a maximum plasma concentration (peak concentration) of the compound in the range of about 1 to about 20 μM. That's enough.

[0510] In certain embodiments, the amount of the formulation of Compound 1 administered is from about 0.001 to about 500μM, approximately 0.002~200μM, approximately 0.005~100μM, approximately 0.01~ Approximately 50μM, approximately 1 to approximately 50μM, approximately 0.01 to approximately 25μM, approximately 0.01 to approximately 20μM, approximately A range of 0.02 to about 20 μM, about 0.02 to about 20 μM, or about 0.01 to about 20 μM In certain embodiments, the concentration is sufficient to produce a minimum plasma concentration (trough concentration) of the compound. In this embodiment, the amount of Compound 1 administered ranges from about 0.001 to about 500 μM. In certain embodiments, the concentration is sufficient to produce a minimum plasma concentration (trough concentration) of the compound. In this embodiment, the amount of Compound 1 administered ranges from about 0.002 to about 200 μM. In certain embodiments, the concentration is sufficient to produce a minimum plasma concentration (trough concentration) of the compound. In this embodiment, the amount of Compound 1 administered ranges from about 0.005 to about 100 μM. In certain embodiments, the concentration is sufficient to produce a minimum plasma concentration (trough concentration) of the compound. In this embodiment, the amount of the compound 1 formulation administered ranges from about 0.01 to about 50 μM, It is sufficient to provide a minimum plasma concentration (trough concentration) of the compound. In the above, the amount of the compound 1 to be administered is about 1 to about 50 μM, about 0.01 to about 25 μM, It is sufficient to produce a minimum plasma concentration (trough concentration) of the compound in the 1 μM range. In certain embodiments, the amount of Compound 1 formulation administered is from about 0.01 to about 20 μM is sufficient to produce a minimum plasma concentration (trough concentration) of the compound in the range of In this embodiment, the amount of the compound 1 formulation administered ranges from about 0.02 to about 20 μM. It is sufficient to produce a minimum plasma concentration (trough concentration) of the compound within the range of In embodiments, the amount of Compound 1 formulation administered ranges from about 0.02 to about 20 μM. , sufficient to produce a minimum plasma concentration (trough concentration) of the compound. In this embodiment, the amount of the compound 1 formulation administered ranges from about 0.01 to about 20 μM. The dose is sufficient to produce a minimum plasma concentration (trough concentration) of the compound.

[0511] In certain embodiments, the amount of the formulation of Compound 1 administered is from about 100 to about 10 0,000ng * hr / mL, approximately 1,000 to approximately 50,000ng * hr / mL, approx. 5, 000 to approximately 25,000ng * hr / mL, or approximately 5,000 to 10,000 ng * It is sufficient to provide an area under the curve (AUC) for the compound in the range of hr / mL. In certain embodiments, the amount of Compound 1 formulation administered is from about 100 to about 100,000 0ng * sufficient to provide an area under the curve (AUC) of the compound in the range of hr / mL In certain embodiments, the amount of the formulation of Compound 1 administered is from about 1,000 to about 50,000ng * to yield the area under the curve (AUC) of the compound in the range of hr / mL. In certain embodiments, the amount of Compound 1 formulation administered is about 5, 000 to approximately 25,000ng * The area under the curve (AUC) of the compound was also calculated in the range of hr / mL. In certain embodiments, the amount of Compound 1 formulation administered is sufficient to is about 5,000 to 10,000 ng * The area under the curve (A) of the compound in the range of hr / mL is sufficient to result in UC.

[0512] In certain embodiments, a patient to be treated with one of the methods provided herein: No anti-cancer therapy was administered prior to administration of the formulations of Compound 1 provided herein. In certain embodiments, a patient to be treated with one of the methods provided herein and having received anti-cancer therapy prior to administration of the formulation of Compound 1 provided herein. In certain embodiments, a patient to be treated with one of the methods provided herein have developed drug resistance to anticancer therapy.

[0513] The methods provided herein encompass treating patients regardless of the patient's age. However, some diseases or disorders are more prevalent in certain age groups.

[0514] The formulations of Compound 1 provided herein may be administered as a single dose, e.g., as a single bolus injection. as a continuous infusion or over time, e.g., as a continuous infusion over time or as a divided bolus over time The formulation of Compound 1 can be administered, if necessary, to a patient with a disease, e.g. until stable or regressing disease, or until the patient experiences disease progression or unacceptable toxicity For example, for solid tumors, stabilization generally occurs after a measurable This means that the perpendicular diameter of the active lesion has not increased by more than 25% since the last measurement. Response Evaluation Criteria in Cancer Oncology (RECIST) guidelines, Journal of the National Cancer Institute 92(3):205-216( 2000). Disease stability, or lack thereof, can be assessed by methods known in the art, e.g., by measuring the patient's Symptom assessment, physical examination, and imaging using X-rays, CAT, PET, or MRI scans The degree of progression may be assessed by visualization of the tumor, or by other commonly accepted modalities of assessment.

[0515] The formulations of Compound 1 provided herein may be administered once daily (QD) or in divided doses. Daily doses include twice daily (BID), three times daily (TID), and four times daily (QID). ), and administration can be sequential (i.e., daily on consecutive days). daily), intermittent, e.g., in cycles (i.e., with drug-free periods of several days, weeks, or As used herein, the term "daily" refers to a period of time during which the administration of a drug is continued for several days or months. The term refers to a regimen in which a therapeutic compound is administered, for example, one or more times each day for a period of time. The term "continuous" means a period of at least 10 days to 52 weeks without interruption. "Intermittent" or "intermittent doses" shall mean administered daily for a period of time without interruption. The term "at" as used herein means at either regular or irregular intervals. For example, intermittent administration of a formulation of Compound 1 means , 1-6 days per week, cyclical administration (e.g., 1 day of a 28-day cycle) 10 consecutive days of daily dosing from day 1, followed by a dose-free rest period for the remainder of the 28-day cycle or 2 to 8 weeks of continuous daily dosing, followed by up to 1 week of no dosing. Cycling therapy with Compound 1 is described elsewhere herein. This will be explained in some places.

[0516] In some embodiments, the frequency of administration ranges from about daily dosing to about monthly dosing. In certain embodiments, administration is once daily, twice daily, three times daily, four times daily, Once every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks In one embodiment, Compound 1 is administered once daily. Compound 1 is administered twice daily. In yet another embodiment, Compound 1 is administered three times daily. Compound 1 is administered four times daily. Compound 1 is administered once every other day. In yet another embodiment, Compound 1 provided herein is administered twice a week. In yet another embodiment, Compound 1 provided herein is administered once a week. In yet another embodiment, Compound 1 as provided herein is administered once every two weeks. In yet another embodiment, the compound 1 provided herein is administered once every three weeks. Provided Compound 1 is administered once every four weeks.

[0517] In certain embodiments, the formulations of Compound 1 provided herein are administered 1 day to 6 months. Month, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks, 1 day In certain embodiments, the formulations of Compound 1 provided herein are In one embodiment, the compound is administered once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks. Therefore, the formulations of Compound 1 provided herein are administered once daily for one day. In embodiments, the formulations of Compound 1 provided herein are administered once daily for two days. In one embodiment, the formulations of Compound 1 provided herein are administered daily for 3 days. In one embodiment, the formulations of Compound 1 provided herein are In one embodiment, Compound 1 provided herein is administered once daily for four days. The formulation is administered once daily for five days. The compound 1 formulation is administered once daily for six days. The formulations of Compound 1 provided herein are administered once daily for one week. In one embodiment, In the present invention, the formulations of Compound 1 provided herein are administered once daily for up to 10 days. In another embodiment, the formulations of Compound 1 provided herein are administered once daily for two weeks. In yet another embodiment, the formulations of Compound 1 provided herein are administered In yet another embodiment, the compounds provided herein are administered once daily for three weeks. Formulation 1 is administered once daily for four weeks.

[0518] Combination therapy In one embodiment, provided herein are methods for treating, preventing, and / or treating cancer. is a method of administering compound 1 to a patient, the method comprising administering to the patient a JAK inhibitor, a FLT3 inhibitor, m TOR inhibitors, spliceosome inhibitors, BET inhibitors, SMG1 inhibitors, ERK inhibitors , LSD1 inhibitors, BH3 mimetics, topoisomerase inhibitors, and RTK inhibitors. in combination with one or more second agents that are effective against the disease, and optionally with radiation therapy, blood transfusion, or Examples of second active agents include those disclosed herein. do.

[0519] In one embodiment, provided herein are methods for treating, preventing, and / or treating cancer. is a method of administering to a patient a formulation of Compound 1 provided herein. or in combination with multiple second agents, and optionally with radiation therapy, blood transfusion, or surgery. Examples of second active agents include those disclosed herein.

[0520] As used herein, the term "in combination" refers to the use of more than one therapy (e.g., However, "in combination" includes the use of one or more prophylactic and / or therapeutic agents. Use of the term refers to providing treatment (e.g., prophylaxis and / or therapy) to a patient with a disease or disorder. For example, "in combination" does not limit the order in which drugs (drugs) are administered. This includes simultaneous administration using the individual formulations, as well as sequential administration in any order. " means that a specific amount of time has elapsed b...

Claims

[Claim 1] The novel products, methods and processes substantially as herein described.

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